Diabetes: An Update for Subspecialistsgims19course.com/uploads/1/2/4/0/124037936/2tues...Diabetes...
58
David M. Nathan, M.D. January, 2020 Diabetes: An Update for Subspecialists
Diabetes: An Update for Subspecialistsgims19course.com/uploads/1/2/4/0/124037936/2tues...Diabetes Care 2006;29:2102-2017 Effect of Weight Loss on Diabetes Prevention Annual Diabetes
Prevalence of all diabetes 291 million (93) Type 1 1+ million (04) Type 2 28 Diagnosed 21 Undiagnosed 6 GDM gt150000 (~5-10 of all
pregnancies) Prediabetes 86 million (20)
1500000 new cases per year
CDC 2015
copy2015 David M Nathan
gt100000000 with diabetes and pre-diabetes
Consequences of Diabetes in the US CDC 2015
copy2015 David M Nathan
bull Most common cause of ESRD in adults bull Most common cause of blindness bull Most common cause of amputations bull 2-5 fold increased risk for CVD bull gt$327 billon per year in US (ADA 2017)
Pathophysiology of Type 2 Diabetes Insulin resistance Genetics Obesity Age Sedentary PCO Steroids GH Impaired glucose tolerance
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
David M Nathan MD has no conflicts of interest
Dualities of Interest
Prevalence of Diabetes in the US
Prevalence of all diabetes 291 million (93) Type 1 1+ million (04) Type 2 28 Diagnosed 21 Undiagnosed 6 GDM gt150000 (~5-10 of all
pregnancies) Prediabetes 86 million (20)
1500000 new cases per year
CDC 2015
copy2015 David M Nathan
gt100000000 with diabetes and pre-diabetes
Consequences of Diabetes in the US CDC 2015
copy2015 David M Nathan
bull Most common cause of ESRD in adults bull Most common cause of blindness bull Most common cause of amputations bull 2-5 fold increased risk for CVD bull gt$327 billon per year in US (ADA 2017)
Pathophysiology of Type 2 Diabetes Insulin resistance Genetics Obesity Age Sedentary PCO Steroids GH Impaired glucose tolerance
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Prevalence of Diabetes in the US
Prevalence of all diabetes 291 million (93) Type 1 1+ million (04) Type 2 28 Diagnosed 21 Undiagnosed 6 GDM gt150000 (~5-10 of all
pregnancies) Prediabetes 86 million (20)
1500000 new cases per year
CDC 2015
copy2015 David M Nathan
gt100000000 with diabetes and pre-diabetes
Consequences of Diabetes in the US CDC 2015
copy2015 David M Nathan
bull Most common cause of ESRD in adults bull Most common cause of blindness bull Most common cause of amputations bull 2-5 fold increased risk for CVD bull gt$327 billon per year in US (ADA 2017)
Pathophysiology of Type 2 Diabetes Insulin resistance Genetics Obesity Age Sedentary PCO Steroids GH Impaired glucose tolerance
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Consequences of Diabetes in the US CDC 2015
copy2015 David M Nathan
bull Most common cause of ESRD in adults bull Most common cause of blindness bull Most common cause of amputations bull 2-5 fold increased risk for CVD bull gt$327 billon per year in US (ADA 2017)
Pathophysiology of Type 2 Diabetes Insulin resistance Genetics Obesity Age Sedentary PCO Steroids GH Impaired glucose tolerance
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Pathophysiology of Type 2 Diabetes Insulin resistance Genetics Obesity Age Sedentary PCO Steroids GH Impaired glucose tolerance
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Pathophysiology of Type 2 Diabetes
The best example of the potential beneficial effects of weight loss derive from bariatric
surgery where loss of 35-50 of excess weight ameliorates the majority of diabetes
including remissions in 30-65
Solving- treating more effectively- the obesity ldquoproblemrdquo is the single greatest
challenge and would be the most effective means of preventing and treating diabetes
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Complications of Diabetes Result of Level of
Glycemia x duration Plus
other risk factors Hypertension
Lipids Smoking
The outpatient and inpatient management of diabetes interfaces with virtually every area of
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
ndash Inpatient ndash Other ldquospecial casesrdquo
copy2017 David M Nathan
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Response to an Epidemic Prevention
IGT Type 2 DM Early Complications MorbidityMortality
10 20 Current 3o Prevention Intervention Diagnosis Intervention
ETDRS DRS BP Lipids Recent CVD studies
UKPDS Kumamoto
FDPS DaQing STOPNIDDM DREAM IND-DPP
copy2017 David M Nathan
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Mean Weight Change from Baseline
0 6 12 18 24 30 36 42 48 Months
Lifestyle (behavioral modification)
Metformin 850 mg bid
+ Placebo
~220 minwk ~190 minwk
72
42
NEJM 2002346 393
DPP high risk cohort = BMI 34 IGT + IFG
Tested a behavioral lifestyle intervention that achieved a 7 weight loss (~15 lb) or metformin to prevent diabetes in a high risk population with pre-diabetes
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Chart1
PL
MET
LS
Weight Change (Kg)
0
0
0
-011
-226
-675
-025
-271
-667
-015
-23
-606
009
-205
-541
006
-166
-41
037
-12
-398
04
-152
-335
-011
-128
-348
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0
0
0
6
6
6
12
12
12
18
18
18
24
24
24
30
30
30
36
36
36
42
42
42
48
48
48
Sheet1
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
0
6
12
18
24
30
36
42
48
PL
0
-011
-025
-015
009
006
037
04
-011
MET
0
-226
-271
-23
-205
-166
-12
-152
-128
LS
0
-675
-667
-606
-541
-41
-398
-335
-348
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082) Metformin (n=1073 plt0001 vs Plac) Lifestyle (n=1079 plt0001 vs Met plt0001 vs Plac )
Percent developing diabetes All participants-28 years
Years from randomization
Cum
ulat
ive
inci
denc
e (
)
31 reduction 58 reduction
NEJM 2002346 393
Placebo
Metformin
Lifestyle
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
-15 -10 -5 0 +5
0 5
10
15
20
Haz
ard
rate
per
100
yr
Mean weight change from baseline (kg)
Diabetes Care 2006292102-2017
Effect of Weight Loss on Diabetes Prevention
Ann
ual D
iabe
tes
Inci
denc
e In the lifestyle group every kg of weight loss was associated with a 16 reduction in risk of diabetes
1 kg
16
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
After 28 y of DPP ILS v PLBO 58 MET v PLBO 31
After 10 y DPPDPPOS 34 18
Other Benefits over Time with ILS (compared with placebo)
bull Lower HbA1c with fewer meds bull Lower BP and lipid levels with fewer meds
Lancet 20093741677 NEJM 2002346393
Long-term Diabetes Prevention Risk Reduction
After 15 y DPPDPPOS 27 18 Lancet DampE 2015 3 866
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
CMS support for DPP programs effective 118
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
Treatment Standards of Care A1c BP+ LDL HDL TRI ADA lt70 lt14090^ Like ACC-moved away from numbers 2019
AACE lt65 lt13080 lt100 gt5040 lt150 2007
CDA lt70 lt13080 lt 80 TCHDL 2008 lt40
NICE lt65 lt14080 lt 80 lt400 2009
copy2019 David M Nathan
AHAACC recommendations- statin use based on gt7 10-yr CVD risk
+SPRINT study (no diabetics) suggests that BP 12080 may be new goal
ACP 70-80 ldquofor most patientsrdquo 2018
^ lt13080 for high CVD risk patients
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
Treatment with Statins No longer primarily LDL level driven (ADA and ACC) Age No CVD CVD lt40 None High gt40 Moderate High Moderate intensity statin can also be considered for patients wo CVD but with risk factors (LDL gt100 hypertension smoking CKD albuminuria family history or premature CVD) Moderate = atorva 10-20 rosuva 5-10 simva 20-40 High intensity = atorva 40-80 rosuva 20-40 add PCSK-9 or ezetemibe if LDL gt 70 mgdl
copy2019 David M Nathan
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
DCCT Retinopathy Results
DCCT Research Group NEJM 1993342381
Primary Prevention Secondary Intervention
76 54
2
Metabolic Therapy and Type 1 Diabetes
ldquoIntensiverdquo therapy was aimed at achieving glucose and HbA1c levels as close to the non-diabetic range as safely possible
Long-term follow-up of DCCT showed ~ 50 reduction of late-stage severe complications (eg need for eye surgery CKD-3 or worse CVD events)
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Risk Reduction with Intensive vs conventional therapy ()
DCCT(65y) M I c r o a l b u m I n N e u r o p a t h y
R e t i n o p a t h y
T Y P E
2
T Y P E
1
UKPDS (10y) Sev Microvasc
ACCORD (4y)
VADT(56y) A l b u m I n u r I a
R e t I n o p a t h y
Kumamoto(6y)
ADVANCE (5y) Microva
R e t i n o p a t h y M I c r o a l b u m I n
-30 -20 -10 0 10 20 30 40 50 60 70 80
copy2019 David M Nathan
20
A1C difference
09
11
15
07
23
Reduction in microvascular complications roughly proportional to A1c reduction
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
5
55
6
65
7
75
8
85
9
95
10
105
11
115
12
DCCT
8
10
18
38
60
105
160
UKPDS
5
10
15
23
40
58
5
5
55
55
6
6
65
65
7
7
75
75
8
8
85
85
9
9
95
95
10
10
105
105
11
11
115
115
12
12
UKPDS
Lancet 1998 352 837
Intensive Therapy and Type 2 Diabetes 79
70 09 5102
Age 53 ldquoNew-onsetrdquo No prior CVD 10-yr median fu 25 reduction in advanced complications during UKPDS Continued benefit with 10 more years follow-up
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
complications limited data in HbA1c range lt65 bull Not clear if the increased expense effort and risk for
hypoglycemia is merited by added benefit bull No data to support benefit for CVD for A1Clt65
ndash ACCORD ADVANCE VADIT bull ACCORD suggests possible harm
copy2018 David M Nathan
A1c Goal lt 7 is justifiable for manymost patients at this time However A1c goals must be individualized based
on age expected survival co-morbidities and risks
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
ADA Standards of Care Diabetes Care 201942 (Suppl 1)
Two major premises 1) Lower glycemia to reduce risk of microvascular disease and 2) In setting of CVD or renal disease use specific drugs demonstrated in recent CVOTs (SGLT-inhib GLP-agonists)
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
How to Achieve Metabolic Goals
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Development of Medications Used in the Treatment of Type 2 Diabetes
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Major Premises
bull Effectiveness in lowering A1c ndash Use more effective drugs if initial A1c higher ndash Can use less effective medications if A1c lt 85
bull Safety bull Side-effects tolerabilityacceptance bull Other characteristics effect (s) on
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Glycemic Potency of Hypoglycemic Agents Decrease in HbA1c Potency of Monotherapy
HbA1c
copy2019 David M Nathan
21st Century 20th Century
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Sheet1
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
Anti-Hyperglycemic Agents in Type 2 Diabetes Mechanisms
Class Primary Mechanism Insulin
Sulfonylureas
ldquoGlinidesrdquo
Biguanides (metformin)
Thiazolidinediones
Alpha-glucosidase inhibitors Amylin-mimetics
(pramlintide)
Incretin agonists
DPP-IV inhibitors
SGLT-2 inhibitors
Insulin Supply
Liver sensitivity(HGO) Peripheral sensitivity
GI absorption rate
GI motility
Glycosuria copy2019 David M Nathan
Insulin Supply
Insulin Supply
Insulin Supply Insulin Supply
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Therapy of Type 2 Diabetes
bull Highly effective in short term bull 5-10 lb weight loss usually sufficient to ameliorate
hyperglycemia bull Long-term benefit parallels results of obesity therapy bull More effective lifestyle interventions (such as those used
in DPP or LookAHEAD) are available but require more effort than the usual ldquodietrdquo
Lifestyle Diet and Exercise
copy2015 David M Nathan
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
W
eigh
t cha
nge
from
bas
elin
e
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4Year
DSE
ILI19 lb
85 lb
-08
-07
-06
-05
-04
-03
-02
-01
0
0 1 2 3 4Year
DSE
ILI
A
1c c
hang
e fr
om b
asel
ine
Effects of Behavioral Intervention 73
66
70
Fewer diabetes medications
Weight HbA1c
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
Chart11
DSE
ILI
Year
0
0
-063
-85
-093
-635
-092
-504
-101
-466
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
029
028
028
028
2
2
029
028
029
028
3
3
028
029
028
028
4
4
029
029
028
0
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
LDL
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
LDL
DSE
ILI
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
Trig
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Trig
DSE
ILI
Year
0
0
0
-1525
-2963
1
-1714
-2491
2
-1973
-257
3
-2751
-229
4
DSE -
DSE +
0
0
298
297
328
327
36
36
422
422
ILI -
ILI +
0
0
297
297
324
325
358
357
418
418
Trig
DSE
ILI
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
0
0
0
0
297
298
297
297
327
328
325
324
36
36
357
358
422
422
418
418
Weight Chg
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Weight Change
DSE
ILI
Year
0
0
0
-063
-85
1
-093
-635
2
-092
-504
3
-101
-466
4
DSE -
DSE +
0
0
028
029
028
029
029
028
029
029
ILI -
ILI +
0
0
028
028
028
029
028
028
0
028
Weight Chg
DSE
ILI
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
0
0
0
0
029
028
028
028
029
028
029
028
028
029
028
028
029
029
028
0
Chart8
DSE
ILI
Year
0
0
-012
-064
-009
-037
-01
-026
-008
-02
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
0
0
0
0
0
0
1
1
004
003
004
003
2
2
004
005
005
004
3
3
004
005
005
004
4
4
005
005
005
005
HDL
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
HDL
DSE
ILI
0
0
0
135
Year 1
338
1
193
Year 2
379
2
205
Year 3
358
3
258
Year 4
395
4
DSE -
DSE +
0
0
027
028
031
031
032
031
033
033
ILI -
ILI +
0
0
028
027
031
03
032
032
034
033
HDL
DSE
ILI
Year
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
0
0
0
0
028
027
027
028
031
031
03
031
032
032
032
032
034
033
033
034
DBP
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
DBP
DSE
ILI
Year
0
0
0
-166
-31
1
-221
-272
2
-273
-278
3
-344
-319
4
DSE -
DSE +
0
0
03
031
032
032
032
033
033
033
ILI -
ILI +
0
0
03
03
032
032
032
033
033
033
DBP
DSE
ILI
Year
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
0
0
0
0
031
03
03
03
032
032
032
032
033
032
033
032
033
033
033
033
A1c
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
A1c
DSE
ILI
Year
0
0
0
-012
-064
1
-009
-037
2
-01
-026
3
-008
-02
4
DSE -
DSE +
0
0
003
004
005
004
005
004
005
005
ILI -
ILI +
0
0
003
004
004
005
004
005
005
005
A1c
DSE
ILI
Year
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
0
0
0
0
004
003
004
003
004
005
005
004
004
005
005
004
005
005
005
005
SBP
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
SBP
DSE
ILI
Year
0
0
0
-236
-708
1
-311
-501
2
-317
-475
3
-341
-466
4
DSE -
DSE +
0
0
059
059
062
063
066
066
067
068
ILI -
ILI +
0
0
059
058
062
062
066
066
067
067
SBP
DSE
ILI
Year
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
0
0
0
0
059
059
058
059
063
062
062
062
066
066
066
066
068
067
067
067
Non-HDL
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
Non-HDL
DSE
ILI
Year
0
0
0
-812
-1076
1
-1415
-141
2
-1986
-1874
3
-2377
-2132
4
DSE -
DSE +
0
0
121
121
138
137
14
139
141
141
ILI -
ILI +
0
0
121
12
136
136
139
139
139
14
Non-HDL
DSE
ILI
Year
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
0
0
0
0
121
121
12
121
137
138
136
136
139
14
139
139
141
141
14
139
LDL
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
LDL
DSE
ILI
Year
0
0
0
-564
-525
1
-1124
-957
2
-1614
-1402
3
-1888
-1677
4
DSE -
DSE +
0
0
105
105
118
117
119
118
119
12
ILI -
ILI +
0
0
104
104
116
116
117
117
118
119
LDL
DSE
ILI
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
0
0
0
0
105
105
104
104
117
118
116
116
118
119
117
117
12
119
119
118
First Step- Metformin + Lifestyle bull Recognizes failure of life-style alone bull Inhibits hepatic glucose output- predominantly lowers
fasting glycemia bull Lowers HbA1c by ~15 bull Effective in obese and non-obese patients and in
preventing diabetes in pre-diabetics (DPP) bull Extremely safe generally well-tolerated including
down to eGFR as low as 45 mlmin bull Glucophage off-patent very inexpensive
copy2005 David M Nathan
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
ldquoIntensiverdquo usually means looking (with SMBG) where BG are high and adding timed rapid-acting insulin
A1c gt7 or not at goal
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Diabetologia 2009 5217-30 Diabetes Care 200932193-203
DPP4 Inh SGLT2-Inh
A1c gt7 or not at goal
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
GLP and DPP4 Inhibitors bull Stimulate insulin
secretion bull Suppress glucagon bull Slow motility bull Lower A1c by ~10 bull Injections twice per
day bull Weight loss of ~ 6 lb bull Associated with
nausea vomiting diarrhea- ~40
bull CVD benefit with lira- and semaglutide
bull Expensive
bull Inhibit breakdown of endogenous GLP raising levels by ~2-fold
bull Decrease A1c by ~06 bull Oral medication bull No weight loss bull No GI side-effects bull Neutral for CVD bull Expensive
GLP and its Analogues DPP 4 Inhibitors
copy2017 David M Nathan
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
GLP and DPP4 Inhibitors
copy2017 David M Nathan
bull SAVOR (saxagliptin) increased CHF hospitalizations bull EXAMINE (alogliptin) no risk bull TECOS (sitagliptin) no risk NO BENEFIT with any of the DPP4 inhibitors GLP-1 agonists bull LEADER CVD Benefit with liraglutide bull SUSTAIN CVD Benefit with semaglutide bull ELIXA NO Benefit with lixisenatide bull EXCSEL NO Benefit with Exenatide-LAR
Results of CVOTs DPP-4 inhibitors
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
copy2015 David M Nathan
Newest Medication SGLT-2 inhibitors
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
copy2015 David M Nathan
ndash Inhibits re-absorption of glucose in proximal tubule ndash Limited lowering of BG on basis of glycosuria ndash Lowers A1c by ~06 ndash Added benefit- +- lower BP minor weight loss ndash Added risk- vaginitis UTIs ndash Dapagliflozin canagliflozin empagliflozin ndash CVD benefit with empagliflozin and canagliflozin ndash Increased risk of amputations with canagliflozin
Newest Medication SGLT-2 inhibitors
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Glycemic Potency vs Costs Decrease in HbA1c Potency of Monotherapy vs Cost
HbA1c
copy2017 David M Nathan
21st Century 20th Century
$ $ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $$
$$ $
$88 411 400 300 770 322 4 4 130300 Average costmo
NPH-Relion $25
Are the new drugs ldquoworth itrdquo
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Chart1
-05
-06
-07
-07
-1
-1
-15
-15
-25
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
Sheet1
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Symilin
AGIs
SGLT-2 inh
DPP-4 inh
Pramlintide
GLP-agonist
TZD
Sulfonylurea
Metformin
Insulin
-05
-06
-07
-07
-1
-1
-15
-15
-25
Treat to Target Trial Riddle et al Diabetes Care 2003 2630380
756 T2DM with A1c gt75 (baseline A1c 86) on OA
Is Glargine better than NPH FPG (mgdl)
A1c () PG lt 56 mgdl
PG lt 72 mgdl
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Singh SR CMAJ 2009180385
Updated Meta-analysis Long-acting Analogues vs Non-analogues 49 RCTs
copy2018 David M Nathan
The consensus for T2DM is that compared with NPH long-acting analogues bull Donrsquot reduce HbA1c (nominally higher) bull Reduce the frequency of nocturnal hypoglycemia modestly bull The frequency of total hypoglycemia is about the same bull Severe hypoglycemia is very rare and generally no
different
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
If you Use a New Drug Class Advantage Disadvantage When to Use DPP-4 Well-tolerated Weak Mild DM Probably safe Expensive One dose GLP-1 Weight loss GI side effects Moderate DM No hypos Limited efficacy Weight gain or Injections risk of hypos Expensive major issue Advanced CVD TZDs No hypos Edema CHF Never NASH CVD risk Expensive SGLT- No hypos Weak DKA Mild DM Inhib Dec BP UTIs yeast Advanced CVD Expensive CHF CKD
copy2009 David M Nathan
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
bull Almost 20 of MGH inpatients have diagnosis of diabetes
bull An additional 9 have undiagnosed diabetes bull Average stay is 20 longer than non-diabetics
Inpatients with Diabetes Background
Wexler Nathan Cagliero JCEM 200893 4238 copy2005 David M Nathan
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Adversely affects bull Schedule- late missed meals bull Diet- different bull Medications- changed delayed held bull Activity- less bull Monitoring- different bull Stress- more bull Self-care- gone
Barriers to Good Care for Inpatients with Diabetes
Impact of Hospitalization
copy2019 David M Nathan
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Principles of Inpatient Care for Persons with Diabetes
bull Maintain metabolic control in a safe acceptable range- probably 80-200 mgdl ndash Avoid large fluctuations in blood glucose that would
lead to dehydration hypoglycemia prevent DKA ndash Never stop insulin in type 1 ndash Usually stop oral agents in type 2 cover with insulin ndash Basal insulin recommended
bull Protect feet bull Decrease risk of macrovascular and
microvascular ldquoeventsrdquo- heart kidney copy2019 David M Nathan
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Effect of Intensive Insulin Therapy in Critically Ill SICU Patients bull 1548 ventilated
surgical ICU patients bull 63 sp cardiac surgery bull Randomized to
-Conventional therapy goal 180-200 mgdL - Intensive therapy with insulin infusions if BG gt 110 mgdL to keep bg 80-110 All patients received ~9 g IV glucosehr followed by enteral or parenteral feeding
bull After discharge from ICU target 180-200 mgdL for all
Van den Berghe Crit Care Med 200331359
van den Berghe G N Engl J Med 20013451359ndash1367
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
van den Berghe G N Engl J Med 20013451359ndash1367
Survival in ICU ()
100
96
92
88
80
84
0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Days After Admission
bull Intensive therapy reduced mortality by 43 (46 vs 8) bull Bacteremia antibiotic use
polyneuropathy duration of ventilation and multi-organ failure reduced
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Subsequent Studies No benefit of intensive insulin in sepsis bull Mean am glucose 112
vs 151 mgdl bull No difference in death or
organ failure at 28 days bull Stopped early for
increased hypoglycemia (17 vs 4) in intensive group
Goal 80-110 mgdl
Goal 180-200 mgdl
Brunkhorst NEJM 2008
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Subsequent Studies NICE-SUGAR Study
bull Multicenter trial in Canada and Australia
bull 6104 patients bull Mean glucose of 115
versus 144 mgdl bull Increased mortality (26)
in intensive control group bull Severe hypoglycemia in
68 versus 05
N Engl J Med 2009 3601283-97
MBG 144 mgdl
MBG 115 mgdl
Prob
abili
ty o
f sur
viva
l
Medical and Surgical ICU Patients
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Summary of Current Evidence
bull Substantial observational data link hyperglycemia in hospitalized pts to poor outcomes- causal marker of disease severity
bull Normalizing glycemia in intensive care units with inconsistent results several meta-analyses have shown no mortality benefit a decrease in post-op infections but with more hypoglycemia
bull Almost no data to demonstrate role of tight glucose control in non-critically ill patients
Inpatient Management of Glycemia
copy2019 David M Nathan
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
American College of Physician 2011 ldquonot using intensive insulin therapy to strictly control blood glucoserdquo
Target glucose levels of 80-110 mgdl
ADA 2019
140-180 mgdl ICU amp Non-ICU
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Special ldquoCasesrdquo
bull Glucocorticoids used in pharmacologic doses (eg prednisone gt 10 mgday dexamethasone gt 1mgday) can precipitate diabetes or raise BG
bull The hyperglycemic effect of prednisone has the same time course as NPH insulin
bull NPH insulin can be given (or dose adjusted) in AM to help control BG during steroid therapy
Glucocorticoids
copy2019 David M Nathan
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Special ldquoCasesrdquo
bull Mechanisms unclear but associated with weight gain insulin resistance and β-cell failure
bull May precipitate worsen DM cause DKA bull Advisable to check a HbA1c prior to initiation and follow BG carefully bull Insulin may be necessary if psych medications canrsquot be changed
Atypical Antipsychotics olanzapine clozapine quetiapine and others
copy2019 David M Nathan
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
Subsequent Studies NICE-SUGAR Study
Summary of Current Evidence
Slide Number 55
Special ldquoCasesrdquo
Special ldquoCasesrdquo
Conclusions
Conclusions bull Diabetes and especially type 2 affects a substantial
minority of the inpatient and outpatient population bull Owing to its frequency and effects on virtually every
aspect of clinical medicine practitioners should be familiar with its prevention diagnosis and treatment
bull Endocrinologists canrsquot do it all on our own
copy2019 David M Nathan
Diabetes An Update for Subspecialists
Slide Number 2
Prevalence of Diabetes in the US
Slide Number 4
Pathophysiology of Type 2 Diabetes
Slide Number 6
Slide Number 7
Slide Number 8
Diabetes and Subspecialties
Diabetes and Subspecialties
Topics
Slide Number 12
Slide Number 13
Slide Number 14
Slide Number 15
Slide Number 16
Slide Number 17
Slide Number 18
Treatment Standards of Care
Treatment with Statins
Slide Number 21
Slide Number 22
Slide Number 23
Slide Number 24
Selecting Metabolic Goals
Slide Number 26
Slide Number 27
Development of Medications Used in the Treatment of Type 2 Diabetes
Major Premises
Slide Number 30
Anti-Hyperglycemic Agents in Type 2 Diabetes
Slide Number 32
Slide Number 33
Effects of Behavioral Intervention
First Step- Metformin + Lifestyle
Slide Number 36
Slide Number 37
GLP and DPP4 Inhibitors
GLP and DPP4 Inhibitors
Newest Medication SGLT-2 inhibitors
Newest Medication SGLT-2 inhibitors
Slide Number 42
Slide Number 43
Slide Number 44
Slide Number 45
If you Use a New Drug
Inpatients with Diabetes
Barriers to Good Care for Inpatients with Diabetes
Principles of Inpatient Care for Persons with Diabetes
Slide Number 50
Slide Number 51
Subsequent StudiesNo benefit of intensive insulin in sepsis
![[PPT]Steroid Induced Diabetes - Healing, Teaching & … Induced... · Web viewACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006;29(8):1955-1962. Bolus insulin to keep](https://img.pdfslide.us/doc/110x75/5ab7ace77f8b9a684c8bcb29/pptsteroid-induced-diabetes-healing-teaching-inducedweb-viewaceada.jpg)
