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Diabetes mellitus: An update
D. HuntMarch 2010
Significance of diabetes mellitus
• 5% of the population has diagnosed diabetes
• prevalence increases with age:20 - 44: 1%45 - 65: 5%> 65: 10%
• the true prevalence of diabetes is estimated to be twice the prevalence of diagnosed diabetes
Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris)
0
5
10
15
20
25
30
35
40
20-34 35-44 45-54 55-64 65-74
% ofpopulation
IGTUndiagnosed diabetesDiagnosed diabetes
Harris. Diabetes Care 1993;16:642-52.
Significance of diabetes mellitus
Eye Disease
Type 1: 25% after 15 yearsType 2: 4% - 12% after 15 years
Diabetes is the leading cause of adult-onset blindness
Kidney Disease
Type 1: 30% after 15 yearsType 2: 20% after 15 years
Diabetes is the leading cause of end-stage renal disease
Foot complications
Loss of foot sensation > foot ulcers and infections > foot amputations
Amputation rate: 2 - 30/1000 patient-years
Diabetes is the leading cause of non-traumatic amputation
Haffner Am J Cardiol 1999;84:11J-4J.
Framingham study: diabetes and CAD mortality at 20-year follow-up
Cardiovascular Disease Risk is Increased 2 to 4 Times
17.4
8.5
17.0
3.602468
101214161820
Annual CAD Deaths per 1,000
Persons
Men Women
Diabetics Nondiabetics
Blood glucose control reduces the risk of diabetic
complications, especially microvascular complications
UK Prospective Diabetes UK Prospective Diabetes StudyStudy
UK Prospective Diabetes Study
20-year Interventional Trial from 1977 to 1997:
5,102 patients with newly-diagnosed DM2
Median follow-up 10.0 years, range 6 to 20 years
Results presented in 1998
Microvascular EndpointsMicrovascular Endpoints
p=0.0099
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
Intensive
Conventional
Risk reduction 25%(95% CI: 7% to 40%)
renal failure or death, vitreous haemorrhage or photocoagulation346 of 3867 patients (9%)
Myocardial InfarctionMyocardial Infarction
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
Intensive
Conventional
p=0.052
Risk reduction 16%(95% CI: 0% to 29%)
fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%)
UK Prospective Diabetes Study
20-year Interventional Trial from 1977 to 1997 5,102 patients with newly-diagnosed DM2
Median follow-up 10.0 years, range 6 to 20 years
Results presented in 1998
10-year Post-Trial Monitoring from 1997 to 2007 Annual follow-up of the survivor cohort
Clinic-based for first five years
Questionnaire-based for last five years
Median overall follow-up 17.0 years, range 16 to 30 years
Post-Trial Changes in HbA1c
UKPDS resultspresented
Microvascular Disease
Intensive (SU/Ins) vs. Conventional glucose control
(photocoagulation, vitreous haemorrhage, renal failure)
HR (95%CI)
Myocardial Infarction(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
All-cause Mortality
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040
Microvascular disease RRR: 25% 24% P: 0.0099 0.001
Myocardial infarction RRR: 16% 15% P: 0.052 0.014
All-cause mortality RRR: 6% 13% P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
Legacy Effect of Earlier Glucose Control
After median 8.8 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 32% 21% P: 0.0023 0.013
Microvascular disease RRR: 29% 16% P: 0.19 0.31
Myocardial infarction RRR: 39% 33% P: 0.010 0.005
All-cause mortality RRR: 36% 27% P: 0.011 0.002
RRR = Relative Risk Reduction, P = Log Rank
Legacy Effect of Earlier Metformin Therapy
• Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for MI and death were observed during 10 years of post-trial follow-up
UKPDS Conclusions
Pharmacologic Management of Type 2 Diabetes
• If glycemic targets are not achieved within 2 to 3 months of lifestyle management, pharmacotherapy should be initiated.
• Timely adjustments should be made to attain target A1C within 6 to 12 months.
• In patients with marked hyperglycemia (A1C ≥ 9.0%), pharmacotherapy should be initiated concomitantly with lifestyle management, and consideration be given to either combination therapy or insulin.
Management of hyperglycemia in type 2 diabetes
A1C >9.0% Symptomatic with metabolic decompensation
A1C <9.0%
Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions:
• Consider initiating metformin concurrently with another agent from a different class or
• Initiate insulin
Initiate metformin Initiate insulin ± metformin
If not at target
L
I
F
E
S T Y L E
Clinical Assessment
Lifestyle intervention (initiation of nutrition therapy and physical activity)
Oral agents:(agents listed in alphabetical order)
Class A1C Hypoglyc. Advantages Disadvantages
Alpha-glucos. inhibitor
↓ Rare Improved postprandial control weight neutral
GI side effects
Incretin: DPP-4 inhib.
↓ - ↓↓
Rare Improved postprandial control; weight neutral
New agents (unknown long-term safety)
Insulin ↓-↓↓↓
Yes No dose ceiling Weight gain
Meglitinides
Sulfonylureas
↓ - ↓↓
↓↓
Yes
Yes
Improved postprandial controlNewer sulfonylureas (gliclazide) are associated with less hypoglycemia than glyburide
Requires TID to QID dosing
Weight gain
*less hypoglycemia in the context of missed meals
TZD ↓ ↓ Rare Durable monotherapy
6-12 weeks for maximal effectEdema, rare CHF, fractures in females
↓ = < 1.0% decrease in A1C
↓ ↓ = 1.0–2.0% decrease in A1C
↓ ↓ ↓ = >2.0% decrease in A1COral agents beyond metformin
If not at target
• Add another drug from a different class; or • Add bedtime basal insulin to other agent(s); or• Intensify insulin regimen
Timely adjustment to and/or addition of antihyperglycemic agents should be made to attain target
A1C within 6 to 12 months
Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada; Canadian Journal of Diabetes: 2008 Vol:32 Supplement
Natural History of Type 2 Diabetes
Normal Impaired glucosetolerance
Type 2 diabetes
Time
Insulinresistance
Insulinproduction
Glucoselevel
b-celldysfunction
Henry. Am J Med 1998;105(1A):20S-6S.
b cell function in type 2 diabetic patients
Natural deterioration of Natural deterioration of bb-cell function-cell function
Years after diagnosis
b-cell
fun
cti
on
Insulin
Type Starts Peaks Duration
Lispro
Aspart
Glulisine
5-10 min 0.5-1 hrs 3.5 hrs
Regular
Toronto
30 min 2-4 hrs 6-8 hrs
N/NPH 1-2 hrs 6-10 hrs 16-24 hrs
Detemir - 6 – 8 hrs Up to 24 hrs
Glargine 1.5 hrs None Up to 24 hrs
Insulin regimens – Type 2 DM
Many different potential regimens!
– Oral + hs insulin (basal)– Oral + AM insulin (basal)– Pre-mixed insulin with breakfast and
supper– Short-acting with meals + bedtime basal
Holman RR. NEJM 2009;361:1736-47
Aims
First Phase
One-year head-to-head comparison of the efficacy of three different types of analogue insulins, when given in addition to dual oral antidiabetic therapy:
Biphasic insulin
Prandial insulin
Basal insulin
Patient Disposition
235Assigned to
biphasic insulin(biphasic aspart)
234Assigned to basal
insulin(detemir)
239Assigned to
prandial insulin(aspart)
34 Discontinued
45 Discontinued51Discontinued
201 (86%)Completedthree years
189 (81%)Completedthree years
188 (79%)Completedthree years
Overall, 18.4% of patients did not complete three years No difference in proportions between groups (p=0.15) No difference in baseline characteristics between those who
completed or did not complete three years follow up
Transition to a Complex Insulin Regimen
* Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia
708 T2DMon dual
oral agents
Add biphasic insulin*twice a day
Add prandial insulin*three times a day
R
First Phase
Add basal insulin*once (or twice) daily
Add prandial insulinat midday
Add basal insulinbefore bed
Second Phase
Add prandial insulinthree times a day
From one year onwards, if HbA1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added
Demographic CharacteristicsBiphasic
N=235PrandialN=239
BasalN=234
Male 68% 64% 61%
White Caucasian 94% 90% 93%
*Diabetes duration (yrs) 9 (6-12) 9 (6-14) 9 (6-12)
Taking sulfonylurea 98% 100% 99%
Taking metformin 96% 95% 97%
Age (years) 61.7±8.9 61.6 ±10.5 61.9±10.0
Body mass index (kg/m2) 30.2 ±4.8 29.6 ±4.5 29.7 ±4.6
HbA1c (%) 8.6 ±0.8 8.6 ±0.8 8.4 ±0.8
*interquartile range No significant differences between groups
Glycaemic targets and Insulin Injections
Fasting and pre-meal: 4.0-5.5 mmol/l (72-99 mg/dl)
Two-hours post meal: 5.0-7.0 mmol/l (90-126 mg/dl)
6 6 1212 624186 6 1212 624186 6 1212 62418
Biphasic
Basal
Prandial*
* Twice a day if required
Complex Insulin Regimens
Proportion eligible for a second type of insulin per protocol
Proportion taking two types of insulin
Insulin Doses Over 3 YearsMedian±95% confidence interval
Biphasic±prandial
Prandial±basal
Basal±prandial
Total Daily Insulin Doses at 3 YearsMedian±95% confidence interval
HbA1c Values Over 3 YearsMedian±95% confidence interval
Biphasic±prandial
Prandial±basal
Basal±prandial
Overall6.9%
(6.8 to 7.1)
Primary Outcome: HbA1c at 3 YearsMedian±95% confidence interval
Body Weight over 3 YearsMedian±95% confidence interval
Biphasic±prandial
Prandial±basal
Basal±prandial
Increase in Body Weight Over 3 YearsMean±1SD
Hypoglycaemia
Categorised as
Grade 1- Symptoms only with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl)
Grade 2- Symptoms plus glucose <3.1 mmol/l (<56 mg/dl)
Grade 3- Third party assistance required
Grade 2 or 3 Hypoglycaemia Over 3 Years
Biphasic±prandial
Prandial±basal
Basal±prandial
Grade 2 or 3 Hypoglycaemia Over 3 Years
Allpatients
Patients withHbA1c ≤6.5%
Overview of Main Results
Biphasic Prandial Basal
Fewer hypoglycaemic episodes ++ + +++Less weight gain + + ++Less increase in waist circumference
+ + ++
4T trial
Three quarters of patients added a second insulin Those commencing therapy with a basal or prandial
insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin
Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain
These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding
a mealtime insulin if glycaemic targets are not met
Beyond Glycemic Control
Blood pressure control
Lipid therapy
Microvascular complication screening and management
Blood Pressure Control Study
UK Prospective Diabetes StudyUK Prospective Diabetes Study
Randomisation
on antihypertensive therapyn = 421
not on antihypertensive therapyn = 727
avoid ACE inhibitor : Beta blockern = 390
34%
less tight blood pressure controlaim : BP < 180/105 mmHg
ACE inhibitorn = 400
35%
Beta blockern = 358
31%
tight blood pressure controlaim : BP < 150 / 85 mmHg
randomisation
1148 hypertensive patients
Blood Pressure : Tight vs Less Tight Control
60
80
100
140
160
180
0 2 4 6 8
mm
Hg
Years from randomisation
cohort, median values
Less tight control Tight control
Any diabetes-related endpoints
0%
10%
20%
30%
40%
50%
0 3 6 9
% o
f pa
tient
s w
ith e
vent
s
Years from randomisation
Tight blood pressure control (758)
Less tight blood pressure control (390)
risk reduction24% p=0.0046
Diabetes-related deaths
0%
5%
10%
15%
20%
0 3 6 9
% o
f pa
tient
s w
ith e
vent
s
Years from randomisation
Tight blood pressure control (758)
Less tight blood pressure control (390)
risk reduction32% p=0.019
Any DM-related endpoint 24% p=0.0046
Diabetes-related deaths 32% p=0.019
Stroke 44% p=0.013
Microvascular disease 37% p=0.0092
Heart failure 56% p=0.0043
Retinopathy progression 34% p=0.0038
Deterioration of vision 47% p=0.0036
Blood Pressure Control Study
Blood Pressure Study
ACCORDACCORD
ACCORD Study Group. NEJM 2010
ACCORD BP TrialACCORD BP Trial
ACCORD Study Group. NEJM 2010
4,733 patients with DM2; high CVS risk
SBP 130 – 180
Randomized to target SBP <140 v. <120
Primary outcome: nonfatal MI, nonfatal CVA; CVS death
Follow-up: 4.7 years; 95% complete
Baseline Characteristics
<120 <140
N 2362 2371
Age 62 62
% females 48% 48%
Hx CVS event 34% 33%
SBP 139.0 139.4
Duration DM 9 10
GHb (%) 8.4 8.3
ACCORD BP TrialACCORD BP Trial
ACCORD Study Group. NEJM 2010
Achieved SBP: 119 v. 133
Antihypertensive medications: 3.4 v. 2.3
ACCORD BP TrialACCORD BP Trial
ACCORD Study Group. NEJM 2010
Achieved SBP: 119 v. 133
Antihypertensive medications: 3.4 v. 2.3
Primary outcome:
Nonfatal MI, nonfatal CVA, CVS death (%/year):
1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)
ACCORD BP Trial: OutcomesACCORD BP Trial: Outcomes
ACCORD Study Group. NEJM 2010
Nonfatal MI, nonfatal CVA, CVS death (%/year):
1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)
Total mortality: 1.3% v. 1.2%, p=0.55
CVS death: 0.5% v. 0.5%
Stroke: 0.3% v. 0.5%, p=0.01
ACCORD BP Trial: ConclusionACCORD BP Trial: Conclusion
ACCORD Study Group. NEJM 2010
Targeting a SBP < 120, as compared to a SBP < 140, does not improve CVS outcomes in patients with DM2 at high risk of CVS events
Lipid Therapy Study
ACCORDACCORD
ACCORD Study Group. NEJM 2010
ACCORD Lipid TrialACCORD Lipid Trial
ACCORD Study Group. NEJM 2010
5,518 patients with DM2; high CVS risk
LDL 1.5 – 4.6; HDL < 1.4; TG < 8.5
All patients received open label simvastatin
Randomized to fenofibrate (160 mg) v. placebo
Primary outcome: nonfatal MI, nonfatal CVA; CVS death
Follow-up: 4.7 years
Baseline Characteristics
Fenofibrate Placebo
N 2765 2753
Age 62 62
% females 31% 31%
Hx CVS event 36% 37%
LDL 2.6 2.6
HDL 1.0 1.0
TG 2.1 2.1
ACCORD Lipid TrialACCORD Lipid Trial
ACCORD Study Group. NEJM 2010
Achieved LDL: 2.1 v. 2.1
Achieved HDL: 1.1 v. 1.0
Achieved TG: 1.7 v. 1.9
ACCORD Lipid TrialACCORD Lipid Trial
ACCORD Study Group. NEJM 2010
Achieved LDL: 2.1 v. 2.1
Achieved HDL: 1.1 v. 1.0
Achieved TG: 1.7 v. 1.9
Primary outcome:
Nonfatal MI, nonfatal CVA, CVS death (%/year):
2.2% v. 2.4%; HR 0.92 (0.79 – 1.08, p=0.32)
• Total mortality: 1.5% v. 1.6%, p=0.33
ACCORD Lipid Trial: OutcomesACCORD Lipid Trial: Outcomes
ACCORD Study Group. NEJM 2010
Pre-specified subgroups:
Sex:
Men: 11.2% v. 13.3%
Women: 9.1% v. 6.6%, p=.01
Dyslipidemia (HDL<0.9, TG > 2.3):
Dyslipidemia patients: 12.4% v. 17.3%
Non-dyslipidemic patients: 10.1% v. 10.1%, p=.057
ACCORD Lipid Trial: ConclusionsACCORD Lipid Trial: Conclusions
ACCORD Study Group. NEJM 2010
Routine fenofibrate therapy, in addition to simvastatin, does not improve CVS outcomes in patients with DM2 at high risk of CVS events
Addition of fenofibrate to simvastatin may benefit patients with significant dyslipidemia
• Glycemic control
• BP control
• Lipid management
Conclusions
Recommended