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Perioperative
considerations for
new type 2 diabetes
medicationsDec 9th, 2018
David Shu
Disclosures
Dr. Shu has received honorarium for speaking
engagements and consulting fees from the following
companies related to the content of this presentation
Astra Zeneca
Boehringer Ingelheim
Janssen
Lilly
Novonordisk
Sanofi
Objectives
Understand the mechanisms of action of the SGLT2
and GLP-1 classes of medications.
Review the CV benefits demonstrated with these
medications.
Perioperative considerations regarding SGLT-2
inhibitors and GLP-1 receptor agonists.
GLP-1 Receptor Agonists
McIntyre N. Lancet. 1964 Jul 4;41:20-21. Copyright © 1964.
Plasma InsulinBlood Glucose
IV/IJ glucose
0
50
100
150
200
250
300
-30 -15 0 15 30 45 60 75 90 105 120 135
Time (min)
Blo
od
Glu
co
se
(m
g/d
L) Intravenous
Intrajejunal
A Fundamental Observation: Insulin
Secretion is Greater with Oral versus IV
Glucose
0
50
100
150
200
250
300
-30 -15 0 15 30 45 60 75 90 105 120 135
Time (min)
Pla
sm
a In
su
lin (
pm
ol/L
)
Incretin Hormones Play a Pivotal Role in Glucose Regulation
7
DPP, dipeptidyl peptidase; GLP, glucagon-like peptide; GIP, glucose-dependent insulinotropic polypeptide
Drucker 2006; Nauck 2009; Kendall 2009
Oral intake of glucose
Muscle
Fat
Small Intestine
Glucose
Incretins
DPP-4enzymatic inactivation
Rapid incretininactivation
Liver
↑Glucoseuptake
↑ Insulin
↓ Glucagon
Hepatic glucose production
↓
Pancreas
Glucose GLP-1 GIP DPP-4
Satiety
Incretin Hormones Also Exhibit a Variety of Actions
on Multiple Target Tissues Implicated in T2DM8
T2DM, type 2 diabetes mellitus; GLP, glucagon-like peptide
Deacon 2008; Drucker 2006; Ahren 2004
Delay gastric
emptying
↑ Chronotropic and
inotropic action
↑ Release of insulin
↑ Inhibition of glucagon
↑ β cell proliferation
↓ β cell apoptosis
Neuroprotection
Induction of satiety
Inhibition of
glucose output
Insulin sensitivity?
GLP-1
Antiapoptotic effect
on cardiac muscle
Approved 2011
Approved 2010
Approved July 2015
Approved Nov 2015
GLP-1 agents available
Approved Oct 2015
Approved Fall 2017
Approved Jan 2018
DAILY AGENTS WEEKLY AGENTS
Parameter EXE BID LIXI† LIRA SEMA DULA EXE QW
GLP-1R Agonist Characteristics10
+ = modest reduction; ++ = strong reduction
Half-life 2.4 hrs ~3 hrs 13 hrs ~7 days ~5 days ~14 days
Time to
steady state
N/D N/D 3–5 days 5 weeks 2–4 weeks 6–7 weeks
A1C reduction -0.4 to -
1.4%
-0.7 to -
0.9%
-0.8 to -
1.5%
-1.5 to -
1.8%
-0.8 to -
1.6%
-1.3 to -
1.9%
FPG
reduction+ + ++ ++ ++ ++
PPG
excursion
reduction
++ ++* + ++ + +
Body weight
change (kg)
-0.9 to -2.8 -0.2 to -2.8 -1.6 to -3.2 -4.5 to -6.5 +0.2 to -3.0 -2.0 to -3.7
†Lixisenatide, not yet approved in Canada * only at meal with injection,
EXE BID: exenatide twice daily; LIXI: lixisenatide; LIRA: liraglutide; SEMA:semaglutide; DULA: dulaglutide; EXE
QW: exenatide once daily; A1C: glycated hemoglobin; FPG: fasting plasma glucose; PPG: post-prandial
glucose
Continued on next slide…
DAILY AGENTS WEEKLY AGENTS
Parameter EXE BID LIXI LIRA SEMA DULA EXE QW
GLP-1R Agonist Characteristics
Gastric
emptying All GLP-1RAs slow gastric emptying,
but less tachyphylaxis with EXE BID and LIXI
Nausea 33–57% 20–40% 10–47% 15–21% 8–28% 9–26%
Vomiting 12–17% 7–18% 4–17% 7–10% 4–17% 4–11%
11
EXE BID: exenatide twice daily; LIXI: lixisenatide; LIRA = liraglutide; DULA: dulaglutide; EXE QW: exenatide
once daily
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
Ch
an
ge
in
A1C
fro
m b
ase
lin
e (
%)
-1.8
-2.0
Wt. Δ (kg):
Pratley R et al. Lancet 2010;375:1447-56. Van Gaal L et al. J Clin Transl Endocrinol 2014;1:31-7. Bergenstal R. Lancet 2010;376:431-39 Ahren B et al. Diabetes Care 2014;37:2141-48. Nauck M et al. Diabetes Care 2014;37:2149-58
*Significant vs. sitagliptin Note that nausea rates associated with DPP-4 inhibitors are negligible.
1860-LIRA-DPP-426 weeks
Add-on to MET BL~8.4%
LIRA vs. SITA
-1.5*
LIR
A 1
.8
-3.4*
-1.2*
LIR
A 1
.2
-2.9*
-0.9
SIT
-1.0
LIXI vs. SITA
24 weeksAdd-on to MET
BL~8.1%
-0.7
LIX
I
-2.5*
-0.7SIT
-1.2
HARMONY-3104 weeks
Add-on to METBL~8.1%
ALBI vs. SITA
-0.6*
ALB
I
-1.2
-0.3
SIT
-0.9
AWARD-5 52 weeks
Add-on to METBL~8.1%
DULA vs. SITA
-1.1*
DU
LA 1
.5
-3.0*
-0.9*
DU
LA 0
.75
-2.6*
-0.4
SIT
-1.5
DURATION-226 weeks
Add-on to METBL~8.5%
EXE QW vs. SITA
-1.5*EX
E Q
W
-2.3*
-0.9
SIT
-0.8
CAUTION: Cross-trial comparisons cannot be made due to differences in study designs, trial durations and patient populations.
GLP-1R Agonists vs. DPP-4 Inhibitors: Head-to-Head Trials
12
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
Ch
an
ge
in
A1C
fro
m b
ase
lin
e (
%)
-1.8
-2.0
Wt. Δ (kg):
Ins dose
(U/d):
Blevins T et al. Postgrad Med 2010;122:118-28. Russell-Jones D et al. Diabetologia 2009;52:2046-55. D’Alessio D et al. Diabetes Obes Metab 2015;17:170-78
Diament M et al. Lancet 2010;375:2234-43. Giorgino F et al. Diabetes Care 2015;38:2241-9. Weissman P et al. Diabetologia 2014;57:2475-84
DULA vs.Glargine (+Met/SU)
(AWARD-2)
-
1.1*
-0.6
BL~8.1%
-1.9* 1.4
55* 69
29
DU
LA 1
.5
GLA
R
EXE QW vs. Glargine (+Met±SU)
(DURATION-3)
-1.3
-1.5*
BL~8.3%
-2.6* 1.4
8 26
31
GLA
R
EX
E Q
W
LIRA vs. Glargine (+Met/SU)
(LEAD-5)
-1.3*
-1.1
BL~8.3%
-1.8* 1.6
27 29
24
GLA
R
LIR
A 1
.8
-1.9
-1.8*
Glargine vs. LIRA (+Met±SU)
(EAGLE)BL~9.1%
-3.0* 2.0
18* 45
52
GLA
R
LIR
A 1
.8
-0.7-0.8
Noninferior
BL~8.3%
-3.5* -5.2 1.2
4.4 5.6 10.6
30
GLA
R
ALB
I
Semaglutide vs Glargine
EXE BID vs. Insulin (+≥1 OAD)
(4-Trial Analysis)
-1.1-1.2
Noninferior
*Significant vs. comparator
-2.0* 1.8
50 54
NA
GLA
R /
BI-
I
EX
E B
ID
Hypos (%):
GLP-1R Agonists vs. Basal Insulin: Head-to-Head Trials
1
3CAUTION: Cross-trial comparisons cannot be made due to differences in study designs, trial durations and patient populations.
GLP-1R Agonists: Effects on Blood Pressure and HR
Blood pressure: Reductions in systolic blood pressure (SBP) have been observed with GLP-1RAs.
14
Heart rate†: Small but statistically significant increases in HR have been observed with GLP1-RA
SEMA
1mg DULA
1.5 mg2*
EXE
10 µg
BID7,9
EXE
2 mg
QW8
LIRA
1.2 mg4–7
LIRA
1.8 mg4–7 LIXI2*
Change in
heart rate
(bpm)
+1 to +6 +2 +1 to +2 +4 +2 to +4 +2 to +4 -0.1 to +0.7
SEMA 1mg
DULA
1.5 mg2*
EXE
BID1
EXE
QW2* LIRA2* LIXI3*
Change in
SBP
(mmHg)
-2.7 to -7.2 -0.1 to -3.36 -1.0 to -4.0 -1.3 to -6.2 -0.6 to -4.0 Up to -2.1
* Based on results from respective Phase III clinical trial programs.† In some studies, “fasting” heart rate was assessed while in others 24-hr heart rate was examined.
1. Seufert J and Gallwitz B. Diabetes Obes Metab 2014;16:673-88. 2. Chilton RJ. J Diabetes Metab 2015;6:483 doi: 10.4172/2155-6156.1000483 3. Lyxumia (lixisenatide) SmPC. sanofi-aventis groupe. 2013. 4. Marre M et al. Diabet Med 2009;26:268-78. 5. Nauck MA et al. Diabetes Care 2009;32:84-9. 6. Zinman B et al. Diabetes Care 2009;32:1224-30. 7. Buse JB et al. Lancet 2009;374:39-47. 8. Diamant M et al. Lancet 2010;26;375:2234-43. 9. Gill A et al. Cardiovasc Diabetol 2010;9:6.
GLP-1 Receptor Agonists
Summary
GLP-1 RA increase glucose-dependent insulin
secretion, reduces glucagon, increase satiety and
delay gastric emptying
Result in significant reductions in A1c, body weight
without hypoglycemia
Side effects are nausea and vomiting, which subside
over time.
CV Effects of the new agents
Microvascular events and glucose control
T1DM T2DM
DCCT/EDIC1
(DCCT N=1,441)(EDIC N=1,375)
UKPDS2
(N=3867)ADVANCE3
(N=11,140)VADT4
(N=1,791)ACCORD
In-trial
6.5 years
Extension
17 years
In-trial
10 years
Extension
20 years
In-trial
4.5 years
Extension
10 years
In-trial
5.6 years
Extension
9.8 years
In-trial5
(N=10,251)
4-5 years
Extension6
(N=1,310)
8 years
A1C achieved (%)*
7.2 vs. 9.1(p<0.001)
7.0vs. 7.9(p<0.001)
6.5vs. 7.3(p<0.001)
6.9 vs. 8.4
(p<0.01)
6.4 vs. 7.5(p<0.01)
All microvascular(HR)
0.75(p=0.009)
0.76(p<0.001)
0.86(p=0.01)
NS NS
Nephropathy (HR) 0.46(p<0.01)
0.18(p<0.01)
NS 0.79(p=0.006)
0.54 (ESRD)(p=0.007)
0.56(p=0.04)
0.71(p=0.0003)
Retinopathy (HR) 0.37(p<0.01)
0.28(p<0.01)
0.79(p=0.015)
NS NS NS 0.67(p=0.003)
0.42(p<0.0001)
Neuropathy (HR) 0.40(p<0.01)
0.70(p<0.01)
NS NS NS 0.92(p=0.027)
*Average A1C achieved, intensive vs. standard; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitusNS, non significant; HR, hazard ratio. 1. DCCT Research Group. N Engl J Med. 1993;329:977-86; DCCT/EDIC Study Research
Group. N Engl J Med 2005;353:2643-53. 2. UKPDS Group. Lancet 1998;352:837–853; UKPDS Group. Lancet 1998;352:854-865;
3. ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–2572; ADVANCE-ON Collaborative Group. N Engl J Med
2014;371:1392-406; 4. Duckworth W et al. N Engl J Med 2009;360:129–139; VADT Investigators. N Engl J Med 2015;372:2197-
2206; 5. Ismail-Beigi F et al. Lancet 2010; 376:419-30; 6. ACCORD Follow-On Eye Study Group. Diabetes Care.
2016;39(7):1089-1100.
Macrovascular events and glucose control
DCCT/EDIC1
(DCCT N=1,441)(EDIC N=1,375)
UKPDS2
(N=3,867)ADVANCE3
(N=11,140)VADT4
(N=1,791)ACCORD5
(N=8,601)
In-trial
6.5 years
Extension
17 years
In-trial
10 years
Extension
20 years
In-trial
4.5 years
Extension
10 years
In-trial
5.6 years
Extension
9.8 years
In-trial
3.7 years
Extension
9 years
A1C achieved (%)*
7.2 vs. 9.1(p<0.001)
7.0vs. 7.9(p<0.001)
6.5vs. 7.3(p<0.001)
6.9 vs. 8.4
(p<0.01)
7.4 vs. 7.8(p<0.001)
All macrovascular
(HR)NS 0.43
(p=0.018)NS NS NS NS 0.83
(p=0.04)NS NS
Myocardialinfarction (HR)
NS 0.85(p=0.01)
NS NS 0.84(p=0.02)
NS
CV mortality (HR) NS
0.87 (total
mortality)(p=0.007)
NS NS NS NS 1.49(p=<0.01)
1.20(p=0.02)
*Average A1C achieved, intensive vs. standardNS, non significant.
1. DCCT Research Group. N Engl J Med. 1993;329:977-86; DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643-53. 2. UKPDS Group. Lancet 1998;352:837–853; UKPDS Group. Lancet 1998;352:854-865; 3. ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–
2572; ADVANCE-ON Collaborative Group. N Engl J Med 2014;371:1392-406; 4. Duckworth W et al. N Engl J Med 2009;360:129–139; VADT
Investigators. N Engl J Med 2015;372:2197-2206; 5. The ACCORD Study Group. Diabetes Care 2016; 39:701-08.
GLP-1 RA and CVOT
Hazard ratio
(95% CI) P value
ELIXA, 4P 1.02 (0.89; 1.17) 0.81
LEADER, 3P 0.87 (0.78; 0.97) 0.01
SUSTAIN-6, 3P 0.74 (0.58; 0.95) 0.02
EXSCEL, 3P 0.91 (0.83; 1.00) 0.06
GLP-1 RA CVOT results to date
3P, 3-point MACE; 4P, 4-point MACESingh AK, et al. Indian J Endocrinol Metab. 2017;21(1):4-10; Neal B, Perkovic V, Mahaffey KW, et al. N Engl J Med. 2017;377(7):644-657; Holman RR, Bethel MA, Mentz RJ, et al. N Engl J
Med. 2017 [epub ahead of print]
0.40 0.60 0.80 1.00 1.20Favours
Treatment
Favours
PlaceboNeutral for MACE
Superior for MACE
Harmony 0.78 (0.68-0.90) 0.0006
Pioneer 0.79 NS (press release)
Rewind Superior but no numbers
(press release)
Perioperative concerns with New Agents
GLP-1 receptor agonists
Perioperative infusion of GLP-1 reduced
hyperglycemia in CABG
77 patients undergoing CABG randomized to GLP-1
infusion or Placebo
Glucose 0.7mmol/L lower during intraoperative course.
No difference in hypoglycemia
Kohl, Benjamin. Journal of Cardiothoracic and Vascular Anesthesia. June
2014.
GLP-1 RA
Pros
Glucose-dependent
insulin release – no lows
Once-daily or weekly
injection
Cons
Delayed gastric
emptying
Nausea and vomiting
are potential side
effects
Elevation in heart rate
Peri-operative management of the surgical
patient with diabetes 2015
Peri-operative management of the surgical patient with diabetes 2015. Anaesthesia. Volume 70, Issue
12. December 2015
Pages 1427–1440
GLP-1 RA in surgery
For patients on long-term GLP-1RA therapy can likely
continue therapy with little adverse effect
Caution should be used in patients who have recently
started these agents given delayed gastric emptying
(first few weeks)
SGLT2 Inhibitors - Mode of
Action
Sodium GLucose Transporter2
Renal Handling of Glucose in
Healthy Patients
SGLT = Sodium-dependent glucose transporter
Adapted from:1. Bailey CJ. Trends in Pharmacol Sci. 2011;32:63-71.2. Chao EC. Core Evid. 2012;7:21-28.
GlomerulusDistal tubule
Collecting duct
Loop of
Henle
Proximal tubule
S3 segment of proximal tubule
• ~10% glucose reabsorbed
• Facilitated by SGLT1
S1 segment of proximal tubule
• ~90% glucose reabsorbed
• Facilitated by SGLT2
Glucosereabsorption
S3~10%
S1
~90%Glucosefiltration
(180 L/day) (1000 mg/L)=180 g/day
No/minimalglucose
excretion
Renal SGLT2 Inhibition - Untreated Type 2 Patients
Adapted from:1. Chao EC & Henry RR. Nat Rev Drug Discov. 2010;9(7):551-559.2. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14.3. Washburn WN. J Med Chem. 2009;52(7):1785-1794.
Urinary excretion
Glucose returns to
the bloodstream
Excess
glucose
Glomerulus
Renal proximal
tubule
Glucose reabsorption
RTG ~ 13.8 mmol/L
In patients with T2DM
and chronic hyperglycemia,
the SGLT system is
maladapted, causing
reabsorption of
excess glucose
RTG = Renal Threshold of Glucose
Renal SGLT2 Inhibition and Insulin - Independent
Glucose Control in Patients Treated with SGLT2i
Adapted from:1. Chao EC & Henry RR. Nat Rev Drug Discov. 2010;9(7):551-559.2. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14. Washburn WN. J Med Chem. 2009;52(7):1785-1794.
Renal proximal
tubule
Excess glucose
Glomerulus
SGLT2 inhibition enables more glucose to be
excreted
Excess glucose
excretion in urine
60-100 g/day
Glucose reabsorption
RTG ~ 5 mmol/L
Reduced blood glucose reabsorbed into the bloodstream
RTG = Renal Threshold of Glucose
0
25
50
75
100
125
150
Healthy
RTG
~10 mmol/L
0 2 4 6 8 10 12 14
Glucose
Excretio
n
(g/day)
Plasma glucose (mmol/L)
16
Above the RTG , glucosuria occurs
Under the RTG , no or minimal glucosuria occurs
Adaptation
in patients
with diabetes
Under treatment
with SGLT2 inhibitors
Effects of SGLT2 Inhibitors on RTG
1. Nair S & Wilding J. J Clin Endocrinol Metab. 2010;95(1):34-42.
2. Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277.
3. Washburn WN. Expert Opin Ther Pat. 2009;19(11):1485-1499.
4. Idris I, et al. Diabetes Obes Metab.
RTG= Renal Threshold of Glucose
5. Polidori D, et al. Poster 2186-PO. Presented at: 70th Annual ADA Meeting, June 2010.
6. Polidori D, et al. Presentation 875. Presented at: 46th Annual EASD Meeting, Sept. 2010.
SGLT2 Inhibitors available
Agent Approved doses
Canagliflozin 100mg , 300mg OD
Dapagliflozin 5mg, 10mg OD
Empagliflozin 10mg, 25mg OD
Ertugliflozin 5mg, 15mg OD (US only)
SGLT2 Inhibitors vs. Sitagliptin
as Add-on to Metformin
N and p values not available. CI: Confidence interval; SBP: Systolic blood pressure 1. Tsapas A. 50th EASD. Sept 15-19 2014 [OP 1359]. 35
-0.21
-2.64 -3.98
-6
-5
-4
-3
-2
-1
0
1
2
Diffe
rence (
95%
CI)
vs.
Sitaglip
tin
1.25
1.00
0.75
0.5
0
0.5
Ris
k ra
tio (9
5%
CI) v
s. s
itag
liptin
for
incid
en
ce o
f an
y h
yp
og
lycem
ia
∆ A1C
(%)
∆ Body Weight
(Kg)
∆ SBP
(mm Hg)
Hypoglycemia
Pooled results for 5 trials of SGLT2 inhibitors with a 12-week duration
1.12
SGLT2 Inhibitors vs. SUs as
Add-on to Metformin
N and p values not available. CI: Confidence interval; SBP: Systolic blood pressure. 1. Tsapas A. 50th EASD. Sept 15-19 2014 [OP 1359]. 36
Pooled results for 3 trials of SGLT2 inhibitors with a 12 week duration
-0.12
-4.81 -5.12
-7
-6
-5
-4
-3
-2
-1
0
1
Diffe
rences (
95%
CI)
vs.
SU 1.00
0.5
0
Ris
k ra
tio (9
5%
CI) v
s. S
U fo
r incid
en
ce o
f
an
y h
yp
og
lycem
ia
∆ A1C
(%)
∆ Body Weight
(Kg)
∆ SBP
(mm Hg)
Hypoglycemia
0.12
-0.03
-0.33
-0.44
-0.8
-0.6
-0.4
0.2
0.0
-0.2
BL Mean A1C (%)
BL Mean eGFR (mL/min/1.73m2)
8.0
39.4
CANA 100 mg CANA 300 mgPlacebo
Canagliflozin in eGFR 30 to <50 mL/min
(N=269) (1 Study)
LS
Me
an
Ch
an
ge
fro
m B
ase
lin
e
(±9
5%
CI)
A1
C(%
)
-0.40*-0.30†
-0.1
-0.57 -0.62-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
LS m
ean c
hange fro
m
baseline (%
)
eGFR 45 to <60 mL/min (n=721)
CANA Pooled Data (4 studies)
–0.47%* –0.52%*
0.05
-0.18
-0.34-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
LS m
ean c
hange fro
m
baseline (%
)
–0.23%* –0.39%*
eGFR 30 to <45 mL/min (n=364)
SGLT2 inhibitors have
reduced efficacy in CKD
* p <0.001; †p <0.051. Yale et al. Diabetes Obes Metab. 2013;15:463-73; 2. Yamout et al. Am J Nephrol. 2014;40:64-74 and Supp. Appendix. 37
Safety of SGLT2 inhibitors:
A meta-analysis of 45 studies
p values not available. CI: confidence interval; RR: risk ratio.1. Vasilakou Det al. Ann Int Med. 2013;159:262-74.
38
Outcome N RR 95% CI
Urinary tract infection
vs. placebo4003 1.34 1.03, 1.74
Urinary tract infection
vs. active comparator2930 1.42 1.06, 1.90
Genital tract infection
vs. placebo4030 3.50 2.46, 4.99
Genital tract infection
vs. active comparator 2930 5.06 4.44, 7.45
Hypotension
vs. placebo3003 1.57 0.74, 3.35
Hypotension
vs. active comparator2503 2.68 1.14, 6.29
SGLT2 Inhibitors: Volume Related Adverse Events
ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; Pts: patients1. FDA. Canagliflozin Advisory Meeting. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. 2. FDA. Dapagliflozin Advisory Meeting – FDA Briefing Document.. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf; 3. Jardiance Product Monograph. July 21, 2015.
39
Events include:
➢ Hypotension
➢ Postural hypotension
➢ Dehydration
➢ Syncope
➢ Reduced urine output
Events more common in:
➢ Pts on loop diuretics
➢ Pts with eGFR
30-60 mL/min
➢ Elderly
➢ Pts on ACEi or ARBs
Canagliflozin Pooled Data1
8 studies; n=9439; broad dataset (26-52 weeks)
CANA 100mg CANA 300mgNon-Cana
Pa
tie
nts
(%
) 3.2
4.6
2.4
0
1
2
3
4
5
78/3262
99/3092
141/3085
Pa
tie
nts
(%
)
Placebo DAPA
10mg
0.8 1.5
Dapagliflozin Pooled Data2
6 studies, n=2411, ≤102 wks
0
2
4
6
8
10
6/78513/859
Empagliflozin Pooled Data3
5 studies, n=2971, 18-24 wks
0.3 0.5 0.3
3/995 5/999 3/977
Placebo EMPA
10mg
EMPA
25mg
1.0
8/767
DAPA
5mg
Counselling Patients About
Sick Days
1. Diabetes Canada. Canadian Practice Guidelines 2018 40
SGLT2 inhibitors summary
Reduce renal threshold for glucosuria.
SGLT2 inhibition results in greater A1c reduction than
sulfonureas and DPP-IV inhibitors
A1c reductions are accompanied by weight loss, no
hypoglycemia and blood pressure improvement
Orthostatic symptoms, genital mycotic infections are
the main adverse effects.
SGLT2 inhibitors
SGLT-2 inhibitors: CV Outcome Trials44
EMPA-REGOutcome
CANVAS CANVAS-R CREDENCEDECLARE (TIMI 58)
ErtugliflozinCVOT
Number 7034 4339 5700 3627 17150 3900
Key
InclusionCVD
CVD or high
CVD risk
CVD or high CVD risk
Stage 2/3 CKD on
ACE/ARB
High CVD risk
CVD
Primary
Endpoint
CV DeathMI
Stroke
CV Death
MIStroke
Progression of
albuminuria
ESKD, 2x Cr, Renal/CV
Death
CV DeathMI
Stroke
CV DeathMI
Stroke
Reporting 2015 2017 2017 2019 2019 2021
Median F/U 3 years 6-7 years 3 years 4 years 4-5 years 5–7 years
Adapted from Table 4, Inzucchi et al
CVOT trials reporting
Empareg (empagliflozin)
Canvas (canagliflozin)
Declare (dapagliflozin)
Zelniker, TA. Lancet Nov 10, 2018
MACE endpoints reduced in
secondary but not primary
prevention
Zelniker, TA. Lancet Nov 10, 2018
CHF hospitalization was
markedly reduced with SGLT2
inhibitor use
Zelniker, TA. Lancet Nov 10, 2018
ESRD, renal death or worsening
of serum creatinine was
reduced by almost half.
Zelniker, TA. Lancet Nov 10, 2018
Bottom Line – SGLT2
inhibitors
Empagliflozin, Canagliflozin, Dapagliflozin* have been showed to reduce MACE outcomes, hospitalizations for heart failure and renal endpoints.
Adverse events are genital mycotic infections
Canagliflozin also had an increase in amputations and fracture risk
Dapagliflozin had significantly higher DKA rate than placebo (0.3 vs 0.1%)
*Dapagliflozin – composite of MACE +HHF
51
52
53
54
N Engl J Med. 2017 Jun 8;376(23):2300-2302
DKA IS TWICE AS LIKELY IN PATIENTS ON SGLT2 INHIBITORS VS DPP-IV INHIBITORS
Why is this happening?
56
J Clin Endocrinol Metab. 2015 Aug;100(8):2849-52
SEVERAL MECHANISMS MAY EXPLAIN INCREASE IN DKA WITH SGLT2 INHIBITORS
ADA 2018 presentation
Mechanism by which Dapagliflozin induce
Euglycemic Ketoacidosis in Rats
R.J. Perry
Key points
SGLT2 inhibitors cause increased risk of DKA
Presenter used rat model to study effect of dapagliflozin on glucose, insulin, catecholamines, glucagon, BHB, volume
Dapagliflozin lowered glucose and insulin, raised catecholamines, glucagon and BHB. Volume depletion occurred in rats denied access to water
After correcting volume status, catecholamines and BHB returned to normal.
Additionally, replacing glucose and insulin could attenuate BHB increase
Interestingly, glucagon did not seem to drive BHB production
DKA in rats require 2 insults to occur.
DKA in rats exposed to dapagliflozin appears to be a 2-hit process
Requires volume depletion and relative insulinopenia
Additionally, increased glucagon appears to be a central process as dapagliflozin given through central administration causes increased glucagonemia.
Key take away
If this evidence can be translated to humans, important for patients to keep well-hydrated while using SGLT2 inhibitors
Sick day management requires volume replacement, and insulin doses should be maintained as best as possible.
SGLT2 inhibitors
Perioperative considerations
From mechanism of action could postulate that issues
may arise with:
Volume depletion
Risk of acute kidney injury
Euglycemic DKA
64
Diabetes Canada CGP 2018
65
Endocr Pract. 2016 Jun;22(6):753-62
To minimize the risk of DKA associated with SGLT-2 inhibitors, AACE recommends the following:
• Consider stopping the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity such as running a marathon. As noted above, urinary glucose loss due to SGLT-2 inhibition may persist after the drug is stopped.
• Avoid stopping insulin or decreasing the dose excessively.
• For emergency surgery or any extreme stress event, the drug should be stopped immediately,
and appropriate clinical care should be provided.
• Routine measurement of urine ketones is not recommended during use of SGLT-2 inhibitors
because this measurement can be misleading. Instead, measurement of blood ketones is preferred for diagnosis of DKA in symptomatic patients.
• Patients taking SGLT-2 inhibitors should avoid excess alcohol intake and very-lowcarbohydrate/
ketogenic diets.
66
Anesth Analg. 2018 Feb;126(2):699-704
67
CASE REPORTS: POST-OPERATIVE euDKA
68
CASE REPORTS: POST-OPERATIVE euDKA
ID AgentDuration OR Pre-op Post-op DKA timingRecovery
51FCana 300 ? Abdominoplasty Continued Continued
POD1, POD6 ?
44F Empa 7moAbdominoplasty / mastoplexy Held day of OR Held POD1 48h on infusion
55FCana 300 ? Breast recon Held day of OR Held POD0 resoved POD4, home POD7
66F Dapa 2yrs CABG ? Continued POD1 extub POD2, ward POD5
54MEmpa 25 ? CABG Held day of OR Held POD1 normalized in hours,
54MEmpa 25 ? CABG Held day prior to OR Held POD1 gap closed in 4h,
58MEmpa 25 ? CABG Held day prior to OR Held POD1 normalized in hours,
64FCana 300 6mo Cervical foraminotomy Held day of OR Held POD1 recovered fully in 6d
72F Dapa ? Hip replacement ? ? POD2 resolved in 3d, to ward on 5th day
42FCana 300 ? RYGB
Held day of OR, low cal x 2 wks Held POD2
gap closed in 14h, extub POD6, home POD10
52FCana 300 ? RYGB
Held day of OR, low carb x 1 wk Held POD1
12h to pH, 3 days norm metabolics, DC POD5
52MCana 300 ? RYGB
Held day of OR, low carb x 5d Held POD2 gap closed in 12h, home 2 days later
53M Dapa ? RYGB ? ? 6wk ?
23FEmpa 10 ? RYGB Held 3d, liquid diet 2d
Resumed POD2 POD6 4d to resolve, 8d hospitalization
58MCana 300 ? Sigmoid colectomy ?
Resumed on DC
5d post-DC ?
57FCana 300 3mo Tibia recon Continued Continued 2wks 36h to resolution, 3 day admission
55M Empa ? Total knee replacement ? Continued POD6 acidosis resolved in 24h, DC home D7
74MCana 300 8mo Whipple Held day prior to OR Held POD10 48h on infusion
69
Clin Ther. 2016 Dec;38(12):2654-2664
70
Anaesth Intensive Care. 2018 Mar;46(2):155-158
“The recent reports suggest that current recommendations to cease SGLT2 inhibitors on the day of surgery, or the day before surgery, may be inadequate. The drugs should, ideally, be ceased four to five half-lives before surgery. The half-life for both empagliflozin and dapagliflozin is approximately 12 hours. We therefore recommend cessation 48 hours or more before surgery.”
“For moderate or major surgery, the drugs should be withheld until the acute phase response and physiological stress has resolved, the patient is eating and drinking normally and the anabolic phase of physiological recovery is established. As a suggested guide for joint arthroplasty, a week or longer may be appropriate; for major body cavity surgery up to two weeks or longer.”
SGLT2 inhibitors
Pros
Insulin-independent
glucose lowering – no
lows
Diuresis
Reduction in CHF
Cons
Volume depletion
Hypotension
Euglycemia DKA
Genital Mycotic
infections
Urinary tract infections
Bottom Line
SGLT2 inhibitors and GLP-1 RA have been shown to
reduce CVD in secondary prevention trials
Perioperatively, limited data available
Current anaesthesia guidelines suggest that GLP-1 RA
can be continued but SGLT2 inhibitors should be held
Exact timing of cessation of therapy is not clear but several of the case reports of euglycemic DKA occurred in patients who had SGLT inhibitor held for 1 day prior to surgery.
2-3 days seems more prudent based on half-life of agents
Bottom Line
Cardiac and Gastric Bypass surgery are disproportionally
represented in case reports
These drugs might be best started on discharge after risk of
acute complications have settled down
Thank you
Thanks to Dr. Pol Darras (R5 endo) for collecting the
case reports and tabulating the results.
Questions?
