1. Cardiovascular Outcomes Trials with Antihyperglycemic Agents
CVOTs

2. Timeline of Major Diabetes Outcomes Trials
UKPDS/ UKPDS Metformin
DCCT
STOP-NIDDM
PROActive
ACCORD
VADT
ORIGIN
SAVOR-TIMI*
TECOS*
LEADER*
DEVOTE*
1995
2000
2005
2010
2015
ADVANCE
RECORD
EXAMINE*
ELIXA*
EMPA-REG*
SUSTAIN 6*
CANVAS*
EXSCEL*
FDA CVOT Guidance—2008
Blue = Intensive vs standard control using same set of glucose-lowering agent(s)
Purple = Intensive control with a specific agent vs standard care
Red = Placebo- or active-controlled study
* = FDA-mandated cardiovascular safety trial
ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; CANVAS, Canagliflozin Cardiovascular Assessment Study; DCCT, Diabetes Control and Complications Trial; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG, EMPA-REG OUTCOME trial; Exenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; PROActive, Prospective Pioglitazone Clinical Trial in Macrovascular Events; RECORD, Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction; STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

3. Cardiovascular Outcomes Trials: A Brief History
2008 FDA guidance mandating assessment of CV safety of all antihyperglycemic agents in RCTs
Designed as noninferiority studies to demonstrate study drug was not associated with more MACE than placebo
Some study designs tested for superiority if noninferiority criteria were met
Primary endpoint: composite of cardiovascular death, nonfatal MI, and nonfatal stroke
Some primary endpoints included additional components
MACE = major adverse cardiovascular events; RCTs, randomized controlled trials.
FDA. Guidance for industry: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.

4. Noninferiority and Superiority Criteria in CVOTs
Upper bound of the confidence interval for the primary endpoint is less than a prespecified threshold (often 1.3, but criteria vary with study design)
Means study drug performed no worse than comparator and is safe
1.3
1.0
Agents Shown to Have CV Safety:
All antihyperglycemic agents evaluated in CVOTs to date
Superiority
Upper bound of confidence interval for the primary endpoint is typically less than 1 (criteria may vary with study design)
Tested after noninferiority criteria are met
Means study drug reduced CV outcomes relative to comparator
Agents Shown to Reduce CV Outcomes:
Canagliflozin
Empagliflozin
Liraglutide
95% Confidence Interval

5. TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)
Clinical Outcomes with Antihyperglycemic Agents
TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)

6. Clinical Outcomes with Sitagliptin
TECOS
Study Design
Key Results
N=14,671 patients with T2D and CVD
Randomization
Sitagliptin: n=7332 (6972 completed)
Placebo: n=7339 (6905 completed)
Noninferiority study: 1.3 marginal upper boundary of 2-sided 95% CI
Primary composite outcome: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina
Secondary composite outcome: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Median follow-up: 3.0 years
Least squares mean difference in A1C: -0.29% (95% CI to -0.27) for sitagliptin vs placebo
Noninferior to placebo for cardiovascular outcomes
Primary HR: 0.98 ( ); P<0.001
Secondary HR: 0.99 ( ); P<0.001
No difference between sitagliptin and placebo in incidence of infections, cancer, renal failure, hypoglycemia, or noncardiovascular death
CI, confidence interval; HR, hazard ratio; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
Green JB, et al. N Engl J Med. 2015;373:

7. Primary and Secondary Outcomes with Sitagliptin
TECOS Per Protocol Analysis
(n=14,523)
Median follow-up: 3.0 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
0.98 ( )
<0.001 (NF)
Secondary composite endpoint†
0.99 ( )
Acute pancreatitis
1.80 ( )
0.12
Any cancer (except nonmelanoma skin cancer)
0.93 ( )
0.38
Pancreatic cancer
0.91 ( )
0.85
Severe hypoglycemia
1.13 ( )
0.31
Favors sitagliptin
*Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
†Secondary composite: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
NF, noninferiority; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
Green JB, et al. N Engl J Med. 2015;373:

8. Individual Secondary Outcomes with Sitagliptin
TECOS Intent to Treat Analysis
(n=14,671)
Median follow-up: 3.0 years
Hazard ratio (95% CI)
P value
CV death
1.03 ( )
0.71
Hospitalization for unstable angina
0.90 ( )
0.42
Fatal or nonfatal MI
0.95 ( )
0.49
Fatal or nonfatal stroke
0.97 ( )
0.76
Death from any cause
1.01 ( )
0.88
Hospitalization for heart failure
1.09 ( )
0.98
Hospitalization for heart failure or CV death
1.02 ( )
0.74
Favors sitagliptin
CV, cardiovascular; MI, myocardial infarction; NF, noninferiority; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
Green JB, et al. N Engl J Med. 2015;373:

9. Clinical Outcomes with Sitagliptin
TECOS
(n=14,671)
TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
Green JB, et al. N Engl J Med. 2015;373:

10. Clinical Outcomes with Antihyperglycemic Agents
EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care)

11. Clinical Outcomes with Alogliptin
EXAMINE
Study Design
Key Results
N=5380 patients with T2D and ACS
Randomization
Alogliptin: n=2701
Placebo: n=2679
Noninferiority study: prespecified HR margin = 1.3 for primary endpoint
Primary composite endpoint: CV death, nonfatal MI, or nonfatal stroke
Secondary: CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina
Median follow-up: 18 months
Least squares mean difference in A1C: -0.36% (95% CI to -0.28; P<0.001) for alogliptin vs placebo
CV outcomes
Primary HR: 0.96 (≤1.16); P=0.32
Secondary HR: 0.95 (≤1.14*); P=0.26
No difference between alogliptin and placebo in incidence of acute and chronic pancreatitis, cancer, renal impairment, angioedema, or severe hypoglycemia
*Upper boundary of 1-sided repeated CI, alpha level 0.01.
CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; HR, hazard ratio; MI, myocardial infarction.
White W, et al. N Engl J Med. 2013;369:

12. Clinical Outcomes with Alogliptin
EXAMINE Safety Endpoints
(n=5380)
Median follow-up: 18 months
Hazard ratio (95% CI)
P value
Primary composite
0.96 (≤1.16)*
0.32
Primary endpoint components
CV death
0.79 ( )
0.10
Nonfatal MI
1.08 ( )
0.47
Nonfatal stroke
0.91 ( )
0.71
Primary secondary endpoint†
0.95 (≤1.14)*
0.26
Death from any cause
0.85 ( )
0.21
Favors alogliptin
*Upper boundary of 1-sided repeated CI, alpha level 0.01.
†CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina.
CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; MI, myocardial infarction.
White W, et al. N Engl J Med. 2013;369:

13. Alogliptin CV Outcomes and Mortality
EXAMINE
CV Death, Nonfatal MI, or Nonfatal Stroke
CV Death
All-Cause Death
EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care.
White W, et al. N Engl J Med. 2013;369:

14. Clinical Outcomes with Antihyperglycemic Agents
SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction)

15. Clinical Outcomes with Saxagliptin
SAVOR-TIMI
Study Design
Key Results
N=16,492 patients with T2D and CVD or CVD risk
Randomization
Saxagliptin: n=8280
Placebo: n=8212
Superiority study with provision to test for noninferiority
Primary composite endpoint: CV death, nonfatal MI, or nonfatal ischemic stroke
Secondary: CV death, nonfatal MI, nonfatal ischemic stroke, hospitalization for HF, coronary revascularization, or unstable angina
Median follow-up: 2.1 years
Endpoint A1C
Saxagliptin: 7.7% ± 1.4% (P<0.001 vs placebo)
Placebo: 7.9% ± 1.5%
CV outcomes
Primary HR: 1.00 ( ); P=0.99
Secondary HR: 1.02 ( ); P=0.66
Higher incidence of HF hospitalization in saxagliptin group
No difference between groups in incidence of acute or chronic pancreatitis; fewer cases of pancreatic cancer in saxagliptin group; more cases of nonfatal angioedema in saxagliptin group (8 vs 1)
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.
Scirica BM, et al. N Engl J Med. 2013;369,

16. Clinical Outcomes with Saxagliptin
SAVOR-TIMI Prespecified Composite Endpoints and Mortality
(n=16,492)
Median follow-up: 2.1 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
1.00 ( )
0.99
Secondary composite endpoint†
1.02 ( )
0.66
Death from any cause
1.11 ( )
0.15
CV death
1.03 ( )
0.52
Favors saxagliptin
*CV death, nonfatal MI, or nonfatal ischemic stroke; †CV death, nonfatal MI, nonfatal ischemic stroke, hospitalization for HF, coronary revascularization, or unstable angina.
CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.
Scirica BM, et al. N Engl J Med. 2013;369,

17. Individual Secondary Outcomes with Saxagliptin
SAVOR-TIMI Prespecified Individual Endpoints
(n=16,492)
Median follow-up: 2.1 years
Hazard ratio (95% CI)
P value
Myocardial infarction
0.95 ( )
0.52
Ischemic stroke
1.11 ( )
0.38
Hospitalization for unstable angina
1.19 ( )
0.24
Hospitalization for heart failure
1.27 ( )
0.007
Hospitalization for coronary revascularization
0.91 ( )
0.18
Renal endpoint*
1.08 ( )
0.46
Hospitalization for hypoglycemia
1.22 ( )
0.33
Favors saxagliptin
*Doubling of creatinine, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL
CI, confidence interval; CV, cardiovascular; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.
Scirica BM, et al. N Engl J Med. 2013;369,

18. SAVOR-TIMI Post-hoc Analysis
Baseline Characteristics and Risk of HF Hospitalization With Saxagliptin
SAVOR-TIMI Post-hoc Analysis
(n=16,492)
Hazard ratio (95% CI)
P value
eGFR ≤60 mL/min
1.36 ( )
0.03
eGFR >60 mL/min
1.16 ( )
0.27
No prior heart failure
1.30 ( )
Prior heart failure
1.23 ( )
0.13
No risk factors*
1.15 ( )
1 risk factor
1.35 ( )
0.02
2 risk factors
1.22 ( )
Q4 NT-proBNP (333-46,627 pg/mL)
1.31 ( )
Favors saxagliptin
*eGFR ≤60 mL/min or history of previous HF.
HF, heart failure; NT-proBNP, N-terminal pro B-type natriuretic peptide; Q, quartile; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.
Scirica BM, et al. Circulation. 2014;130:

19. Risk of HF Hospitalization with Saxagliptin vs Placebo
SAVOR-TIMI Post-hoc Analysis
(n=16,492)
eGFR (mL/min)
HF history
No. HF risk factors†
NT-proBNP quartiles (pg/mL)
No. excess HHF events in patients treated with saxagliptin vs placebo per 1000 pt-y
(5-64)
(65-141)
( )
(334-46,647)
n =
11637
4855
14387
2105
10418
5188
866
3076
3073 1 5 6 4 9 7
Absolute risk difference*
*Saxagliptin vs placebo.
†eGFR ≤60 mL/min or history of previous HF.
HF, heart failure; HHF, hospitalizations for heart failure.
Scirica BM, et al. Circulation. 2014;130:

20. Clinical Outcomes with Antihyperglycemic Agents
EMPA-REG outcome (Empagliflozin cardiovascular Outcome event trial in type 2 diabetes mellitus patients)

21. Clinical Outcomes with Empagliflozin
EMPA-REG OUTCOME
Study Design
Key Results
N=7020 patients with T2D and CVD
Randomization
Empagliflozin: n=4687
Placebo: n=2333
Noninferiority study: prespecified HR margin = 1.3 for primary endpoint
Primary endpoint: composite of CV death, nonfatal MI (excluding silent MI), or nonfatal stroke
Secondary endpoint: composite of CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina
Median follow-up: 3.1 years
Week 206 A1C, difference from placebo
Empagliflozin 10 mg: -0.24% (95% CI, -0.40% to -0.08%)
Empagliflozin 25 mg: -0.36% (95% CI, -0.51% to -0.20%)
CV outcomes (pooled analysis)
Primary: HR 0.86 (95% CI 0.74 to 0.99); P=0.04 for superiority
Secondary HR: 0.89 (95% CI 0.78 to 1.01); P<0.001 for noninferiority and P=0.08 for superiority
Significantly lower rates of all-cause death, CV death, and HF hospitalization with empagliflozin
Increased rates of genital infections in empagliflozin-treated patients
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Zinman B, et al. N Engl J Med. 2015;373:

22. Clinical Outcomes with Empagliflozin
EMPA-REG OUTCOME Pooled Analysis
(N=7020)
Median follow-up: 3.1 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
0.86 ( )
0.04
Secondary composite endpoint†
0.89 ( )
0.08
Death from any cause
0.68 ( )
<0.001
CV death
0.62 ( )
Fatal or nonfatal MI
0.87 ( )
0.23
Hospitalization for HF
0.65 ( )
0.002
Hospitalization for HF or CV death
0.66 ( )
Favors empagliflozin
*CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; †CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina.
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Zinman B, et al. N Engl J Med. 2015;373:

23. Clinical Outcomes with Empagliflozin
EMPA-REG OUTCOME Pooled Analysis
(N=7020)
*CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; †CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina.
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Zinman B, et al. N Engl J Med. 2015;373:

24. Microvascular and Renal Outcomes with Empagliflozin
EMPA-REG RENAL
(N=7020)
Median follow-up: 3.1 years
Hazard ratio (95% CI)
P value
Composite microvascular endpoint*
0.62 ( )
<0.001
Incident or worsening nephropathy or CV death
0.61 ( )
Incident or worsening nephropathy
0.61 ( )
Progression to microalbuminuria
0.62 ( )
Doubling of SCr plus eGFR ≤45 mL/min/1.73 m2
0.56 ( )
Initiation of renal replacement therapy
0.45 ( )
0.04
Severe renal outcomes†
0.54 ( )
Incident albuminuria in patients with normal albumin at baseline
0.95 ( )
0.25
Favors empagliflozin
*In patients with normal albuminuria at baseline.
CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate in mL/min/1.73 m2; HR, hazard ratio; SCr, serum creatinine.
Wanner C, et al. N Engl J Med. 2016;375:

25. Renal Outcomes with Empagliflozin
EMPA-REG RENAL
(N=7020)
Incident or Worsening Nephropathy
Post-hoc Renal Composite Outcome*
*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.
CI, confidence interval; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.
Wanner C, et al. N Engl J Med. 2016;375:

26. Renal Outcomes with Empagliflozin Over 3.2 Years
EMPA-REG RENAL
(N=7020)
39%
P<0.001
44%
P<0.001
Patients (%)
Patients (%)
38%
P<0.001
Patients (%)
Arrows = relative risk reduction.
*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.
CI, confidence interval; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.
Wanner C, et al. N Engl J Med. 2016;375:

27. Clinical Outcomes with Empagliflozin
EMPA-REG OUTCOME Safety Results
Event
Pooled Empagliflozin (%)
Placebo (%)
Any adverse event
90.2
91.7
Serious adverse event
38.2
42.3
Death
3.8
5.1
Any hypoglycemia
27.8
27.9
Severe hypoglycemia
1.3
1.5
Urinary tract infection Male
10.5
9.4
Female
36.4
40.6
Genital infection Male
5.0
10.0
2.6
Volume depletion
4.9
Diabetic ketoacidosis
0.1
<0.1
Bone fracture
3.9
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Zinman B, et al. N Engl J Med. 2015;373:

28. Canvas (Canaglflozin Cardiovascular Assessment Study)
Clinical Outcomes with Antihyperglycemic Agents
Canvas (Canaglflozin Cardiovascular Assessment Study)

29. Clinical Outcomes with Canagliflozin
CANVAS Program Study Design
N=10,142 patients with T2D and high CV risk
CANVAS: n=4330
CANVAS-R: n=5812
Randomization (across both studies)
Canagliflozin: n=5795
Placebo: n=4347
Noninferiority/superiority criteria
Noninferiority = upper bound of 95% CI of the HR <1.3
Superiority = upper bound of 95% CI of the HR <1.0
Endpoints
Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke
Secondary endpoints:
All-cause death
CV death
Albuminuria progression
Composite of CV death and HF hospitalization
CANVAS, Canaglflozin Cardiovascular Assessment Study; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Neal B, et al. N Engl J Med. 2017;377:

30. Clinical Outcomes with Canagliflozin
CANVAS Program
(N=10,142)
Median follow-up: 2.4 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
0.86 ( )
0.02†
CV death
0.87 ( )
Nonfatal MI
0.85 ( )
Nonfatal stroke
0.90 ( )
Fatal or nonfatal MI
0.89 ( )
Fatal or nonfatal stroke
0.87 ( )
HF hospitalization
0.67 ( )
CV death or HF hospitalization
0.78 ( )
All-cause death
0.87 ( )
Progression of albuminuria
0.73 ( )
40% reduction in eGFR, renal replacement therapy, or renal death
0.60 ( )
Favors canagliflozin
*CV death, nonfatal MI, or nonfatal stroke. †Superiority.
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Neal B, et al. N Engl J Med Jun 12 [epub ahead of print].

31. Adverse Events with Canagliflozin
CANVAS Program* Safety Results
Event
Canagliflozin
Placebo
P value
Events per 1000-patient years
All serious adverse events
104.3
120.0
0.04
Adverse events leading to discontinuation
35.5
32.8
0.07
Diabetic ketoacidosis (adjudicated)
0.6
0.3
0.14
Events of interest occurring in significantly more canagliflozin-treated patients
Amputation
6.3
3.4
<0.001
Bone fracture (adjudicated)
All
15.4
11.9
0.02
Low trauma
11.6
9.2
0.06
Infection of male genitalia
34.9
10.8
Osmotic diuresis†
34.5
13.3
Volume depletion†
26.0
18.5
0.009
Mycotic genital infection in women†
68.8
17.5
*Includes patients from CANVAS and CANVAS-R (N=10,142). †CANVAS-only population (n=4330).
Neal B, et al. N Engl J Med Jun 12 [epub ahead of print].

32. elixa (evaluation of lixisenatide in acute coronary syndrome)
Clinical Outcomes with Antihyperglycemic Agents
elixa (evaluation of lixisenatide in acute coronary syndrome)

33. Clinical Outcomes with Lixisenatide
ELIXA Study Design
Study Design
Key Results
N=6068 patients with T2D and MI or unstable angina within 180 days prior to enrollment
Randomization
Lixisenatide: n=3034
Placebo: n=3034
Noninferiority criteria: upper bound of 95% CI of the HR for the primary endpoint <1.3
Primary endpoint: composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina
Key secondary endpoints
Composite of composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina or HF
Composite of composite of CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina or HF, or coronary revascularization
Median follow-up: 25 months
Difference from placebo at 25 weeks
A1C: −0.27% (95% CI −0.31 to −0.22; P<0.001)
Weight: −0.7 kg (95% CI, −0.9 to −0.5 kg; P<0.001)
SBP: −0.8 mm Hg (95% CI, −1.3 to −0.3 mm Hg)
CV outcomes
Primary: HR 1.02 (95% CI 0.89 to 1.17); P<0.001 for noninferiority; P=0.81 for superiority
Increased rates of gastrointestinal events in lixisenatide-treated patients
Rates of serious adverse events, severe hypoglycemia, pancreatitis, pancreatic neoplasms similar to placebo
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Pfeffer MA, et al. N Engl J Med. 2015;373:

34. Clinical Outcomes with Lixisenatide
ELIXA
(Patients with T2D and CVD; N=6068)
Hazard ratio (95% CI)
P value
Primary composite endpoint*
1.02 ( )
0.81
Secondary composite endpoint†
0.97 ( )
0.63
CV death
0.98 ( )
0.85
Fatal or nonfatal MI
1.03 ( )
0.71
Stroke
1.12 ( )
0.54
Unstable angina
1.11 ( )
Hospitalization for heart failure
0.96 ( )
0.75
Death from any cause
0.94 ( )
0.50
Favors lixisenatide
*CV death, nonfatal MI, or nonfatal stroke, and hospitalization for unstable angina; †CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, hospitalization for HF, and coronary revascularization.
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Pfeffer MA, et al. N Engl J Med. 2015;373:

35. Clinical Outcomes with Lixisenatide
ELIXA Adverse Events
Event
Lixisenatide (%)
(n=3031)
Placebo (%)
(n=3032)
Hypoglycemia
16.6
15.2
Serious adverse event
20.6
22.1
Hypoglycemia requiring assistance from another person
0.4
0.8
Gastrointestinal event
2.2
2.7
Acute pancreatitis
0.16
0.26
Pancreatic cancer
0.09
0.3
Systemic allergic reactions
0.9
Adverse events leading to treatment discontinuation
11.4
7.2
Gastrointestinal
4.9
1.2
Pfeffer MA, et al. N Engl J Med. 2015;373:

36. Clinical Outcomes with Antihyperglycemic Agents
LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results)

37. Clinical Outcomes with Liraglutide
LEADER
Study Design
Key Results
N=9340 patients with T2D and high CV risk
Randomization
Liraglutide: n=4672
Placebo: n=4668
Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the HR for the primary endpoint
Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke
Secondary endpoint: composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF
Median follow-up: 3.5 years
Difference from placebo at 36 months
A1C: −0.40% (95% CI, −0.45% to −0.34%)
Weight: −2.3 kg (95% CI, −2.0 to −2.5 kg)
SBP: −1.2 mm Hg (95% CI, −0.5 to −1.9 mm Hg)
CV outcomes
Primary: HR 0.87 (95% CI 0.78 to 0.97); P=0.01 for superiority
Secondary HR: 0.88 (95% CI 0.81 to 0.96); P=0.005 for superiority
Significantly lower rates of all-cause death and CV death with liraglutide
Increased rates of gastrointestinal events in liraglutide-treated patients
Lower numerical incidence of pancreatitis in liraglutide group (not statistically significant)
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Marso SP, et al. N Engl J Med. 2016:375:

38. Clinical Outcomes with Liraglutide
LEADER
(N=9340)
Median follow-up: 3.5 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
0.87 ( )
0.01
Expanded composite endpoint†
0.88 ( )
0.005
Death from any cause
0.85 ( )
0.02
CV death
0.78 ( )
0.007
Fatal or nonfatal MI
0.86 ( )
0.046
Nephropathy
0.78 ( )
0.003
Favors liraglutide
*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF.
CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.
Marso SP, et al. N Engl J Med. 2016:375:

39. Clinical Outcomes with Liraglutide
LEADER
(N=9340)
*CV death, nonfatal MI (including silent MI), or nonfatal stroke.
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Marso SP, et al. N Engl J Med. 2016:375:

40. Clinical Outcomes with Liraglutide
LEADER Adverse Events Leading to Discontinuation
Event
Liraglutide (%)
(n=4668)
Placebo (%)
(n=4672)
P value
Any adverse event
9.5
7.3
<0.001
Serious adverse event
4.1
5.2
0.01
Nausea
1.6
0.4
Vomiting
0.7
<0.1
Diarrhea
0.6
0.1
Increased lipase level
0.3
0.2
0.43
Decreased appetite
Abdominal discomfort
0.002
Marso SP, et al. N Engl J Med. 2016:375:

41. exscel (Exenatide study of cardiovascular event lowering)
Clinical Outcomes with Antihyperglycemic Agents
exscel (Exenatide study of cardiovascular event lowering)

42. Clinical Outcomes with Exenatide
EXSCEL
Study Design
Key Results
N=14,752 patients with T2D with or without CVD
By design, ≥70% had CVD (n=10,782; 73.1%)
Randomization
Exenatide: n=7356
Placebo: n=7396
Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the primary endpoint HR
Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke
Secondary endpoints: all-cause death, CV death, nonfatal or fatal MI, nonfatal or fatal stroke, and hospitalization for acute coronary syndrome or HF
Median follow-up: 3.2 years
Difference from placebo at trial end
A1C: −0.53% (95% CI, −0.57% to −0.50%; P<0.001)
Weight: −1.3 kg (95% CI, −1.4 to −1.1 kg; P<0.001)
SBP: −1.6 mm Hg (95% CI, −1.9 to −1.2 mm Hg; P<0.001)
CV outcomes
Primary endpoint: HR 0.91 (95% CI 0.83 to 1.00); P<0.001 for noninferiority, P=0.06 for superiority
No difference between treatment groups in confirmed cases of pancreatitis, pancreatic cancer, or medullary thyroid carcinoma
More cases of thyroid papillary carcinoma in exenatide (n=10) than placebo group (n=4)
CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Holman RR, et al. N Engl J Med Sept 14 [Epub before print].

43. Clinical Outcomes with Exenatide
EXSCEL
(N=14,752)
Median follow-up: 3.2 years
Hazard ratio (95% CI)
P value†
Primary composite endpoint*
0.91 ( )
0.06
Death from any cause
0.86 ( ) NS
CV death
0.88 ( )
Fatal or nonfatal MI
0.97 ( )
Fatal MI
1.29 ( )
Fatal or nonfatal stroke
0.85 ( )
Fatal stroke
0.71 ( )
Hospitalization for HF
0.94 ( )
Hospitalization for ACS
1.05 ( )
Favors exenatide
*CV death, nonfatal MI, or nonfatal stroke. †For superiority.
ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; MI, myocardial infarction; NS, not statistically significant based on hierarchical testing plan.
Holman RR, et al. N Engl J Med Sept 14 [Epub before print].

44. Clinical Outcomes with Exenatide
EXSCEL
(N=14,752)
Holman RR, et al. N Engl J Med Sept 14 [Epub before print].

45. Clinical Outcomes with Exenatide
EXSCEL
Serious Adverse Events and Events of Special Interest
Event
Exenatide (%)
(n=7344)
Placebo (%)
(n=7372)
Any serious AE
16.8
16.6
Serious adverse treatment-related event
0.8
0.5
Serious AE leading to study withdrawal
1.5
1.4
Events of Clinical Interest
Adjudicated pancreatitis
0.4
0.3
Severe pancreatitis
<0.1
Adjudicated cancer (any)
4.8
4.9
Adjudicated medullary thyroid carcinoma
Adjudicated pancreatic cancer
0.2
Severe hypoglycemia
3.4
3.0
Event rate
1.6 per 100 pt-years
1.8 per 100 pt-years
AE, adverse event.
Holman RR, et al. N Engl J Med Sept 14 [Epub before print].

46. Clinical Outcomes with Antihyperglycemic Agents
Sustain 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes)

47. Clinical Outcomes with Semaglutide
SUSTAIN 6 Study Design
N=3297 patients with T2D with CVD, CHF, CKD, or age ≥60 with ≥1 CV risk factor
Randomization
Semaglutide: n=1648
Placebo: n=1649
Noninferiority study: prespecified margin <1.8 for upper bound of 95% CI of the HR for the primary endpoint
Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke
Key secondary endpoints
Composite of CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF
Composite of all-cause death, nonfatal MI, nonfatal stroke
Retinopathy complications
New or worsening nephropathy
CI, confidence interval; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes.
Marso SP, et al. N Engl J Med. 2016:375:

48. Clinical Outcomes with Semaglutide
SUSTAIN 6 Results
(N=3297)
Median follow-up: 2.1 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
0.74 ( )
0.02
Expanded composite endpoint†
0.88 ( )
0.002
All-cause death, nonfatal MI, nonfatal stroke
0.77 ( )
0.03
Death from any cause
1.05 ( )
0.79
CV death
0.98 ( )
0.92
Nonfatal MI
0.74 ( )
0.12
Nonfatal stroke
0.61 ( )
0.04
Revascularization
0.65 ( )
0.003
Retinopathy complications
1.76 ( )
New or worsening nephropathy
0.64 ( )
0.005
Favors semaglutide
*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF.
CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction.
Marso SP, et al. N Engl J Med. 2016:375:

49. Clinical Outcomes with Semaglutide
SUSTAIN 6 Selected Adverse Events
Event
Semaglutide 1 mg (%)
(n=822)
Placebo 1 mg (%)
(n=825)
Any adverse event
89.1
89.2
Serious adverse event
33.6
36.1
Gastrointestinal disorder
52.3
35.2
Diarrhea
18.4
10.5
Nausea
21.9
8.1
Vomiting
14.8
4.1
Acute pancreatitis
0.4
1.1
Gallbladder disorder
3.2
2.8
Cholelithiasis
2.1
1.5
Acute cholecystitis
0.2
Severe or symptomatic hypoglycemia
21.7
21.0
Injection site reaction
0.7
0.3
Neoplasm (any)
10.8
8.4
Any malignant
4.9
4.2
Malignant pancreatic
0.1
Marso SP, et al. N Engl J Med. 2016:375:

50. Clinical Outcomes with Antihyperglycemic Agents
Devote (Trial comparing cardiovascular safety of insulin degludec with insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events)

51. Clinical Outcomes with Insulin Degludec
DEVOTE Study Design
N=7637 patients with T2D at high risk of CV events
Age ≥50 years with with CVD or renal disease
Age ≥60 years with ≥1 CV risk factor
Randomization
Degludec: n=3818
Glargine: n=3819
Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the HR for the primary endpoint; superiority tested if noninferiority criterion met
Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke
Key secondary endpoints
Adjudicated severe hypoglycemia
Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina
All-cause death
CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin Degludec With Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events; HR, hazard ratio; MI, myocardial infarction.
Marso SP, et al. N Engl J Med. 2017;377:

52. Clinical Outcomes with Insulin Degludec and Glargine
DEVOTE CV Outcomes
(N=7637)
Median follow-up: 1.99 years
Hazard ratio (95% CI)
P value
Primary composite endpoint*
0.91 ( )
<0.001 (NI)†
Expanded composite endpoint‡
0.92 ( )
0.22
All-cause death
0.91 ( )
0.35
Noncardiovascular death
0.84 ( )
0.28
CV death
0.96 ( )
0.71
CV death excluding undetermined cause of death
0.91 ( )
0.52
Nonfatal MI
0.85 ( )
0.15
Nonfatal stroke
0.90 ( )
0.50
Unstable angina hospitalization
0.95 ( )
0.74
*CV death, nonfatal MI, or nonfatal stroke; †Confirmed noninferiority; superiority, P=0.21. ‡CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina.
CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; NI, noninferiority.
Marso SP, et al. N Engl J Med. 2017;377:
Favors degludec
Favors glargine

53. Clinical Outcomes with Insulin Degludec and Glargine
DEVOTE Safety Outcomes
(N=7637)
Median follow-up: 1.99 years
Hazard ratio (95% CI)
P value
Severe hypoglycemia*
0.60 ( )
<0.001†
Unconsciousness or coma
0.81 ( )
0.28
Seizure
1.02 ( )
0.97
Nocturnal severe hypoglycemia
0.47 ( )
<0.001
≥1 severe hypoglycemia event
0.73 ( )
Favors degludec
Favors glargine
*Episode requiring assistance from another person to actively administer carbohydrate or glucagon or take other corrective actions.
CI, confidence interval.
Marso SP, et al. N Engl J Med. 2017;377:

54. Clinical Outcomes with Insulin Degludec and Glargine
DEVOTE Selected Adverse Events
Event
Degludec (%)
(n=3818)
Glargine (%)
(n=3819)
Any adverse event
39.0
40.0
Any serious adverse event
38.6
39.7
Any serious adverse event except severe hypoglycemia
38.0
Events leading to permanent discontinuation
5.2
5.8
Externally classified neoplasms
3.2
3.0
Malignant
2.4
2.6
Benign
0.7
0.5
Unclassifiable
0.1
Marso SP, et al. N Engl J Med. 2017;377: