Update on Diabetes Cardiovascular Outcome Trials

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1 Update on Diabetes Cardiovascular Outcome Trials Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism and Diabetes Research Institute University of Miami Miller School of Medicine

2 Disclosures Dualities of Interest: Jay Skyler has acted as an advisor to Adocia, Boehringer-Ingelheim, Dance Biopharm, Elcelyx, Eli Lilly, Ideal Life, Immunomolecular Therapeutics, Intarcia, Intrexon, Merck, Orgenesis, Sanofi, Valeritas, and Viacyte. He has research funding from NIH, JDRF, and DRIF. He chairs the Strategic Advisory Board of the EU INNODIA consortium. He is a member of the board of directors of Dexcom, Intarcia, and Moerae Matrix.

3 SAVOR-TIMI 53 n = 16,492 3-P MACE EXAMINE n = 5,380 3-P MACE TECOS n = 14,671 4-P MACE CARMELINA n = 8,300 3-P MACE, renal composite CAROLINA n = 6,115 3-P MACE EMPA-REG OUTCOME n = 7,020 3-P MACE ELIXA n = 6,068 4-P MACE LEADER n = 9,340 3-P MACE CANVAS Program n = 10,142 3-P MACE FREEDOM-CVO n = 4,000 4-P MACE VERTIS CV n = 8,000 3-P MACE Dapa-HF n = 4,500 CV death, HF hospitalization, HF urgent visit REWIND n = 9,901 3-P MACE CREDENCE n = 4,200 ESRD, doubling of creatinine, renal/cv death DECLARE-TIMI 58 n = 17,150 3-P MACE, CVD Dapa-CKD n = 4,000 50% sustained decline in egfr or reaching ESRD or CV death or renal death EMPEROR- Reduced n = 2,850 CV death or HF hospitalization DPP-4 inhibitors SGLT2 inhibitors GLP-1 receptor agonists Insulin TZD α-glucosidase inhibitor SUSTAIN-6 n = 3,297 3-P MACE DEVOTE n = 7,637 3-P MACE IRIS n = 3,876 Fatal or nonfatal stroke or MI EXSCEL n = 14,752 3-P MACE ACE n = 6,526 5-P MACE (3-P MACE + hospitalization for HF or unstable angina) PIONEER 6 n = 3,176 3-P MACE HARMONY Outcomes n = 9,400 3-P MACE EMPEROR- Preserved n = 4,126 CV death or HF hospitalization

4 Typical Trial Design Screening Randomized Active Drug Both arms receive glucose lowering therapy as per standard of care

5 DPP4s

6 DPP4 CVO Trials: Baseline Population Trial SAVOR Saxagliptin EXAMINE Alogliptin TECOS Sitagliptin N 16,492 5,380 14,671 Main Inclusion Criteria Age > 40 years with history of CVD Age > 18 years ACS event days prior to randomization Age > 50 years with history of CVD % CV disease % Heart Failure % egfr < ml/min/m 2 Mortality rate (events/100 pt-yrs)

7 SAVOR TIMI 53 Cumulative Percent of Time to First Cardiovascular Event for Primary Composite Endpoint Percentage (%) HR 1.00 (95% CI: 0.89, 1.12) p (NI) p=0.99 (superiority) Saxagliptin: 613 (7.4%)* Rate/100 PY 3.76 Saxagliptin : 609 (7.4%)* Rate/100 PY Number of Patients at Risk Days from Randomization All SAXA Scirica BM et al. N Engl J Med :

8 Cumulative Incidence of Primary End-Point Events (%) EXAMINE Primary End Point Standard MACE HR, 0.96 (upper boundary of the one-sided repeated CI, 1.16) p = 0.32 Alogliptin No. at Risk Alogliptin Months from Randomization White WB et al. N Engl J Med :

9 Patients with Event (%) TECOS Primary End Point MACE + Hospitalization for Unstable Angina HR, 0.98 (95% CI, ) p = 0.65 Sitagliptin 5 No. at Risk Sitagliptin Months from Randomization Green JB et al. N Engl J Med 2015;373:

10 Patients with Event (%) TECOS Secondary End Point Standard MACE HR, 0.99 (95% CI, ) p = 0.84 Sitagliptin No. at Risk Sitagliptin Months from Randomization Green JB et al. N Engl J Med 2015;373:

11 DPP4s and Heart Failure

12 Kaplan-Meier Percentage (%) SAVOR-TIMI 53 Hospitalization for Heart Failure HR 1.27 (95% CI: 1.07, 1.51) p=0.007 Saxagliptin n=289 n=228 8 KM 2yr rate KM 2yr rate 2.8% Days from Randomization Scirica BM et al. Circulation :

13 Patients with Event (%) TECOS Hospitalization for Heart Failure HR, 1.00 (95% CI, ) p = 0.98 Sitagliptin 1 No. at Risk Sitagliptin Months from Randomization Green JB et al. N Engl J Med 2015;373:

14 Heart FaIlure from 3 DPP4 Trials (saxagliptin) (alogliptin) (sitagliptin)

15 DPP4s and Pancreatitis or Pancreatic Cancer

16 Pancreatic Cancer

17 Pancreatic Cancer in DPP4 Trials DPP4 SAVOR 5/ /8212 EXAMINE 0/2701 0/2679 TECOS 9/ /7266 TOTAL 14/ /18157

18 Acute Pancreatitis in DPP4 Trials DPP4 SAVOR 17/8280 9/8212 EXAMINE 12/2701 8/2679 TECOS 23/ /7266 TOTAL 52/ /18157 Odds Ratio (95% CI: ) p=0.013

19 GLP-1 RAs

20 Trial GLP-1 RA CVO Trials: Baseline Population ELIXA Lixisenatide LEADER Liraglutide SUSTAIN-6 Semaglutide EXSCEL Exenatide N 6,068 9,340 3,297 14,752 Main Inclusion Criteria Age > 30 years ACS event within 180 days prior to screening Age > 50 years with history of CV event Age > 60 years with > 1 CV risk factor Age > 50 years with history of CVD and/or CKD (83%) Age > 60 years with > 1 CV risk factor (17%) Age >18 years with CV risk factors or primary prevention % CV disease % Heart Failure % egfr < ml/min/m 2 Mortality rate (events/100 pt-yrs)

21 Percent ELIXA Primary Outcome MACE plus Hospitalization for Unstable Angina 20 HR = 1.01 (95 % CI, ) p = Lixisenatide: 406/3034 = 13.4% : 399/3034 = 13.2% Number at Risk Lixisenatide Months from Randomization Pfeffer MA et al. N Engl J Med 2015;373:

22 Patients with Event (%) LEADER: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke HR, 0.87 (95% CI, ) p<0.001 for non-inferiority p=0.01 for superiority Liraglutide 5 Patients at risk Liraglutide Time from Randomization (Months) Marso S et al. NEJM 2016; 375:

23 Patients with Event (%) LEADER: CV Death 8 6 HR: 0.78 (95% CI, ) p< Liraglutide Patients at risk Time from Randomization (Months) Liraglutide Marso S et al. NEJM 2016; 375:

24 Subjects with an event (%) SUSTAIN-6: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke HR, 0.74 (95% CI, 0.58; 0.95) Events: 108 semaglutide; 146 placebo p<0.001 for non-inferiority p=0.02 for superiority, 8.9% 5 Semaglutide, 6.6% Number of subjects at risk Time since Randomization (weeks) Semaglutide Marso SP et al. N Engl J Med :

25 Patients with an event (%) SUSTAIN-6: CV Death HR, 0.98 (95% CI, 0.65; 1.48) Events: 44 semaglutide; 46 placebo p=0.92, 2.8% Semaglutide, 2.7% Number of subjects at risk Time since Randomization (weeks) Semaglutide Marso SP et al. N Engl J Med :

26 Patients with an event (%) SUSTAIN-6: Non-Fatal Myocardial Infarction HR, 0.74 (95% CI, 0.51; 1.08) Events: 47 semaglutide; 64 placebo p=0.12, 3.9% Semaglutide, 2.9% Number of subjects at risk Time since Randomization (weeks) Semaglutide Marso SP et al. N Engl J Med :

27 Patients with an event (%) SUSTAIN-6: Non-Fatal Stroke HR, 0.61 (95% CI, 0.38; 0.99) Events: 27 semaglutide; 44 placebo p=0.04, 2.7% Semaglutide, 1.6% Number of subjects at risk Time since Randomization (weeks) Semaglutide Marso SP et al. N Engl J Med :

28 Patients with an event (%) SUSTAIN-6 Diabetic Retinopathy HR, 1.76 (95% CI, 1.11; 2.78) Events: 50 semaglutide; 29 placebo P= Semaglutide, 3.0%, 1.8% Weeks since randomisation Number of patients at risk Semaglutide Marso SP et al. N Engl J Med :

29 EXSCEL Primary Composite Cardiovascular Outcome Intention-to-Treat Analysis for Non-inferiority & Superiority Patients with an Event (%) HR (95% CI) 0.91 (0.83, 1.00) P value (non-inferiority) <.001 P value (superiority) Years from Randomization Holman RR et al. NEJM 2017; 377:

30 EXSCEL Primary Composite Cardiovascular Outcome Exenatide N=7356 N=7396 Hazard Ratio 95% CI P value MACE 839 (11.4%) 3.7 per 100 pt-yrs 905 (12.2%) 4.0 per 100 pt-yrs , 1.00 <.001 (non-inferiority) (superiority) CV-death Non-fatal MI Non-fatal stroke 229 (3.1%) 455 (6.2%) 155 (2.1%) 258 (3.5%) 470 (6.4%) 177 (2.4%) , , , (homogeneity among components) Exenatide favored favored Holman RR et al. NEJM 2017; 377:

31 Patients with an Event (%) EXSCEL All-Cause Mortality HR (95% CI) 0.86 (0.77, 0.97) P value Years from Randomization Holman RR et al. NEJM 2017; 377:

32 EXSCEL Secondary Endpoints Exenatide N=7356 N=7396 Hazard Ratio 95% CI P value All-cause mortality 507 (6.9%) 584 (7.9%) , CV-death 340 (4.6%) 383 (5.2%) , Fatal or non-fatal MI 483 (6.6%) 493 (6.7%) , Fatal or non-fatal stroke 187 (2.5%) 218 (2.9%) , Hospitalization for ACS 602 (8.2%) 570 (7.7%) , Hospitalization for heart failure 219 (3.0%) 231 (3.1%) , Exenatide favored favored Holman RR et al. NEJM 2017; 377:

33 EXSCEL Large, pragmatic, international trial designed to characterise the effects of once weekly GLP-1 receptor agonist, exenatide, on CVrelated outcomes in patients with T2DM, when added to usual diabetes care Double-blind, placebo-controlled trial randomising participants to exenatide 2 mg once weekly injection or matching placebo Problem: premature study medication discontinuation in 43% of exenatide subjects and 45% of placebo subjects Holman RR et al. NEJM 2017; 377:

34 GLP-1 RAs and Pancreatitis or Pancreatic Cancer

35 Pancreatic Cancer in GLP1 Trials GLP1-RA ELIXA 3/3032 9/3031 LEADER 13/4668 9/4672 SUSTAIN-6 1/1648 4/1649 EXSCEL 15/ /7372 TOTAL 32/ /16724 OR 0.83 (95% CI 0.33, 2.11), p=0.70

36 Acute Pancreatitis in GLP1 Trials GLP1-RA ELIXA 5/3032 8/3031 LEADER 18/ /4672 SUSTAIN-6 9/ /1649 EXSCEL 26/ /7372 TOTAL 58/ /16724 OR 0.90 (95% CI 0.63, 1.28), p=0.54

37 Completed GLP-1 Receptor Agonist Cardiovascular Outcome Trials Key inclusion criteria A 1C, % Median follow-up duration (y) Drug exposure time (y) Primary End point N=6068 (1) ACS within 180 days 30y R Lixisenatide MACE-4 (non-inferiority) N=9340 (2) 50y with CVD/renal dysfunction/hf, or 60y with CV RFs Liraglutide 7.0 R MACE-3 (non-inferiority) SUSTAIN-6 N=3297 (3) 50y with CVD, or 60y with subclinical CVD Semaglutide 7.0 R MACE-3 (non-inferiority) N=14752 Established CVD as well as primary prevention (70/30 split), 18y R Exenatide MACE-3 (non-inferiority for safety/ superiority for efficacy) Median Follow-up Duration (years) Bethel at al. Lancet Diabetes Endocrinol 2018; 6:

38 Meta-analysis: MACE-3 endpoint Bethel at al. Lancet Diabetes Endocrinol 2018; 6:

39 Meta-analysis: All-cause mortality Bethel at al. Lancet Diabetes Endocrinol 2018; 6:

40 Meta-analysis: CV mortality Bethel at al. Lancet Diabetes Endocrinol 2018; 6:

41 Meta-analysis: Other CV outcomes Neutral impact of GLP-1 RA treatment Endpoint HR (95% CI) p-value Fatal and nonfatal myocardial infarction 0.94 (0.86, 1.03) 0.18 Fatal and nonfatal stroke 0.87 (0.75, 1.00) Heart failure hospitalization 0.93 (0.83, 1.04) 0.20 Unstable angina hospitalization 1.09 (0.90, 1.32) 0.39 Bethel at al. Lancet Diabetes Endocrinol 2018; 6:

42 GLP1s: Patients Without Prior CV Events Did Not Benefit Comparison of Patients With and Without Prior CVD LEADER 50 yrs of age with established CVD 60 yrs of age with risk factors for CVD /3831 (14.0) 72/837 (8.6) 629/3767 (16.7) 65/905 (7.2) 0.83 ( ( ) SUSTAIN-6 50 yrs of age with established CVD 60 yrs of age with risk factors for CVD /1353 (5.4) 10/295 (3.4) 137/1382 (9.9) 9/267 (3.4) 0.72 ( ) 1.0 ( ) EXSCEL Prior CV event No Prior CV event /5394 (13.4) 117/1962 (6.0) 786/5388 (14.6) 119/2008 (5.9) 0.9 ( ) 0.99 ( ) Favors Treatment Favors

43 Results of GLP-1 CVOTs are Not Generalizable to the T2D Population Trial Individuals Likely to Have a Diagnosis of T2D Individuals Who Would Meet All Trial Inclusion Criteria % of Individuals with T2D Who meet Trial Criteria ELIXA 23,941,512 1,538, % LEADER 23,941,512 3,063, % SUSTAIN-6 23,941,512 2,815, % EXSCEL 23,941,512 11,347, % Adapted from Wittbrodt ET, et al. Generalizability of GLP-1 RA Cardiovascular Outcomes Trials Enrollment Criteria to the US Type 2 Diabetes Population. Poster presented at the America Diabetes Association 77 th Scientific Sessions; June 9-13, 2017; San Diego, CA.

44 SGLT2s

45 SGLT2 CVO Trials: Baseline Population Trial EMPA-REG OUTCOME Empagliflozin CANVAS PROGRAM Canagliflozin N 7,020 10,172 Main Inclusion Criteria Age > 18 years with history of CVD Age > 30 years with history of CVD Age > 50 years with > 2 CV risk factors % CV disease % Heart Failure % egfr < ml/min/m 2 Mortality rate (events/100 pt-yrs)

46 Patients with Event (%) EMPA-REG Outcome Primary Outcome 3-point MACE HR, 0.86 (95% CI, ) p=0.0382* Empagliflozin Patients at Risk Empagliflozin Time from Randomization (Months) Zinman B et al. N Engl J Med 2015; 373:

47 Patients with Event (%) EMPA-REG Outcome CV death Empagliflozin Patients at Risk HR, 0.62 (95% CI, ) p= Time from Randomization (Months) Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 2015; 373: Empagliflozin

48 Patients with Event (%) EMPA-REG Outcome Hospitalization for Heart Failure Patients at Risk Empagliflozin HR, 0.65 (95% CI, ) p= Time from Randomization (Months) Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 2015; 373: Empagliflozin

49 Patients with Event (%) EMPA-REG Outcome Death from Any Cause HR, 0.68 (95% CI, ) p= Empagliflozin Patients at risk Empagliflozin Kaplan-Meier estimate. HR, hazard ratio Time from Randomization (Months) Zinman B et al. N Engl J Med 2015; 373:

50 CV Death, MI and Stroke Patients with event/analysed Empagliflozin HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) Favors empagliflozin Favors placebo Zinman B et al. N Engl J Med 2015; 373:

51 Fatal and Non-Fatal Stroke Intent-to-treat population Patients with event/analysed Empagliflozin HR (95% CI) p-value 164/ / (0.89, 1.56) Numerical difference largely driven by events occurring >30 days after treatment stop On-treatment analysis* Favors empagliflozin 141/ / (0.78, 1.40) Favors empagliflozin Favors placebo Favors placebo Zinman B et al. N Engl J Med 2015; 373:

52 CANVAS: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke Neal B et al. N Engl J Med 2017; 377:

53 CANVAS CV Death Neal B et al. N Engl J Med 2017; 377:

54 CANVAS All Cause Mortality Neal B et al. N Engl J Med 2017; 377:

55 CANVAS Hospitalization for Heart Failure Neal B et al. N Engl J Med 2017; 377:

56 CANVAS End Point Summary Neal B et al. N Engl J Med 2017; 377:

57 CANVAS Lower Extremity Amputations Neal B et al. N Engl J Med 2017; 377:

58 CANVAS Level of Amputation Neal B et al. N Engl J Med 2017; 377:

59 CANVAS Benefits and Risks

61 Comparison: Size of Trials, # Events No. of Subjects Mean Duration (yrs) No. of Events SAVOR-TIMI EXAMINE TECOS ELIXA EMPA-REG OC LEADER SUSTAIN CANVAS EXSCEL

62 Summary of Major CVOTs in T2DM Lim S, Eckel RH, Koh KK. Atherosclerosis 2018; 272:33-40.

63 Outstanding Questions Head-to-Head studies of different agents Should metformin still be 1 st line therapy in patients with T2D? In patients with T2D with CVD? Modern day UKPDS testing normalization of A1c in newly diagnosed patients? Can we still do placebo-controlled trial in T2D? Do all patients with T2D entering these trials need to be on SGLT2i or GLP1 receptor agonist Class effect or drug specific? Implications are huge as each new agent will require CVOT

64 Take Away Messages CVOTs have demonstrated that most of the tested diabetes drugs do not show increased CV risk Some CVOTs have demonstrated reduced CV risk Some unexpected findings have emerged CVOTs have been valuable additions to our knowledge base

Update on Cardiovascular Outcome Trials in Diabetes Jay S. Skyler, MD, MACP

Update on Cardiovascular Outcome Trials in Diabetes Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism and Diabetes Research InsAtute University of Miami Miller School of Medicine