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

Transcription

1 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

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

3 SAVOR- TIMI 53 n = 16, P MACE EXAMINE n = 5,38 3- P MACE TECOS n = 14, P MACE CARMELINA n = 8,3 3- P MACE, renal composite CAROLINA n = 6, P MACE EMPA- REG OUTCOME n = 7,2 3- P MACE ELIXA n = 6,68 4- P MACE SUSTAIN- 6 n = 3, P MACE CANVAS n = 4,33 3- P MACE CANVAS- R n = 5,813 Progression of albuminuria EXSCEL n = 14, 3- P MACE VERTIS CV n = 3,9 3- P MACE Dapa- HF n = 4,5 CV death, HF hospitalizaaon, HF urgent visit REWIND n = 9, P MACE CREDENCE n = 4,2 ESRD, doubling of creaanine, renal/cv death DECLARE- TIMI 58 n = 17,15 3- P MACE, CVD Dapa- CKD n = 4, 5% sustained decline in egfr or reaching ESRD or CV death or renal death EMPEROR- Reduced n = 2,85 CV death or HF hospitalizaaon DPP- 4 inhibitors SGLT2 inhibitors LEADER n = 9,34 3- P MACE FREEDOM- CVO n = 4, 4- P MACE HARMONY n = 9,4 3- P MACE EMPEROR- Preserved n = 4,126 CV death or HF hospitalizaaon GLP- 1 receptor agonists Insulin TZD Acarbose DEVOTE n = 7, P MACE TOSCA.IT n = 3, P MACE ACE n = 6, P MACE (3- P MACE plus hospitalizaaon for HF or unstable angina)

4 Completed Trials ORIGIN Insulin Glargine SAVOR- TIMI SaxaglipAn EXAMINE AloglipAn TECOS SitaglipAn ELIXA LixisenaAde EMPA- REG OUTCOME Empagliflozin LEADER LiragluAde SUSTAIN- 6 SemagluAde CANVAS & CANVAS- R Canagliflozin DEVOTE Insulin Degludec EXSCEL & FREEDOM- CVD ExenaAde [forthcoming]

5 DPP4s

6 SAVOR TIMI 53 Cumulative Percent of Time to First Cardiovascular Event for Primary Composite Endpoint Saxagliptin: 613 (7.4%)* Rate/1 PY 3.76 Percentage (%) HR 1. (95% CI:.89, 1.12) p.1 (NI) p=.99 (superiority) Saxagliptin : 69 (7.4%)* Rate/1 PY Number of Patients at Risk Days from Randomization All SAXA Scirica BM et al. N Engl J Med :

7 SAVOR-TIMI 53: All-Cause Mortality Kaplan-Meier Percentage (%) HR 1.11 (95% CI:.96, 1.27) p=.15 Saxagliptin 42 (KM 2yr rate 4.9%) 378 (KM 2yr rate 4.2%) Number of Patients at Risk Saxagliptin Days from Randomization Scirica BM et al. N Engl J Med :

8 EXAMINE Primary End Point Standard MACE Cumulative Incidence of Primary End-Point Events (%) No. at Risk Alogliptin HR,.96 (upper boundary of the one-sided repeated CI, 1.16) p = Months from Randomization Alogliptin White WB et al. N Engl J Med :

9 EXAMINE Secondary End Point CVD Death Cumulative Incidence of Death From Cardiovascular Causes (%) HR,.85 (95% CI, ) p =.21 Alogliptin Months from Randomization No. at Risk Alogliptin White WB et al. N Engl J Med :

10 EXAMINE Secondary End Point Death from Any Cause Cumulative Incidence of Death From Any Cause (%) HR,.85 (95% CI, ) p =.23 Alogliptin Months from Randomization No. at Risk Alogliptin White WB et al. N Engl J Med :

11 TECOS Primary End Point MACE + Hospitalization for Unstable Angina Patients with Event (%) 15 1 No. at Risk Sitagliptin HR,.98 (95% CI, ) p = Months from Randomization Sitagliptin Green JB et al. N Engl J Med 215;373:

12 Patients with Event (%) No. at Risk Sitagliptin TECOS Secondary End Point Standard MACE HR,.99 (95% CI, ) p = Months from Randomization Sitagliptin Green JB et al. N Engl J Med 215;373:

13 TECOS Death From Any Cause Patients with Event (%) No. at Risk Sitagliptin HR, 1.1 (95% CI, ) p = Months from Randomization Sitagliptin Green JB et al. N Engl J Med 215;373:

14 DPP4s and Heart Failure

15 SAVOR-TIMI 53 Hospitalization for Heart Failure Kaplan-Meier Percentage (%) HR 1.27 (95% CI: 1.7, 1.51) p= Days from Randomization Saxagliptin n=289 n=228 KM 2yr rate 3.5 KM 2yr rate 2.8% 9 Scirica BM et al. Circulation :

16 TECOS Hospitalization for Heart Failure Patients with Event (%) No. at Risk Sitagliptin HR, 1. (95% CI, ) p = Months from Randomization Sitagliptin Green JB et al. N Engl J Med 215;373:

17 Combining Evidence from 3 Related Trials (saxagliptin) (alogliptin) (sitagliptin)

18 GLP- 1 RAs

19 ELIXA Primary Outcome MACE plus Hospitalization for Unstable Angina 2 HR = 1.1 (95 % CI, ) p = Percent 1 5 Lixisenatide: 46/334 = 13.4% : 399/334 = 13.2% Number at Risk 334 Lixisenatide Months from Randomization Pfeffer MA et al. N Engl J Med 215;373:

20 ELIXA CV Mortality 15 HR =.98 (95% CI, ) p =.85 Percent Lixisenatide: 156/334 = 5.1% : 158/334 = 5.2% Months from Randomization Pfeffer MA et al. N Engl J Med 215;373:

21 ELIXA Death from Any Cause 2 HR =.94 (95% CI, ) p =.5 15 Percent Lixisenatide: 211/334 = 7.% : 223/334 = 7.4% Months from Randomization Pfeffer MA et al. N Engl J Med 215;373:

22 LEADER: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke Patients with Event (%) HR,.87 (95% CI, ) p<.1 for non-inferiority p=.1 for superiority Liraglutide Patients at risk Liraglutide Time from Randomization (Months) Marso S et al. NEJM 216; 375:

23 LEADER: CV Death Patients with Event (%) HR:.78 (95% CI, ) p<.7 Liraglutide Patients at risk Liraglutide Time from Randomization (Months) Marso S et al. NEJM 216; 375:

24 LEADER: Expanded MACE CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure Patients with Event (%) HR:.88 (95% CI, ) p<.5 Liraglutide Patients at risk Liraglutide Time from Randomization (Months) Marso S et al. NEJM 216; 375:

25 LEADER: Death from Any Cause Patients with Event (%) HR:.85 (95% CI, ) p=.2 Liraglutide Patients at risk Liraglutide Time from Randomization (Months) Marso S et al. NEJM 216; 375:

26 SUSTAIN-6: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke Subjects with an event (%) HR,.74 (95% CI,.58;.95) Events: 18 semaglutide; 146 placebo p<.1 for non-inferiority p=.2 for superiority, 8.9% Semaglutide, 6.6% Number of subjects at risk Time since Randomization (weeks) Semaglutide Marso SP et al. N Engl J Med :

27 SUSTAIN-6: CV Death 5 Patients with an event (%) HR,.98 (95% CI,.65; 1.48) Events: 44 semaglutide; 46 placebo p=.92, 2.8% Semaglutide, 2.7% Time since Randomization (weeks) Number of subjects at risk Semaglutide Marso SP et al. N Engl J Med :

28 SUSTAIN-6 Death from Any Cause Subjects with an Event (%) HR, 1.5 (95% CI, ) Events: 62 semaglutide; 6 placebo p= Time since Randomization (weeks) 3.8% Semaglutide 3.6% Number of subjects at risk Semaglutide Marso SP et al. N Engl J Med :

29 SUSTAIN-6 Diabetic Retinopathy 29 Patients with an event (%) HR, 1.76 (95% CI, 1.11; 2.78) Events: 5 semaglutide; 29 placebo P=.2 Semaglutide, 3.%, 1.8% Weeks since randomisation Number of patients at risk Semaglutide Marso SP et al. N Engl J Med :

30 SGLT2s

31 EMPA-REG Outcome Primary Outcome 3-point MACE Patients with Event (%) Patients at Risk Empagliflozin HR,.86 (95% CI, ) p=.382* Time from Randomization (Months) Empagliflozin Zinman B et al. N Engl J Med 215; 373:

32 Patients with Event (%) Patients at Risk Empagliflozin EMPA-REG Outcome CV death HR,.62 (95% CI, ) p= Time from Randomization (Months) Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 215; 373: Empagliflozin

33 Patients with Event (%) Patients at Risk Empagliflozin EMPA-REG Outcome Hospitalization for Heart Failure HR,.65 (95% CI,.5-.85) p= Time from Randomization (Months) Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 215; 373: Empagliflozin

34 EMPA-REG Outcome Death from Any Cause Patients with Event (%) HR,.68 (95% CI, ) p=.1 Empagliflozin Patients at risk Empagliflozin Kaplan-Meier estimate. HR, hazard ratio Time from Randomization (Months) Zinman B et al. N Engl J Med 215; 373:

35 CANVAS: Primary Outcome CV death, non- fatal myocardial infarcaon, or non- fatal stroke

36 CANVAS CV Death

37 CANVAS All Cause Mortality

38 CANVAS HospitalizaAon for Heart Failure

39 CANVAS Lower Extremity AmputaAons

40 CANVAS Level of AmputaAon

41 CANVAS Benefits and Risks

42 Insulins

43 ORIGIN: 1st Co- primary endpoint: MI, stroke, or CV death Proportion with event Nb at risk: Glargine Standard Care Adj. HR 1.2 (.94, 1.11) log Rank p =.63 (NS) Years of follow-up Glargine Standard Care N Engl J Med 212;367:

44 ORIGIN: 2nd Co- primary endpoint: MI, stroke, CV death, revascularizaaon, or heart failure Proportion with event Adj. HR 1.4 (.97, 1.11) log Rank p =.27 (NS) Glargine Standard Care. Nb at risk: Glargine Standard Care Years of follow-up N Engl J Med 212;367:

45 DEVOTE: Primary Outcome CV death, non- fatal myocardial infarcaon, or non- fatal stroke Patients with an event (%) HR,.91 (95% CI,.78; 1.6) Events: 325 degludec; 356 glargine Non- inferiority p<.1 Rate: 4.71/1 PYO Rate: 4.29/1 PYO IGlar U1 Insulin degludec 356 patients 325 patients Time to first EAC-confirmed event (months) Insulin degludec (N) IGlar U1 (N) Marso SP et al. N Engl J Med 217. On-Line June 12

46 DEVOTE: Mean HbA1c Insulin degludec IGlar U1. Observed mean change from baseline at month 24 Insulin degludec IGlar U1 HbA1c (%) % ET 3 Months since randomization Insulin degludec (N) IGlar U1 (N) Post hoc ETD:.1% [-.5;.7] 95% CI Full analysis set CI, confidence interval; ET, end treatment visit; ETD, estimated treatment difference Marso SP et al. N Engl J Med 217. On-Line June 12

47 DEVOTE: FasAng Plasma Glucose Insulin degludec IGlar U Observed mean change from baseline at month 24 Insulin degludec IGlar U1. FPG (mg/dl) ET 36 Months since randomization Insulin degludec (N) IGlar U1 (N) FPG (mmol/l) mg/dl mg/dl -2.2 mmol/l mg/dl -1.9 mmol/l Post hoc ETD: -7.2 mg/dl [-1.3; -4.1] 95% CI -.4 mmol/l [-.6; -.2] 95% CI mmol/l Full analysis set FPG, fasting plasma glucose Marso SP et al. N Engl J Med 217. On-Line June 12

48 DEVOTE Rates of Severe Hypoglycemia Mean number of events/1 PYO Rate ratio:.6 [.48;.76] 95% CI p<.1 IGlar U1 Insulin degludec Time from randomization (months) Insulin degludec (N=3818) IGlar U1 (N=3819) E R E R EAC-confirmed episodes Full analysis set; Mean number of confirmed severe hypoglycemic episodes. The number of events is analyzed using a negative binomial regression model using a log link and the logarithm of the observation time (1 years) as offset E, number of events; R, events per 1 patient-years of observation; PYO, patient-years of observation Marso SP et al. N Engl J Med 217. On-Line June 12

49 DEVOTE Rates of Nocturnal Severe Hypoglycemia Mean number of events/1 PYO Rate ratio:.47 [.31;.73] 95% CI p<.1 IGlar U1 Insulin degludec Time from randomization (months) EAC-confirmed episodes Insulin degludec (N=3818) IGlar U1 (N=3819) N % E R N % E R Full analysis set; Nocturnal hypoglycemia: EAC-confirmed severe hypoglycemic episode with an investigator-reported onset between :1 and 5:59. Mean number of nocturnal EAC-confirmed severe hypoglycemic episodes. The number of events is analyzed using a negative binomial regression model using a log link and the logarithm of the observation time (1 years) as offset Marso SP et al. N Engl J Med 217. On-Line June 12

50 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 addiaons to our knowledge base

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