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
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.
SAVOR- TIMI 53 n = 16,492 3- P MACE EXAMINE n = 5,38 3- P MACE TECOS n = 14,671 4- P MACE CARMELINA n = 8,3 3- P MACE, renal composite CAROLINA n = 6,115 3- P MACE 213 215 216 217 218 219 22 EMPA- REG OUTCOME n = 7,2 3- P MACE ELIXA n = 6,68 4- P MACE SUSTAIN- 6 n = 3,297 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 = 9,622 3- 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 = 7,637 3- P MACE TOSCA.IT n = 3,371 4- P MACE ACE n = 6,526 5- P MACE (3- P MACE plus hospitalizaaon for HF or unstable angina)
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]
DPP4s
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 (%) 1 8 6 4 HR 1. (95% CI:.89, 1.12) p.1 (NI) p=.99 (superiority) Saxagliptin : 69 (7.4%)* Rate/1 PY 3.77 2 Number of Patients at Risk 18 36 54 72 9 18 Days from Randomization All SAXA 828 871 7836 7313 492 847 8212 7983 7761 7267 4855 851 Scirica BM et al. N Engl J Med 213. 369:1317-1326
SAVOR-TIMI 53: All-Cause Mortality Kaplan-Meier Percentage (%) 2 16 12 8 4 HR 1.11 (95% CI:.96, 1.27) p=.15 Saxagliptin 42 (KM 2yr rate 4.9%) 378 (KM 2yr rate 4.2%) 18 36 54 72 9 Number of Patients at Risk Saxagliptin 828 8212 Days from Randomization 8182 87 7636 5181 96 8134 832 7615 5152 92 Scirica BM et al. N Engl J Med 213. 369:1317-1326
EXAMINE Primary End Point Standard MACE Cumulative Incidence of Primary End-Point Events (%) No. at Risk Alogliptin 24 18 12 6 2679 271 HR,.96 (upper boundary of the one-sided repeated CI, 1.16) p =.32 6 12 18 24 3 2299 2316 Months from Randomization 1891 1899 1375 1394 85 821 Alogliptin 286 296 White WB et al. N Engl J Med 213. 369:1327-1335
EXAMINE Secondary End Point CVD Death Cumulative Incidence of Death From Cardiovascular Causes (%) 24 18 12 6 HR,.85 (95% CI,.66-1.1) p =.21 Alogliptin 6 12 18 24 3 Months from Randomization No. at Risk Alogliptin 2679 271 2384 242 1996 223 1477 154 889 894 324 32 White WB et al. N Engl J Med 213. 369:1327-1335
EXAMINE Secondary End Point Death from Any Cause Cumulative Incidence of Death From Any Cause (%) 24 18 12 6 HR,.85 (95% CI,.71-1.9) p =.23 Alogliptin 6 12 18 24 3 Months from Randomization No. at Risk Alogliptin 2679 271 2284 241 1996 223 1477 154 889 894 324 32 White WB et al. N Engl J Med 213. 369:1327-1335
TECOS Primary End Point MACE + Hospitalization for Unstable Angina Patients with Event (%) 15 1 No. at Risk Sitagliptin 5 4 8 12 18 24 3 36 42 48 7332 7339 HR,.98 (95% CI,.89-1.8) p =.65 7131 7146 6937 692 6777 6751 Months from Randomization 6579 6512 6386 6292 4525 4411 3346 3272 258 234 Sitagliptin 1248 1234 Green JB et al. N Engl J Med 215;373:232-242
Patients with Event (%) 12.5 1. 7.5 5. 2.5. No. at Risk Sitagliptin 7332 7339 TECOS Secondary End Point Standard MACE HR,.99 (95% CI,.89-1.1) p =.84 4 8 12 18 24 3 36 42 48 7145 7161 6969 6939 6817 6796 6638 6573 Months from Randomization 6386 6359 4584 4472 3396 3332 297 27 Sitagliptin 127 126 Green JB et al. N Engl J Med 215;373:232-242
TECOS Death From Any Cause Patients with Event (%) 1 8 6 4 2 No. at Risk Sitagliptin 7332 7339 HR, 1.1 (95% CI,.9-1.14) p =.88 4 8 12 18 24 3 36 42 48 7162 7271 718 7176 713 798 71 6982 Months from Randomization 694 6864 4964 4891 3739 3673 2321 2293 Sitagliptin 1435 1412 Green JB et al. N Engl J Med 215;373:232-242
DPP4s and Heart Failure
SAVOR-TIMI 53 Hospitalization for Heart Failure Kaplan-Meier Percentage (%) 2 16 12 8 4 HR 1.27 (95% CI: 1.7, 1.51) p=.7 18 36 54 72 Days from Randomization Saxagliptin n=289 n=228 KM 2yr rate 3.5 KM 2yr rate 2.8% 9 Scirica BM et al. Circulation 214. 13:1579-1588
TECOS Hospitalization for Heart Failure Patients with Event (%) No. at Risk Sitagliptin 5 4 3 2 1 4 8 12 18 24 3 36 42 48 7332 7339 HR, 1. (95% CI,.83-1.2) p =.98 7189 724 736 725 6917 693 678 6712 6619 6549 Months from Randomization 4728 459 3515 3443 Sitagliptin 2175 2131 1324 1315 Green JB et al. N Engl J Med 215;373:232-242
Combining Evidence from 3 Related Trials (saxagliptin) (alogliptin) (sitagliptin)
GLP- 1 RAs
ELIXA Primary Outcome MACE plus Hospitalization for Unstable Angina 2 HR = 1.1 (95 % CI,.89-1.17) p =.81 15 Percent 1 5 Lixisenatide: 46/334 = 13.4% : 399/334 = 13.2% Number at Risk 334 Lixisenatide 334 12 Months from Randomization 2759 1566 2785 1558 24 36 476 484 Pfeffer MA et al. N Engl J Med 215;373:2247-2257
ELIXA CV Mortality 15 HR =.98 (95% CI,.78-1.22) p =.85 Percent 1 5 12 Lixisenatide: 156/334 = 5.1% : 158/334 = 5.2% 24 36 Months from Randomization Pfeffer MA et al. N Engl J Med 215;373:2247-2257
ELIXA Death from Any Cause 2 HR =.94 (95% CI,.78-1.13) p =.5 15 Percent 1 5 12 Lixisenatide: 211/334 = 7.% : 223/334 = 7.4% 24 36 Months from Randomization Pfeffer MA et al. N Engl J Med 215;373:2247-2257
LEADER: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke Patients with Event (%) 2 15 1 5 HR,.87 (95% CI,.78-.97) p<.1 for non-inferiority p=.1 for superiority Liraglutide Patients at risk Liraglutide 4668 4672 6 12 18 24 3 36 42 48 4593 4588 4696 4473 Time from Randomization (Months) 44 4352 428 4237 4172 4123 472 41 3982 3914 1562 1543 54 424 47 Marso S et al. NEJM 216; 375:311-322
LEADER: CV Death Patients with Event (%) 8 6 4 2 HR:.78 (95% CI,.66-.93) p<.7 Liraglutide Patients at risk Liraglutide 4668 4672 6 12 18 24 3 36 42 48 4641 4648 4599 461 Time from Randomization (Months) 4558 4546 455 4479 4445 447 4382 4338 4322 4267 1723 179 54 484 465 Marso S et al. NEJM 216; 375:311-322
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 (%) 25 2 15 1 5 HR:.88 (95% CI,.81-.96) p<.5 Liraglutide Patients at risk Liraglutide 4668 4672 6 12 18 24 3 36 42 48 4515 456 4356 4336 Time from Randomization (Months) 4221 4157 463 42 3914 3857 3793 3697 3682 3581 1452 141 54 395 366 Marso S et al. NEJM 216; 375:311-322
LEADER: Death from Any Cause Patients with Event (%) 2 15 1 5 HR:.85 (95% CI,.74-.97) p=.2 Liraglutide Patients at risk Liraglutide 4668 4672 6 12 18 24 3 36 42 48 4641 4648 4599 461 Time from Randomization (Months) 4558 4546 455 4479 4445 447 4382 4338 4322 4268 1723 179 54 484 465 Marso S et al. NEJM 216; 375:311-322
SUSTAIN-6: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke Subjects with an event (%) 15 1 5 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% 8 16 24 32 4 48 56 64 72 8 88 96 14 19 Number of subjects at risk Time since Randomization (weeks) Semaglutide 1648 1619 161 1584 1568 1543 1524 1513 1649 1616 1586 1567 1534 158 1479 1466 Marso SP et al. N Engl J Med 216. 375: 1834-44
SUSTAIN-6: CV Death 5 Patients with an event (%) 4 3 2 1 HR,.98 (95% CI,.65; 1.48) Events: 44 semaglutide; 46 placebo p=.92, 2.8% Semaglutide, 2.7% 8 16 24 32 4 48 56 64 72 8 88 96 14 19 Time since Randomization (weeks) Number of subjects at risk Semaglutide 1648 1634 1627 1617 167 1589 1579 1572 1649 1637 1623 1617 16 1584 1566 1558 Marso SP et al. N Engl J Med 216. 375: 1834-44
SUSTAIN-6 Death from Any Cause Subjects with an Event (%) 5 4 3 2 1 HR, 1.5 (95% CI,.74-1.5) Events: 62 semaglutide; 6 placebo p=.79 8 16 24 32 4 48 56 64 72 Time since Randomization (weeks) 3.8% Semaglutide 3.6% 8 88 96 14 Number of subjects at risk Semaglutide 1648 1649 1634 1637 1627 1623 1617 1617 167 16 1589 1584 1579 1566 1572 1558 Marso SP et al. N Engl J Med 216. 375: 1834-44
SUSTAIN-6 Diabetic Retinopathy 29 Patients with an event (%) 8 6 4 2 HR, 1.76 (95% CI, 1.11; 2.78) Events: 5 semaglutide; 29 placebo P=.2 Semaglutide, 3.%, 1.8% 8 16 24 32 4 48 56 64 72 8 88 96 14 19 Weeks since randomisation Number of patients at risk Semaglutide 1648 1622 1612 1595 157 1548 1535 1525 1649 1636 1617 165 1576 1558 1539 153 Marso SP et al. N Engl J Med 216. 375: 1834-44
SGLT2s
EMPA-REG Outcome Primary Outcome 3-point MACE Patients with Event (%) 2 15 1 5 Patients at Risk Empagliflozin 4687 2333 HR,.86 (95% CI,.74-.99) p=.382* 6 12 18 24 3 36 42 48 458 2256 4455 2194 Time from Randomization (Months) 4328 2112 3851 1875 2821 138 2359 1161 1534 741 Empagliflozin 37 166 Zinman B et al. N Engl J Med 215; 373:2117-2128
Patients with Event (%) 9 8 7 6 5 4 3 2 1 Patients at Risk Empagliflozin 4687 2333 EMPA-REG Outcome CV death HR,.62 (95% CI,.49-.77) p=.1 6 12 18 24 3 36 42 48 4651 233 468 228 Time from Randomization (Months) 4556 2243 4128 212 Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 215; 373:2117-2128 379 153 2617 1281 1722 825 Empagliflozin 416 177
Patients with Event (%) 7 6 5 4 3 2 1 Patients at Risk Empagliflozin 4687 2333 EMPA-REG Outcome Hospitalization for Heart Failure HR,.65 (95% CI,.5-.85) p=.17 6 12 18 24 3 36 42 48 4614 2271 4523 2226 Time from Randomization (Months) 4427 2173 3988 1932 Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 215; 373:2117-2128 295 1424 2487 122 1634 775 Empagliflozin 395 168
EMPA-REG Outcome Death from Any Cause Patients with Event (%) 2 15 1 5 HR,.68 (95% CI,.57-.82) p=.1 Empagliflozin Patients at risk Empagliflozin 4687 2333 6 12 18 24 3 36 42 48 4651 233 468 228 Kaplan-Meier estimate. HR, hazard ratio Time from Randomization (Months) 4556 2243 4128 212 379 153 2617 1281 1722 825 414 177 Zinman B et al. N Engl J Med 215; 373:2117-2128
CANVAS: Primary Outcome CV death, non- fatal myocardial infarcaon, or non- fatal stroke
CANVAS CV Death
CANVAS All Cause Mortality
CANVAS HospitalizaAon for Heart Failure
CANVAS Lower Extremity AmputaAons
CANVAS Level of AmputaAon
CANVAS Benefits and Risks
Insulins
ORIGIN: 1st Co- primary endpoint: MI, stroke, or CV death Proportion with event.5.4.3.2.1. Nb at risk: Glargine Standard Care 6264 6273 Adj. HR 1.2 (.94, 1.11) log Rank p =.63 (NS) 1 657 643 2 585 5847 3 4 5 Years of follow-up 5619 5632 5379 5415 5151 5156 Glargine Standard Care 6 3611 3639 7 766 8 N Engl J Med 212;367:319-328
ORIGIN: 2nd Co- primary endpoint: MI, stroke, CV death, revascularizaaon, or heart failure Proportion with event.5.4.3.2.1 Adj. HR 1.4 (.97, 1.11) log Rank p =.27 (NS) Glargine Standard Care. Nb at risk: Glargine Standard Care 6264 6273 1 5827 5833 2 5474 5493 3 4 5 Years of follow-up 5153 5186 4835 488 4523 4555 6 376 3142 7 631 663 N Engl J Med 212;367:319-328
DEVOTE: Primary Outcome CV death, non- fatal myocardial infarcaon, or non- fatal stroke Patients with an event (%) 12 1 8 6 4 2 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 3 6 9 12 15 18 21 24 27 3 Time to first EAC-confirmed event (months) Insulin degludec (N) 3818 3765 3721 3699 3611 3563 354 2851 1767 811 217 IGlar U1 (N) 3819 3758 373 3655 3595 353 3472 2832 1742 811 25 Marso SP et al. N Engl J Med 217. On-Line June 12
DEVOTE: Mean HbA1c 9. 8.5 Insulin degludec IGlar U1. Observed mean change from baseline at month 24 Insulin degludec IGlar U1 HbA1c (%) 8. 7.5 % -.5 7. 6.5 3 6 9 12 15 18 21 24 27 ET 3 Months since randomization Insulin degludec (N) 3774 3656 368 3535 3525 2458 3344 IGlar U1 (N) 3776 364 3562 3516 35 2424 3277-1. -.86 -.84 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
DEVOTE: FasAng Plasma Glucose 18 171 162 Insulin degludec IGlar U1 1. 9.5 9. Observed mean change from baseline at month 24 Insulin degludec IGlar U1. FPG (mg/dl) 153 144 135 126 117 18 12 24 ET 36 Months since randomization Insulin degludec (N) 3757 3521 2457 3345 IGlar U1 (N) 376 3498 2425 3277 8.5 8. 7.5 7. 6.5 FPG (mmol/l) mg/dl -1-2 -3-4 -39.9 mg/dl -2.2 mmol/l -34.9 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 -.5-1. -1.5-2. -2.5 mmol/l Full analysis set FPG, fasting plasma glucose Marso SP et al. N Engl J Med 217. On-Line June 12
DEVOTE Rates of Severe Hypoglycemia Mean number of events/1 PYO 16 12 8 4 Rate ratio:.6 [.48;.76] 95% CI p<.1 IGlar U1 Insulin degludec 3 6 9 12 15 18 21 Time from randomization (months) 24 27 3 Insulin degludec (N=3818) IGlar U1 (N=3819) E R E R EAC-confirmed episodes 28 3.7 472 6.25 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
DEVOTE Rates of Nocturnal Severe Hypoglycemia Mean number of events/1 PYO 5 4 3 2 1 Rate ratio:.47 [.31;.73] 95% CI p<.1 IGlar U1 Insulin degludec 3 6 9 12 15 18 21 24 27 3 Time from randomization (months) EAC-confirmed episodes Insulin degludec (N=3818) IGlar U1 (N=3819) N % E R N % E R 37 1. 48.64 73 1.9 16 1.39 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
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