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
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.
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 2013 2015 2016 2017 2018 2019 2020 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
Typical Trial Design Screening Randomized Active Drug Both arms receive glucose lowering therapy as per standard of care
DPP4s
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 15-90 days prior to randomization Age > 50 years with history of CVD % CV disease 100 100 100 % Heart Failure 13 28 18 % egfr <60 29.4 29.1 22.7 ml/min/m 2 Mortality rate (events/100 pt-yrs) 2.3 4.0 2.5
SAVOR TIMI 53 Cumulative Percent of Time to First Cardiovascular Event for Primary Composite Endpoint Percentage (%) 10 8 6 HR 1.00 (95% CI: 0.89, 1.12) p 0.001 (NI) p=0.99 (superiority) Saxagliptin: 613 (7.4%)* Rate/100 PY 3.76 Saxagliptin : 609 (7.4%)* Rate/100 PY 3.77 4 2 0 0 18 360 540 720 900 1080 Number of Patients at Risk Days from Randomization All SAXA 8280 8071 7836 7313 4920 847 0 8212 7983 7761 7267 4855 851 0 Scirica BM et al. N Engl J Med 2013. 369:1317-1326
Cumulative Incidence of Primary End-Point Events (%) EXAMINE Primary End Point Standard MACE 24 18 12 6 HR, 0.96 (upper boundary of the one-sided repeated CI, 1.16) p = 0.32 Alogliptin No. at Risk Alogliptin 0 2679 2701 0 6 12 18 24 30 2299 2316 Months from Randomization 1891 1899 1375 1394 805 821 286 296 White WB et al. N Engl J Med 2013. 369:1327-1335
Patients with Event (%) TECOS Primary End Point MACE + Hospitalization for Unstable Angina 15 10 HR, 0.98 (95% CI, 0.89-1.08) p = 0.65 Sitagliptin 5 No. at Risk Sitagliptin 0 0 4 8 12 18 24 30 36 42 48 7332 7339 7131 7146 6937 6902 6777 6751 Months from Randomization 6579 6512 6386 6292 4525 4411 3346 3272 2058 2034 1248 1234 Green JB et al. N Engl J Med 2015;373:232-242
Patients with Event (%) TECOS Secondary End Point Standard MACE 12.5 10. 0 7.5 5.0 2.5 HR, 0.99 (95% CI, 0.89-1.10) p = 0.84 Sitagliptin No. at Risk Sitagliptin 0.0 0 4 8 12 18 24 30 36 42 48 7332 7339 7145 7161 6969 6939 6817 6796 6638 6573 Months from Randomization 6386 6359 4584 4472 3396 3332 2097 2070 1270 1260 Green JB et al. N Engl J Med 2015;373:232-242
DPP4s and Heart Failure
Kaplan-Meier Percentage (%) SAVOR-TIMI 53 Hospitalization for Heart Failure 20 16 12 HR 1.27 (95% CI: 1.07, 1.51) p=0.007 Saxagliptin n=289 n=228 8 KM 2yr rate 3.5 4 0 KM 2yr rate 2.8% 0 180 360 540 720 900 Days from Randomization Scirica BM et al. Circulation 2014. 130:1579-1588
Patients with Event (%) TECOS Hospitalization for Heart Failure 5 4 3 2 HR, 1.00 (95% CI, 0.83-1.20) p = 0.98 Sitagliptin 1 No. at Risk Sitagliptin 0 0 4 8 12 18 24 30 36 42 48 7332 7339 7189 7204 7036 7025 6917 6903 Months from Randomization 6780 6712 6619 6549 4728 4590 3515 3443 2175 2131 1324 1315 Green JB et al. N Engl J Med 2015;373:232-242
Heart FaIlure from 3 DPP4 Trials (saxagliptin) (alogliptin) (sitagliptin)
DPP4s and Pancreatitis or Pancreatic Cancer
Pancreatic Cancer 5 12 0.095
Pancreatic Cancer in DPP4 Trials DPP4 SAVOR 5/8280 12/8212 EXAMINE 0/2701 0/2679 TECOS 9/7257 14/7266 TOTAL 14/18238 26/18157
Acute Pancreatitis in DPP4 Trials DPP4 SAVOR 17/8280 9/8212 EXAMINE 12/2701 8/2679 TECOS 23/7257 12/7266 TOTAL 52/18238 29/18157 Odds Ratio 1.786 (95% CI: 1.133-2.816) p=0.013
GLP-1 RAs
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 100 81 72.2 73.1 % Heart Failure 22.4 17.8 23.6 16.2 % egfr <60 23.2 21.7 24.1 18.6 ml/min/m 2 Mortality rate (events/100 pt-yrs) 3.1-3.3 2.1-2.5 3.7-4.8 2.0-2.3
Percent ELIXA Primary Outcome MACE plus Hospitalization for Unstable Angina 20 HR = 1.01 (95 % CI, 0.89-1.17) p = 0.81 15 10 5 Lixisenatide: 406/3034 = 13.4% : 399/3034 = 13.2% Number at Risk Lixisenatide 0 0 12 3034 3034 Months from Randomization 2759 1566 2785 1558 24 36 476 484 Pfeffer MA et al. N Engl J Med 2015;373:2247-2257
Patients with Event (%) LEADER: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke 20 15 10 HR, 0.87 (95% CI, 0.78-0.97) p<0.001 for non-inferiority p=0.01 for superiority Liraglutide 5 Patients at risk Liraglutide 0 0 6 12 18 24 30 36 42 48 4668 4672 4593 4588 4696 4473 Time from Randomization (Months) 4400 4352 4280 4237 4172 4123 4072 4010 3982 3914 1562 1543 54 424 407 Marso S et al. NEJM 2016; 375:311-322
Patients with Event (%) LEADER: CV Death 8 6 HR: 0.78 (95% CI, 0.66-0.93) p<0.007 4 2 Liraglutide 0 0 6 12 18 24 30 36 42 48 Patients at risk Time from Randomization (Months) Liraglutide 4668 4672 4641 4648 4599 4601 4558 4546 4505 4479 4445 4407 4382 4338 4322 4267 1723 1709 54 484 465 Marso S et al. NEJM 2016; 375:311-322
Subjects with an event (%) SUSTAIN-6: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke 15 10 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% 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 109 Number of subjects at risk Time since Randomization (weeks) Semaglutide 1648 1619 1601 1584 1568 1543 1524 1513 1649 1616 1586 1567 1534 1508 1479 1466 Marso SP et al. N Engl J Med 2016. 375: 1834-44
Patients with an event (%) 5 4 3 2 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% 1 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 109 Number of subjects at risk Time since Randomization (weeks) Semaglutide 1648 1634 1627 1617 1607 1589 1579 1572 1649 1637 1623 1617 1600 1584 1566 1558 Marso SP et al. N Engl J Med 2016. 375: 1834-44
Patients with an event (%) SUSTAIN-6: Non-Fatal Myocardial Infarction 5 4 3 2 HR, 0.74 (95% CI, 0.51; 1.08) Events: 47 semaglutide; 64 placebo p=0.12, 3.9% Semaglutide, 2.9% 1 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104109 Number of subjects at risk Time since Randomization (weeks) Semaglutide 1648 1623 1609 1595 1582 1560 1543 1535 1649 1624 1598 1587 1562 1542 1516 1502 Marso SP et al. N Engl J Med 2016. 375: 1834-44
Patients with an event (%) 5 4 3 2 1 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% 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 Number of subjects at risk Time since Randomization (weeks) Semaglutide 1648 1630 1619 1606 1593 1572 1558 1558 109 1649 1629 1611 1597 1571 1548 1528 1521 Marso SP et al. N Engl J Med 2016. 375: 1834-44
Patients with an event (%) SUSTAIN-6 Diabetic Retinopathy 28 8 6 HR, 1.76 (95% CI, 1.11; 2.78) Events: 50 semaglutide; 29 placebo P=0.02 4 2 Semaglutide, 3.0%, 1.8% 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 109 Weeks since randomisation Number of patients at risk Semaglutide 1648 1622 1612 1595 1570 1548 1535 1525 1649 1636 1617 1605 1576 1558 1539 1530 Marso SP et al. N Engl J Med 2016. 375: 1834-44
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) 0.061 Years from Randomization Holman RR et al. NEJM 2017; 377:1228-1239
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 0.91 0.83, 1.00 <.001 (non-inferiority) 0.061 (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%) 0.88 0.95 0.86 0.73, 1.05 0.84, 1.09 0.70, 1.07 0.628 (homogeneity among components) 0 0.5 1 1.5 2 Exenatide favored favored Holman RR et al. NEJM 2017; 377:1228-1239
Patients with an Event (%) EXSCEL All-Cause Mortality HR (95% CI) 0.86 (0.77, 0.97) P value 0.016 Years from Randomization Holman RR et al. NEJM 2017; 377:1228-1239
EXSCEL Secondary Endpoints Exenatide N=7356 N=7396 Hazard Ratio 95% CI P value All-cause mortality 507 (6.9%) 584 (7.9%) 0.86 0.77, 0.97 0.016 CV-death 340 (4.6%) 383 (5.2%) 0.88 0.76, 1.02 0.096 Fatal or non-fatal MI 483 (6.6%) 493 (6.7%) 0.97 0.85, 1.10 0.622 Fatal or non-fatal stroke 187 (2.5%) 218 (2.9%) 0.85 0.70, 1.03 0.095 Hospitalization for ACS 602 (8.2%) 570 (7.7%) 1.05 0.94, 1.18 0.402 Hospitalization for heart failure 219 (3.0%) 231 (3.1%) 0.94 0.78, 1.13 0.485 0 0.5 1 1.5 2 Exenatide favored favored Holman RR et al. NEJM 2017; 377:1228-1239
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; 377:1228-1239
GLP-1 RAs and Pancreatitis or Pancreatic Cancer
Pancreatic Cancer in GLP1 Trials GLP1-RA ELIXA 3/3032 9/3031 LEADER 13/4668 9/4672 SUSTAIN-6 1/1648 4/1649 EXSCEL 15/7344 16/7372 TOTAL 32/16692 38/16724 OR 0.83 (95% CI 0.33, 2.11), p=0.70
Acute Pancreatitis in GLP1 Trials GLP1-RA ELIXA 5/3032 8/3031 LEADER 18/4668 23/4672 SUSTAIN-6 9/1648 12/1649 EXSCEL 26/7344 22/7372 TOTAL 58/16692 65/16724 OR 0.90 (95% CI 0.63, 1.28), p=0.54
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 5.5-11.0 R Lixisenatide 2.1 1.9 2.0 MACE-4 (non-inferiority) N=9340 (2) 50y with CVD/renal dysfunction/hf, or 60y with CV RFs Liraglutide 7.0 R 3.8 3.5 3.5 MACE-3 (non-inferiority) SUSTAIN-6 N=3297 (3) 50y with CVD, or 60y with subclinical CVD Semaglutide 7.0 R 2.1 1.8 1.9 MACE-3 (non-inferiority) N=14752 Established CVD as well as primary prevention (70/30 split), 18y 6.5-10.0 R Exenatide 3.2 2.4 2.3 MACE-3 (non-inferiority for safety/ superiority for efficacy) 0 1 2 3 4 Median Follow-up Duration (years) Bethel at al. Lancet Diabetes Endocrinol 2018; 6: 105 113
Meta-analysis: MACE-3 endpoint Bethel at al. Lancet Diabetes Endocrinol 2018; 6: 105 113
Meta-analysis: All-cause mortality Bethel at al. Lancet Diabetes Endocrinol 2018; 6: 105 113
Meta-analysis: CV mortality Bethel at al. Lancet Diabetes Endocrinol 2018; 6: 105 113
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) 0.052 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: 105 113
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 7598 1742 536/3831 (14.0) 72/837 (8.6) 629/3767 (16.7) 65/905 (7.2) 0.83 (0.74-0.93 1.2 (0.86-1.67) SUSTAIN-6 50 yrs of age with established CVD 60 yrs of age with risk factors for CVD 2735 562 98/1353 (5.4) 10/295 (3.4) 137/1382 (9.9) 9/267 (3.4) 0.72 (0.55-0.93) 1.0 (0.41-2.46) EXSCEL Prior CV event No Prior CV event 10782 3970 722/5394 (13.4) 117/1962 (6.0) 786/5388 (14.6) 119/2008 (5.9) 0.9 (0.82-1.0) 0.99 (0.77-1.28) 0 0.5 1 1.5 2 Favors Treatment Favors
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 1,538,856 6.4% LEADER 23,941,512 3,063,663 12.8% SUSTAIN-6 23,941,512 2,815,927 11.8% EXSCEL 23,941,512 11,347,155 47.4% 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.
SGLT2s
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 100 65.6 % Heart Failure 10 14 % egfr <60 25.9 20.1 ml/min/m 2 Mortality rate (events/100 pt-yrs) 1.9-2.9 1.7-2.0
Patients with Event (%) EMPA-REG Outcome Primary Outcome 3-point MACE 20 15 10 HR, 0.86 (95% CI, 0.74-0.99) p=0.0382* Empagliflozin 5 0 6 12 18 24 30 36 42 48 Patients at Risk Empagliflozin 0 4687 2333 4580 2256 4455 2194 Time from Randomization (Months) 4328 2112 3851 1875 2821 1380 2359 1161 1534 741 370 166 Zinman B et al. N Engl J Med 2015; 373:2117-2128
Patients with Event (%) EMPA-REG Outcome CV death Empagliflozin 9 8 7 6 5 4 3 2 1 0 Patients at Risk 0 6 12 18 24 30 36 42 48 4687 2333 HR, 0.62 (95% CI, 0.49-0.77) p=0.0001 4651 2303 4608 2280 Time from Randomization (Months) 4556 2243 4128 2012 Cumulative incidence function. HR, hazard ratio Zinman B et al. N Engl J Med 2015; 373:2117-2128 3079 1503 2617 1281 1722 825 Empagliflozin 416 177
Patients with Event (%) EMPA-REG Outcome Hospitalization for Heart Failure Patients at Risk Empagliflozin 7 6 5 4 3 2 1 0 0 6 12 18 24 30 36 42 48 4687 2333 HR, 0.65 (95% CI, 0.50-0.85) p=0.0017 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 2015; 373:2117-2128 2950 1424 2487 1202 1634 775 Empagliflozin 395 168
Patients with Event (%) EMPA-REG Outcome Death from Any Cause 20 15 HR, 0.68 (95% CI, 0.57-0.82) p=0.0001 10 5 Empagliflozin 0 0 6 12 18 24 30 36 42 48 Patients at risk Empagliflozin 4687 2333 4651 2303 4608 2280 Kaplan-Meier estimate. HR, hazard ratio Time from Randomization (Months) 4556 2243 4128 2012 3079 1503 2617 1281 1722 825 414 177 Zinman B et al. N Engl J Med 2015; 373:2117-2128
CV Death, MI and Stroke Patients with event/analysed Empagliflozin HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 0.25 0.50 1.00 2.00 Favors empagliflozin Favors placebo Zinman B et al. N Engl J Med 2015; 373:2117-2128
Fatal and Non-Fatal Stroke Intent-to-treat population Patients with event/analysed Empagliflozin HR (95% CI) p-value 164/4687 69/2333 1.18 (0.89, 1.56) 0.2567 Numerical difference largely driven by events occurring >30 days after treatment stop On-treatment analysis* 0.5 1.0 2.0 Favors empagliflozin 141/4607 66/2308 1.04 (0.78, 1.40) 0.7849 0.5 1.0 2.0 Favors empagliflozin Favors placebo Favors placebo Zinman B et al. N Engl J Med 2015; 373:2117-2128
CANVAS: Primary Outcome CV death, non-fatal myocardial infarction, or non-fatal stroke Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS CV Death Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS All Cause Mortality Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS Hospitalization for Heart Failure Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS End Point Summary Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS Lower Extremity Amputations Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS Level of Amputation Neal B et al. N Engl J Med 2017; 377:644-657
CANVAS Benefits and Risks
Comparison: Size of Trials, # Events No. of Subjects Mean Duration (yrs) No. of Events SAVOR-TIMI 14692 2.1 1222 EXAMINE 5380 1.5 621 TECOS 14671 3.0 1690 ELIXA 6068 2.1 805 EMPA-REG OC 7020 3.1 772 LEADER 9340 3.8 1302 SUSTAIN-6 3297 2.1 254 CANVAS 10172 3.6 1011 EXSCEL 14752 3.2 1744
Summary of Major CVOTs in T2DM Lim S, Eckel RH, Koh KK. Atherosclerosis 2018; 272:33-40.
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
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