Skip to main content

10-11-2017 | Cardiovascular disorders | Review | Article

Updates on cardiovascular outcome trials in diabetes

Journal: Cardiovascular Diabetology

Authors: Oliver Schnell, Lars Rydén, Eberhard Standl, Antonio Ceriello, on behalf of the D&CVD EASD Study Group

Publisher: BioMed Central


In 2008 the Food and Drug Administration introduced a guidance for industry that requires the investigation of cardiovascular outcomes of glucose-lowering medications. Since then, an increasing number of cardiovascular outcome trials have been completed in diabetes patients with high cardiovascular risk for members of the SGLT-2 and DPP4 inhibitors and GLP-1 receptor agonist classes. The trials confirmed cardiovascular safety for all tested anti-hyperglycaemic drugs and, in addition empagliflozin, semaglutide and liraglutide could even reduce cardiovascular risk. The present review summarizes the results of the DEVOTE, CANVAS, EXSCEL and ACE trials that tested cardiovascular safety of Insulin degludec, canagliflozin, once-weekly exenatide and acarbose and were published in 2017. We provide context on these results by comparing them with earlier trials of glucose-lowering drugs and give an outlook on what to expect in coming years.
Dailey G. Overall mortality in diabetes mellitus: where do we stand today? Diabetes Technol Ther. 2011;13(Suppl 1):S65–74. PubMed
Barnett KN, et al. A 12-year follow-up study of all-cause and cardiovascular mortality among 10,532 people newly diagnosed with Type 2 diabetes in Tayside, Scotland. Diabet Med. 2010;27(10):1124–9. CrossRefPubMed
Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89. CrossRefPubMed
Bergenstal RM. Glycemic variability and diabetes complications: does it matter? Simply put, there are better glycemic markers! Diabetes Care. 2015;38(8):1615–21. CrossRefPubMed
FDA. Guidance for industry diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring: FDA; 2008.
EMA. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: EMA; 2012.
Hirshberg B, Raz I. Impact of the US Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care. 2011;34(Suppl 2):S101–6. CrossRefPubMedPubMedCentral
Schnell O, et al. Current perspectives on cardiovascular outcome trials in diabetes. Cardiovasc Diabetol. 2016;15(1):139. CrossRefPubMedPubMedCentral
Gerstein HC, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28. CrossRefPubMed
Marso SP, et al. Efficacy and safety of degludec versus glargine in Type 2 diabetes. N Engl J Med. 2017;377(8):723-32. CrossRefPubMed
Regier EE, Venkat MV, Close KL. More than 7 years of hindsight: revisiting the FDA’s 2008 guidance on cardiovascular outcomes trials for Type 2 diabetes medications. Clin Diabetes. 2016;34(4):173–80. CrossRefPubMedPubMedCentral
Scirica BM, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. CrossRefPubMed
White WB, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35. CrossRefPubMed
Green JB, et al. Effect of sitagliptin on cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2015;373(3):232–42. CrossRefPubMed
Pfeffer MA, et al. Lixisenatide in patients with Type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57. CrossRefPubMed
Marso SP, et al. Liraglutide and cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2016;375(4):311–22. CrossRefPubMedPubMedCentral
Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. CrossRefPubMed
Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. CrossRefPubMed
Marso SP, et al. Design of DEVOTE (trial comparing cardiovascular safety of insulin degludec vs insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events)—DEVOTE 1. Am Heart J. 2016;179:175–83. CrossRefPubMed
Neal B, et al. Optimizing the analysis strategy for the CANVAS Program: a prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab. 2017;19(7):926–35. CrossRefPubMedPubMedCentral
Neal B, et al. Canagliflozin and cardiovascular and renal events in Type 2 diabetes. N Engl J Med. 2017;377(7):644-57. CrossRefPubMed
Holman RR, et al. Rationale for and design of the acarbose cardiovascular evaluation (ACE) trial. Am Heart J. 2014;168(1):23–9. CrossRefPubMed
Holman RR, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017. pii: S2213-8587(17)30309-1.
Holman RR, et al. Effects of once-weekly exenatide on cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2017;377(13):1228–39. CrossRefPubMed
Zinman B, et al. Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2). Diabetologia. 2017. doi: 10.​1007/​s00125-017-4423-z.
Frontoni S, et al. Glucose variability: an emerging target for the treatment of diabetes mellitus. Diabetes Res Clin Pract. 2013;102(2):86–95. CrossRefPubMed
Heise T, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53(6):1614–20. CrossRefPubMed
Wanner C, et al. Empagliflozin and progression of kidney disease in Type 2 diabetes. N Engl J Med. 2016;375(4):323–34. CrossRefPubMed
Watts NB, et al. Effects of canagliflozin on fracture risk in patients With Type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101(1):157–66. CrossRefPubMed
FDA Drug Safety Communication. FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density; 2015.
FDA Drug Safety Communications. FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Silver Spring: FDA Drug Safety Communications; 2016.
Fadini GP, Avogaro A. SGTL2 inhibitors and amputations in the US FDA adverse event reporting system. Lancet Diabetes Endocrinol. 2017;5(9):680–1. CrossRefPubMed
Agency EM. SGLT-2 inhibitors: information on potential risk of toe amputation to be included in prescribing information; 2017.
Kosiborod M, et al. Lower risk of heart failure and death in patients initiated on SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study. Circulation. 2017;136(3):249–59. CrossRefPubMedPubMedCentral
Wu JH, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411–9. CrossRefPubMed
Standl E, et al. On the potential of acarbose to reduce cardiovascular disease. Cardiovasc Diabetol. 2014;13:81. CrossRefPubMedPubMedCentral
Ponikowski P, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed). 2016;69(12):1167. CrossRef
Rydén L, et al. Corrections needed to 2016 ESC guideline and AHA scientific statement on heart failure. Lancet Diabetes Endocrinol. 2017;5(5):325–6. CrossRefPubMed
Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017. doi: 10.​1007/​s00125-017-4337-9. PubMedCentral
Petrie JR, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):597–609. CrossRefPubMed
Standl E. Metformin in type 1 diabetes. Lancet Diabetes Endocrinol. 2017;5:567–9. CrossRefPubMed
Vaccaro O, et al. The TOSCA.IT trial: a study designed to evaluate the effect of pioglitazone versus sulfonylureas on cardiovascular disease in type 2 diabetes. Diabetes Care. 2012;35(12):e82. CrossRefPubMedPubMedCentral
Vaccaro O, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017;35(12):e82.
Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89. CrossRefPubMed
Ridker PM, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. CrossRefPubMed
Standl E, et al. Integration of recent evidence into management of patients with atherosclerotic cardiovascular disease and type 2 diabetes. Lancet Diabetes Endocrinol. 2017;5(5):391–402. CrossRefPubMed
Leiter LA, et al. Efficacy and safety of saxagliptin in older participants in the SAVOR-TIMI 53 trial. Diabetes Care. 2015;38(6):1145–53. CrossRefPubMed
Zannad F, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067–76. CrossRefPubMed
Marso SP, et al. Liraglutide and cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2016;375(4):311-22 CrossRefPubMedPubMedCentral
Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »