Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors' Expert Forum

William T Cefalu, Sanjay Kaul, Hertzel C Gerstein, Rury R Holman, Bernard Zinman, Jay S Skyler, Jennifer B Green, John B Buse, Silvio E Inzucchi, Lawrence A Leiter, Itamar Raz, Julio Rosenstock, Matthew C Riddle, William T Cefalu, Sanjay Kaul, Hertzel C Gerstein, Rury R Holman, Bernard Zinman, Jay S Skyler, Jennifer B Green, John B Buse, Silvio E Inzucchi, Lawrence A Leiter, Itamar Raz, Julio Rosenstock, Matthew C Riddle

Abstract

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.

© 2017 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Completed and ongoing CVOTs (–,,–58). 3-P, 3-point; 4-P, 4-point; 5-P, 5-point. DECLARE-TIMI 58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; ESRD, end-stage renal disease; HARMONY Outcomes, Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus; PIONEER 6, A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.

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