Finding Efficacy in a Safety Trial: Empagliflozin and Cardiovascular Death.

Abstract

In late June 2016, the Endocrinologic and Metabolic Drugs Advisory Committee of the US Food and Drug Administration (FDA), on which we serve, met to consider whether empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 currently approved for the treatment of type 2 diabetes mellitus, qualifies for a new indication to reduce the risk of cardiovascular death. The committee’s discussion focused on the results of the EMPA-REG OUTCOME [BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients] cardiovascular outcome trial, which was designed primarily as a cardiovascular safety study to meet the FDA’s 2008 guidance for new antihyperglycemic medications. That guidance requires pharmaceutical companies to statistically exclude the possibility that their medications are associated with a ≥30% increase in the risk of cardiovascular events.1 Thus, EMPA-REG OUTCOME was designed with a prespecified primary end point of the composite of cardiovascular death, myocardial infarction, and stroke and randomized 7020 patients to once-daily empagliflozin 10 mg, empagliflozin 25 mg, or placebo in a 1:1:1 ratio. In EMPA-REG OUTCOME, the combined empagliflozin groups had a reduction in the primary composite outcome of 14% (hazard ratio, 0.86; 95.02% confidence interval, 0.74–0.99; P =0.038).2 This is the first large, prospective, randomized trial of an antihyperglycemic drug under review by the FDA to show a cardiovascular benefit. The reduction in the primary cardiovascular end point in EMPA-REG OUTCOME was driven by a 38% reduction (hazard …