When added to standard care and compared to placebo, empagliflozin lowered the rate of primary composite outcomes and of death from any cause in patients with type 2 diabetes at high risk for cardiovascular events, in a study of 7,020 individuals treated for a median observation time of 3 years. The primary outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in 10.5% in the pooled empagliflozin group (HR 0.86) and in 12.1% in the placebo group. Further details included:

• There were no significant between-group differences in rates of myocardial infarction or stroke.

• There were significantly lower rates of death from cardiovascular causes in the empagliflozin group when compared to the placebo group (3.7% vs 5.9%, RR=38%), hospitalization from heart failure (2.7% vs 4.1%, RR=35%); and death from any cause (5.7% vs 8.3%, RR=32%).

• There was no significant between-group difference in the key secondary outcome of primary outcomes plus hospitalization for unstable angina.

• Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.

Citation: Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM. [Published online ahead of print September 17, 2015]. doi: 10.1056/NEJMoa1504720.

Commentary: This study shows a positive effect on both macrovascular outcomes and total mortality over a relatively short period of time, 3 years. The differences between the placebo group and the empagliflozin group actually begin to diverge after only 3 months. The questions that remain are twofold: 1) Is this result a reflection of a class effect of SGLT-2 inhibitors on cardiovascular outcomes or is it an effect particular to empagliflozin?; 2) How should we best use these results – should empagliflozin and SGLT-2s become the treatment of choice for patients with diabetes and cardiovascular disease, for those with diabetes who are at high risk for cardiovascular disease, or for all patients with diabetes? —Neil Skolnik, MD