COMPARATIVE STUDY
JOURNAL ARTICLE
MULTICENTER STUDY
RANDOMIZED CONTROLLED TRIAL

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Bernard Zinman, Christoph Wanner, John M Lachin, David Fitchett, Erich Bluhmki, Stefan Hantel, Michaela Mattheus, Theresa Devins, Odd Erik Johansen, Hans J Woerle, Uli C Broedl, Silvio E Inzucchi
New England Journal of Medicine 2015 November 26, 373 (22): 2117-28
26378978

BACKGROUND: The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.

METHODS: We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.

RESULTS: A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.

CONCLUSIONS: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

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A Raut

Modest reductions in HbA1C were achieved (about -0.5%) and there was associated weight loss (about -2kg) and systolic BP reduction (about -4mmHg). Thus, a hypothesis to explain the positive CV outcome may be that it was driven by the drug’s diuretic effect instead of just its glucose reducing effect.  Limitations of this study include the the inability of each empagliflozin dose arm by itself to achieve a significant reduction in the primary outcome.  Also, DM2 patients studied had higher CV risk overall and these findings may not necessarily extend to diabetics with lower CV risk.  It remains to be seen if the CV outcome results seen in this study are specific to empagliflozin or a class effect of all SGLT2i -- CV outcome trials for the other SGLT2i drugs are ongoing. In the meantime, this is the first agent since metformin to show useful reductions in cardiovascular end-points.

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