Empagliflozin Shown to Lower Rate of CV Death in Patients with Type 2 Diabetes

Empagliflozin, an inhibitor of sodium-glucose cotransporter 2, plus standard care, may lower the rate of the primary composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, in patients with type 2 diabetes at high risk for cardiovascular events, according to results of the EMPA-REG OUTCOME trial presented Sept. 17 during the European Association for the Study of Diabetes Annual Meeting in Stockholm, and simultaneously published in the New England Journal of Medicine.

A team of researchers, led by Bernard Zinman, MD, director, Diabetes Centre, Mount Sinai Hospital; senior scientist, Lunenfeld Tanenbaum Research Institute; and professor of medicine, University of Toronto, Canada, randomly assigned 7,020 patients from 42 countries to receive 10 mg or 25 mg of empagliflozin or placebo once daily for a median of 3.1 years.

Results showed that the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in 490 of 4,687 patients (10.5 percent) in the pooled empagliflozin group and in 282 of 2,333 patients (12.1 percent) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02 percent confidence interval, 0.74 to 0.99; P=0.04 for superiority).

Researchers note that 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, hospitalization for heart failure and death from any cause.

“Addressing the burden of cardiovascular events, including death, is at the core of diabetes care, and until now no single diabetes medication has been associated with a reduction in mortality,” says Zinman. “In this study, empagliflozin was shown to prevent one out of three cardiovascular deaths,” he adds.

The researchers conclude that their trial “provides data to support the long-term use of empagliflozin, as well as strong evidence for a reduction in cardiovascular risk.”

“Until now, the effect of diabetes drugs on cardiovascular disease has been somewhat unclear,” explains Richard A. Chazal, MD, FACC, president-elect of the ACC. “It is encouraging that this initial study of this new class of drugs, SGLT2 inhibitors, suggests a reduced risk of cardiovascular death. We want to be cautious since this is just the first of three large studies expected in the next several years looking at this class. This study suggests the mechanism for reducing blood sugar is important in terms of its impact on cardiovascular disease.”

Commenting on the study, Silvio Inzucchi, MD, chair of the Diabetes Collaborative Registry, notes, “I think the EMPA-REG OUTCOME results are so striking and so surprising, that they may force us to change the way we look at type 2 diabetes. This may be a little hyperbole, but it's been so long since we've had a positive cardiovascular trial in diabetes! Study after study have proven neutral and, honestly, we've all become a bit discouraged in this field. So, placing our results in their proper historical context is important. The key finding was the 38 percent relative reduction in cardiovascular death, which drove the overall 14 percent risk reduction in our primary endpoint, 3-point MACE. Moreover, unlike some other cardiovascular studies in the past, there was no compensatory increase in in non-cardiovascular mortality. So, a highly statistically significant 32 percent benefit on overall mortality was demonstrated. That is very unusual in a diabetes trial. Complimenting these findings was a 35 percent relative risk reduction in heart failure hospitalization – another key finding. Heart failure is a very important complication in patients with diabetes – one that has actually moved in the wrong direction with some diabetes drugs.” 

“As to mechanisms, we can only speculate,” says Inzucchi. “I personally feel this may have to do with osmotic diuresis in patients with heart failure (who constituted only 10 percent of our population) but also in those with subclinical or undiagnosed ventricular dysfunction, possibly diastolic in nature. Maybe we were benefiting some patients by diuresing them a bit before they developed heart failure complications or even sudden death as a result? This will be an area of active investigation over the next few years.”

He adds that moving forward, “Professional organizations will at least need to consider how the EMPA-REG results will affect treatment guidelines type 2 diabetes.”

Keywords: Benzhydryl Compounds, Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Glucose, Mortality, Glucosides, Hospitalization, Confidence Intervals, Hypoglycemic Agents, Myocardial Infarction, Stroke, Sodium

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