Boehringer Ingelheim and Eli Lilly announced on Wednesday that they were planning two separate outcomes trials to test the effect of the diabetes drug empagliflozin (Jardiance) in patients with chronic heart failure.

The trials herald a remarkable shift in emphasis, as there have been repeated concerns that some classes of diabetes drugs might actually worsen or increase the risk of developing heart failure. Only earlier this month the FDA added a new heart failure warning to the labels of the diabetes drugs saxagliptin (Onglyza) and alogliptin (Nesina).

The new hope for empagliflozin is based on the highly positive results of last year’s EMPA-REG OUTCOME trial, which found a significant reduction in cardiovascular events in patients with type 2 diabetes taking the drug, which is an SGLT2 inhibitor. A second paper examining the heart failure outcomes was published in January in theEuropean Heart Journal. The trial investigators reported “consistent reductions” in hospitalization for heart failure and cardiovascular death in patients with heart failure at baseline or who were taking heart failure medications. Patients in the empagliflozin group were also less likely to need loop diuretics.

Heart failure hospitalization or cardiovascular death was reduced by 34% from 8.5% in the placebo group to 5.7% in the empagliflozin group. The authors calculated a number needed to treat of 35 to prevent one heart failure hospitalization or cardiovascular death over 3 years.

The cardiovascular benefit “was observed very early and was sustained throughout the trial,” according to the researchers. “This suggests that the benefit was not driven by an effect on atherosclerosis.” Although the precise mechanism of benefit is unknown, they speculated about several possible mechanisms, including “osmotic diuresis, effects on plasma volume and sodium retention with modulation of the cardio-renal axis, reductions in arterial stiffness and the rate pressure product, indicating diminished left ventricular afterload, reductions in weight and blood pressure without increases in sympathetic nervous activity, reductions in hyperglycemia with concomitant reductions in insulin levels, and reductions in uric acid.”

Boehringer Ingelheim and Lilly said they would conduct two trials in patients with chronic heart failure, one in patients with type 2 diabetes and one without diabetes.

Diabetes and heart failure are urgent and growing problems, perhaps inevitable results of an aging and increasingly obese population. And they are closely related. Sanjay Kaul, MD, of Cedars-Sinai Heart Institute in Los Angeles, pointed out that “diabetes is prevalent in 25% to 40% of patients with heart failure. Diabetes increases the risk of developing heart failure by two- to five-fold. In patients with established heart failure, diabetes is associated with a 60% to 80% increased risk of cardiovascular and all-cause mortality.”

Kaul said that “the heart failure findings in the EMPA-REG OUTCOME trial were clinically meaningful and statistically persuasive. However, they were not systematically evaluated, in part because they were not highly anticipated. Logically these findings need to be replicated in heart failure patients with and without diabetes. Simultaneously, studies need to be conducted to understand the mechanism(s) of benefit. The planned studies, if positive, will expand the portfolio of evidence in favor of the cardioprotective effects of empagliflozin.”

Milton Packer, MD, of Baylor University in Dallas, also supported the studies. “It makes a great deal of sense to study empagliflozin in heart failure, even in those without diabetes. The mechanisms by which the drug may reduce hospitalizations for heart failure in diabetics are not likely to be specific to diabetics.”

“The real question,” Packer wondered, “is what type of heart failure? The best decision here would be to study empagliflozin in patients with heart failure with a PRESERVED ejection fraction. There are reasons to believe that such patients are likely to have been the type that showed particular benefit in the EMPA-REG trial.”