Diuretic Effect May Not Mediate Most Empagliflozin Benefits In Heart-Failure Patients

Diuresis does not appear to play a big role in mediating the benefits of empagliflozin in heart-failure patients, according to results from a large clinical trial.

"SGLT2 inhibitors, such as empagliflozin, represent an important new advance in the treatment of heart failure in patients with a reduced ejection fraction," said Dr. Milton Packer of the Baylor Heart and Vascular Institute, in Dallas, Texas.

"Some physicians," he told Reuters Health by email, "have suggested that these drugs are beneficial because of their diuretic effect. The study shows that that belief is unlikely to be true, since patients who would have been most likely to have benefited from a diuretic effect were not those who benefited the most from empagliflozin."

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Dr. Packer and his colleagues examined data on 3,730 patients who were randomized to receive either empagliflozin or placebo. All had heart failure and a reduced ejection fraction, with or without diabetes, and about 40% of the patients had had volume overload in the four weeks before study enrollment.

The latter group was more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in the previous 12 months, the researchers report in the Journal of the American College of Cardiology. After randomization, they were also more likely to suffer a heart-failure event despite being significantly more apt to be treated with high doses of a loop diuretic as an outpatient.

Overall, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure and improved health status and functional class.

When treated with placebo, patients with recent volume overload were significantly more likely to reach the composite endpoint of cardiovascular death or hospitalization for heart failure (hazard ratio, 1.31) and had a higher number of hospitalizations for heart failure (HR, 1.36).

Dr. Mikhail N. Kosiborod, co-author of an accompanying editorial, told Reuters Health by email, "Although SGLT2i have been frequently described as 'smart diuretics,' these findings - especially when added to the data from several previous studies - underscore that the effects of SGLT2i in patients with heart failure and reduced ejection fraction (HFrEF) cannot be simply explained by their diuretic properties, and other mechanisms are likely at play."

Dr. Kosiborod, of Saint Luke’s Mid America Heart Institute, Kansas City, in Missouri, concluded, "What has also become very clear is that these agents provide substantial and rapid benefits in HFrEF, regardless of volume status or for that matter almost any other clinical factors, making effective and expeditious implementation into clinical practice a major priority".

The study was supported by Boehringer Ingelheim and Eli Lilly and Company. Dr. Packer received personal fees from Boehringer Ingelheim during its conduct. Other authors also have relationships with these and other companies, as does Dr. Kosiborod.

—David Douglas

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