New York—Sodium-glucose cotransporter-2 inhibitors have proven benefits in patients with diabetes and heart failure with reduced ejection fraction (HFrEF). Now, a large clinical trial has shown early and significant improvement in clinical outcomes in HFrEF patients without hyperglycemia.

Results of the study to assess the effect of empagliflozin on LV function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients was published in the Journal of the American College of Cardiology and simultaneously presented at the American Heart Association Scientific Sessions 2020.

Icahn School of Medicine at Mount Sinai–led researchers demonstrated that the SGLT2 inhibitor can improve the heart’s size, shape, and function. That leads to better exercise capacity and quality of life and reduces hospitalizations for heart-failure patients.

“Our clinical trial’s promising results show this diabetes drug can ameliorate lives of heart failure patients with reduced ejection fraction, enhance their exercise capacity, and improve their quality of life with little to no side effects. We expect this work will help lead to U.S. Food and Drug Administration approval of empagliflozin for this patient population in the coming months,” explained first author Carlos Santos-Gallego, MD, postdoctoral fellow at the Icahn School of Medicine at Mount Sinai. “Our study also identifies why this drug is effective: because it improves heart function, something that has not been understood until now. Many doctors are afraid of prescribing a drug they do not understand, and our findings will help clinicians feel more comfortable giving this to patients once approved.”

He added, “A cornerstone finding is that, although this drug was initially developed for diabetes, it is also incredibly effective in patients without diabetes.” The study also points out that empagliflozin didn’t appear to cause hypoglycemia in patients without diabetes.

In conducting the trial, the study team suggests that the early and significant improvement in clinical outcomes seen with empagliflozin is likely explained by effects beyond a reduction in hyperglycemia.

For the double-blind, placebo-controlled trial, 84 nondiabetic HFrEF patients were randomized to empagliflozin or placebo for 6 months. Defined as the primary endpoint was change in left ventricle end-diastolic volume (LVEDV) and left ventricle end-systolic volume (LVESV) assessed by cardiac magnetic resonance. Changes in LV mass, LVEF, peak oxygen consumption in the cardiopulmonary exercise test, 6-minute walk test, and quality of life were secondary endpoints.

Results indicate that empagliflozin was associated with a significant reduction of LVEDV (-25.1 ± 26.0 vs. -1.5 ± 25.4mL for empagliflozin vs. placebo, respectively, P <.001) and LVESV (-26.6 ± 20.5 vs. -0.5 ± 21.9 mL for empagliflozin vs placebo, P <.001). Researchers also note that empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively, P <.001) and improvements in LVEF (6 ± 4.2 vs. -0.1 ± 3.9 P <.001).

In addition, significant improvements were documented in those patients’ peak O2 consumption (1.1 ± 2.6 vs. -0.5 ± 1.9mL/min/kg for empagliflozin vs. placebo, respectively, P = .017), oxygen uptake efficiency slope (111 ±. 267 vs. -146 ± 318, P <.001), as well as in 6-minute walk test (81 ± 64 vs. -35 ± 68 meters, P <.001) and quality of life (KCCQ-12: 21 ± 18 vs. 2 ± 15, P <.001).

“Empagliflozin administration to non-diabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo,” the authors conclude. “Our observations strongly support a role for SGLT2 inhibitors in the treatment of HFrEF patients independently of their glycemic status.”

Analysis in the study suggests that, in heart failure, the heart goes through “adverse remodeling,” in which the left ventricle dilates, becomes hypertrophic and more spherical, and pumps in a weaker way with a lower ejection fraction. Empagliflozin appears to lessen and reverse adverse remodeling, according to researchers, while reducing dilation and hypertrophy of the left ventricle, increasing the ejection fraction and changing the shape of the left ventricle, making it more elongated and less spherical.

“We were very surprised at how fast the benefits appeared with empagliflozin. The patients were already feeling better in the first few weeks of taking it,” said coauthor Juan Badimon, PhD, professor of medicine (Cardiology) and director of the Atherothrombosis Research Unit at the Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai. “Another key issue is how safe this drug is; we saw no severe side effects, despite being an antidiabetic drug, no hypoglycemia was noticed. This shows that empagliflozin is a safe and potent treatment for heart failure with reduced ejection fraction independently of the diabetic status of the patient.”

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