Treatment with the SGLT2 inhibitor empagliflozin led to significant reductions in both left ventricular end systolic and diastolic volumes in two independent randomized studies of patients with heart failure with reduced ejection fraction.
These results provide important new evidence that one way a drug from this class exerts its beneficial effects on cardiovascular outcomes in these patients is by producing favorable left-ventricular remodeling.
One of the two studies involved only patients with heart failure with reduced ejection fraction (HFrEF) with diabetes and examined treatment impact after 36 weeks. The second study focused exclusively on HFrEF patients without diabetes and followed patients for 6 months. Both studies also generated additional significant evidence of favorable left-ventricular effects.
“The results of these two new trials are incredibly important, as they tell cardiologists one of the mechanisms by which SGLT2 [sodium glucose co-transporter 2] inhibitors reduce heart failure hospitalizations and cardiovascular death,” said Mark C. Petrie, MBChB , professor at the Institute of Cardiovascular & Medical Sciences at the University of Glasgow, and principal investigator for one of the two studies.
“Many cardiologists want to know mechanisms as well as clinical benefit. These remodeling data showing that these drugs reduce the size of abnormally large hearts [and] are also very important for patients,” Dr. Petrie said in an interview. “There have been more than 50 publications on potential mechanisms of benefit of SGLT2 inhibitors in HFrEF, but these are the first randomized, mechanistic data.”
Mechanistic clues follow large cardiovascular outcome trials
Results from a large randomized trial, EMPEROR-Reduced, recently showed that treatment with empagliflozin (Jardiance) on top of standard HFrEF treatment led to significant benefits in patients with or without type 2 diabetes (T2D), compared with placebo, for major cardiovascular and renal endpoints, including the combination of cardiovascular death or hospitalization for heart failure. And results from a second large randomized trial, DAPA-HF, showed similar results with a different drug from the same class, dapagliflozin (Farxiga), in an earlier report.
But while these reports led to quick uptake of these two drugs for the treatment of patients with HFrEF, the means by which these agents exert their HFrEF benefits have been unclear.
“Our study identifies why this drug [empagliflozin] is effective – because it improves heart function, something that has not been understood until now,” Carlos G. Santos-Gallego, MD, lead investigator for the second new report, said in a written statement. “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.”
On the strength of the DAPA-HF results, dapagliflozin received a revised U.S. label in May 2020 that added the indication for treating patients with HFrEF regardless of the whether patients also have T2D, the original indication for prescribing the drug. Many experts anticipate that a similar addition to the label for empagliflozin will soon occur.
EMPA-TROPISM examines patients with no T2D
The single-center study reported by Dr. Santos-Gallego randomized 84 patients with HFrEF and no diabetes to standard treatment with empagliflozin or placebo and measured several parameters in 80 patients who completed the planned 6 months of treatment. The primary endpoints were the changes in both left ventricular end systolic and diastolic volume from baseline in the empagliflozin-treated patients compared with patients on placebo, measured by cardiac MR.