Over the past 20 years, the field of cardiology has made tremendous strides in advancing treatments for patients with heart failure who have a low ejection fraction (at or below 40%). But for heart failure patients with only mildly reduced or preserved ejection fraction (above 40%), developing effective therapies has proven more challenging.

Now that’s finally changing. An international, multicenter team led by Brigham and Women’s Hospital investigators has reported findings from the largest-ever study to look at whether these patients could benefit from treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin.

The randomized, placebo-controlled trial, which was published online in the New England Journal of Medicine (NEJM) in August 2022 and simultaneously presented at the European Society of Cardiology Congress, found that dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 18% in heart failure patients with all ejection fractions.

“What was most novel about this finding was that in addition to showing an overall benefit, we saw consistency of outcomes across all groups, including patients at the lower and upper ends of the ejection-fraction spectrum and in those patients enrolled in a hospital or recently hospitalized,” says first author Scott David Solomon, MD, the Edward D. Frohlich distinguished chair and professor of Medicine at Harvard Medical School and the director of the Brigham’s Clinical Trials Outcomes Center. “This study suggests that SGLT2 inhibitors should be a foundational therapy for all patients with heart failure, regardless of ejection fraction or care setting.”

Expanding SGLT2 Inhibitors Beyond Diabetes Care

Dapagliflozin and other SGLT2 inhibitors were originally developed as treatments for type 2 diabetes. The drugs work primarily through the kidneys, causing an increase in the excretion of both glucose and sodium in the urine. But investigators observed that patients taking these drugs had fewer cardiac events, leading to the study of these drugs in patients with heart failure.

In 2020, dapagliflozin was approved by the FDA for treating heart failure in patients with low ejection fraction, regardless of whether they had diabetes. Other SGLT2 inhibitors have also shown success in treating heart failure. But how this family of drugs functions in this context is not well understood.

“There is a lot of room for debate as to the exact mechanism by which SGLT2 inhibitors reduce the risk of heart failure, beyond their effects on the kidneys,” Dr. Solomon says.

Improving Care for a Range of Heart Failure Patients

The trial, known as DELIVER, randomized 6,263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive either 10 mg of dapagliflozin or a placebo once a day. Patients were treated in 20 countries throughout North and South America, Europe, and Asia. Coordination of and data analysis for the trial were led by investigators at the Brigham and at the University of Glasgow, with whom the Brigham has a longstanding collaboration.

After a median follow-up of 2.3 years, the researchers found that daily dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 18%. The drug also improved participants’ symptoms and quality of life, independent of whether they had diabetes. The side effects of the drug were low. Urinary tract infections, one of the most common side effects, were treatable and not severe.

Dr. Solomon hopes that based on the findings, the FDA will approve the drug for a broad range of heart failure patients.

Broader Data Analysis Provides More Study Details

At the same time the NEJM study was published, Dr. Solomon and his colleagues, including Brigham cardiologist Muthiah Vaduganathan, MD, MPH, also published a paper in The Lancet that was a meta-analysis of five randomized, controlled trials of SGLT2 inhibitors in patients with heart failure, including from the DELIVER trial.

That analysis, which comprised a total of 21,947 trial participants, found that SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalization for heart failure by 20%. “Although these findings are important, we have not cured heart failure,” Dr. Solomon says. “Even patients who received this therapy had a fairly high rate of events. Much more work needs to be done to reduce the risk in patients with heart failure.”

Dr. Solomon and his collaborators plan to continue analyzing the data from the DELIVER trial to learn more about how dapagliflozin works and who can benefit. “When you have a trial that enrolls more than 6,200 patients, you want to learn as much as you possibly can from it,” he concludes.