Semaglutide Helps Heart Failure ‘Regardless of Diuretics’

LISBON — The diabetes and weight-loss drug semaglutide improves heart failure–related symptoms and physical limitations regardless of diuretic use in patients with obesity-related heart failure and preserved ejection fraction, according to a new analysis.

The research from the STEP-HFpEF program was presented here at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024 Congress and simultaneously published in the European Heart Journal.

Semaglutide “produced consistent beneficial effects on body weight, exercise function, and biomarkers of inflammation and congestion across the subgroups of diuretic use and dose,” said study presenter Subodh Verma, MD, PhD, a cardiovascular surgeon at the University of Toronto, Ontario, Canada, and the benefits were “especially large in patients receiving loop diuretics at baseline.”

The study found that semaglutide led to a reduction in daily loop diuretic dose of approximately 20% over placebo, reduced the initiation of new loop diuretics by 77%, and increased by over 2.5-fold loop diuretic discontinuations.

“These results suggest disease-modifying effects of semaglutide in obesity-related heart failure with preserved ejection fraction,” Verma said.

Dimitrios T. Farmakis, MD, PhD, from the National and Kapodistrian University of Athens in Greece, who was not involved in the study, commented that the STEP-HFpEF program has been an important step in the treatment of heart failure.

“We now have evidence that semaglutide provides more than just weight loss,” he said, with “some degree of improvement of the syndrome itself.”

However, Farmakis added there remain some “missing pieces of the puzzle.”

Important Step but Missing Pieces

In patients with obesity, this includes its efficacy and safety after 1 year and whether there are any renal or other side effects. In patients with heart failure, generally, it needs to be shown whether semaglutide is effective irrespective of left ventricular ejection fraction and regardless of the presence of obesity, whether the effects are drug-specific or common to all glucagon-like peptide 1 receptor agonist analogs, and what happens when patients stop taking the drug.

It is also not clear whether the results can be generalized to different ethnic groups because non-White individuals were underrepresented in the trials.

Verma acknowledged these limitations and added that the loop diuretic dose changes were analyzed in isolation without considering changes in other medications. 

The mechanism by which semaglutide promotes changes in plasma volume, natriuresis, and cardiac structure and function data is also currently unclear.

Patients with heart failure with preserved ejection fraction are frequently given loop diuretics as a first-line treatment for decongestion, but this can cause electrolyte abnormalities, worsening kidney function, and hypotension, Verma told the conference audience.

Benefits of Reducing Diuretics

The drugs have also been found to be less effective for decongestion in patients with obesity-related heart failure with preserved ejection fraction and have “exaggerated unfavorable impacts on kidney function.”

The STEP-HFpEF program has already shown that compared with placebo, semaglutide improved heart failure–related symptoms, physical limitations, and exercise function; reduced inflammation; and led to greater weight loss.

The current analysis pooled data from two trials, STEP-HFpEF and STEP HFpEF DM, to examine the efficacy and safety of once-weekly semaglutide 2.4 mg across diuretic doses and changes in diuretic use over 52 weeks.

The STEP-HFpEF trials randomly assigned 1145 patients aged 18 years or older with a body mass index > 30 to standard-of-care treatment plus semaglutide or placebo, with dose escalation over the first 16 weeks.

The patients were assessed for diuretic use, type, and dose at weeks 20, 36, and 52, with loop diuretics, thiazide diuretics, and mineralocorticoid receptor agonists all considered as diuretics but not sodium-glucose cotransporter 2 inhibitors. All diuretic doses were converted to furosemide equivalents.

Verma reported that across the diuretic use groups, the addition of semaglutide to standard-of-care therapy led to greater improvements in Kansas City Cardiomyopathy Questionnaire–Clinical Summary Scores than did placebo. Patients receiving no diuretics improved their score by 3.2 points; those treated with > 40 mg/d of loop diuretics improved by 11.6 points.

In contrast, semaglutide was consistently effective in reducing body weight irrespective of diuretic dose or diuretics used, he said, with patients losing 6.9%-9.4% of body weight over the study period. It also improved 6-minute walking distance, as well as C-reactive protein and N-terminal pro b-type natriuretic peptide levels.

Over the course of the study, patients given semaglutide were significantly more likely to decrease their loop diuretic dose than were those in the placebo group and were also less likely to increase their dose. On average, semaglutide users reduced their dose of loop diuretics by 17%, whereas the placebo group increased their dose by 2.4%, which resulted in an estimated treatment difference of 11.8 mg/d.

The semaglutide groups was also significantly less likely to initiate a new loop diuretic than were those taking the placebo, at 20.1% vs 6.1%, and were more likely to discontinue loop diuretics, at 5.9% vs 2.3%.