Semaglutide 2.4 mg eases obesity-related heart failure symptoms in trial

Results of the STEP-HFpEF trial, published in the New England Journal of Medicine, show that weekly semaglutide 2.4 mg reduced heart failure symptoms and physical limitations, improved exercise capacity and produced more weight loss than placebo in people with obesity-related heart failure with preserved ejection fraction, or HFpEF ^[1][2].

The trial assigned 529 patients at 96 sites in 13 countries in Asia, Europe, and North and South America ^[1]. Participants were 18 or older with a body-mass index of at least 30, an ejection fraction of at least 45 percent, New York Heart Association class II, III, or IV symptoms, a Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) below 90 points, and a six-minute walk distance of at least 100 meters ^[1]. They were randomly assigned to once-weekly semaglutide or placebo for 52 weeks, followed by a five-week follow-up period ^[1]. Semaglutide began at 0.25 mg and was increased every four weeks toward 2.4 mg by week 16 ^[1]. People with diabetes were excluded from the trial ^[1].

On the two primary measures, KCCQ-CSS rose 16.6 points with semaglutide and 8.7 points with placebo, an estimated difference of 7.8 points (95% confidence interval, 4.8 to 10.9; P<0.001) ^[1][2]. Body weight fell 13.3 percent with semaglutide and 2.6 percent with placebo, a difference of 10.7 percentage points (95% CI, −11.9 to −9.4; P<0.001) ^[1][2]. Six-minute walk distance increased 21.5 meters with semaglutide and 1.2 meters with placebo, a difference of 20.3 meters (95% CI, 8.6 to 32.1; P<0.001) ^[1][2]. C-reactive protein, a marker of inflammation, fell 43.5 percent with semaglutide and 7.3 percent with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001) ^[1][2].

On a composite endpoint that included death, heart failure events and differences in symptom score and walk distance, semaglutide recorded more wins than placebo, with a win ratio of 1.72 (95% CI, 1.37 to 2.15; P<0.001) ^[1][2].

Serious adverse events were reported in 35 participants (13.3 percent) taking semaglutide and 71 (26.7 percent) taking placebo ^[1][2]. The published abstract does not give a breakdown of specific side effects ^[1][2].

The authors note that HFpEF accounts for more than half of all cases of heart failure in the United States and is increasing in prevalence, that most people with the condition have overweight or obesity, and that patients with both HFpEF and obesity have more symptoms and worse functional capacity and quality of life than those without obesity ^[1]. No therapies had been approved to target obesity-related HFpEF, according to the paper ^[1][2]. Once-weekly subcutaneous semaglutide at 2.4 mg is approved for long-term weight management ^[1].

Why it matters for patients

HFpEF is common, and the trial measured outcomes that shape daily life: symptom burden and physical limitations on a patient-reported questionnaire, and how far someone can walk in six minutes ^[1]. Both improved more with semaglutide than with placebo, though the placebo group also improved on both measures ^[1][2].

The results apply to a specific group: adults with a BMI of 30 or higher and no diabetes ^[1]. Whether the same effects would appear in people with diabetes, or in people with a lower BMI, has not been established by this trial ^[1].

The 7.8-point difference in symptom scores and the 20.3-meter difference in walking distance are the differences between groups, not the full changes seen in either group ^[1][2]. The trial ran for 52 weeks; effects beyond that period are not reported in the abstract ^[1][2].

What happens next

The trial was funded by Novo Nordisk, which makes semaglutide, and is registered as NCT04788511 ^[1][2]. The publication does not state whether the company will seek approval for a heart failure indication, and no such approval has been disclosed ^[1][2].

A pooled analysis of STEP-HFpEF and STEP-HFpEF DM, a companion trial that enrolled people with type 2 diabetes, has since been published ^[2]. Prespecified analyses of the STEP-HFpEF data examining quality of life and effects by sex have also appeared ^[2].