Evidence supports semaglutide for obesity-related HFpEF

Semaglutide improves exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF) in a secondary analysis of the prespecified pooled STEP-HFpEF and STEP-HFpEF DM trials presented at HFSA 2024.

“The greatest improvements were observed in patients with the most weight loss at 52 weeks,” reported study author Dr Mikhail Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, Missouri, US.

“HFpEF represents the majority of HF cases in the community, and among those with the condition, the majority are also living with overweight or obesity,” he said. “Previous studies have shown that patients with obesity-related HFpEF experience worse burden of symptoms, physical limitations, and a greater degree of exercise impairment.”

Semaglutide impact on 6MWD

Kosiborod and colleagues sought to evaluate the efficacy of semaglutide 2.4 mg once weekly in relation to improving patients’ 6-minute walking distance (6MWD). “Specifically, we wanted to know the change in 6MWD according to the magnitude of weight loss.”

The pooled trials included 1,145 adult patients with HFpEF and a BMI of ≥30 kg/m² with (STEP-HFpEF DM) or without diabetes (STEP-HFpEF).

Participants were randomly assigned to semaglutide 2.4 mg once weekly or placebo. The dual primary endpoints were changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score and body weight from baseline to 52 weeks. The main findings reported previously showed that semaglutide 2.4 mg improved HF-related symptoms and physical limitations and reduced body weight vs placebo. [Lancet 2024;403:1635-1648]

In the current subanalysis, researchers evaluated semaglutide 2.4 mg for 20- and 52-week changes in 6MWD across subgroups based on weight loss and the impact of baseline walk distance on the primary and key secondary endpoints.

Participants were grouped into one of three tertiles of increasing 6MWD at baseline. The lowest tertile on 6MWD at baseline was older with higher waist circumference, BMI, C-reactive protein and N-terminal pro-B-type natriuretic peptide levels. This group had a higher NYHA class and lower KCCQ score. The left ventricular ejection fraction was not significantly different between tertiles of baseline walk distance.

“Early improvement in 6MWD was observed in patients assigned to semaglutide 2.4 mg vs placebo at 20 weeks [difference of 14.6 m] and was sustained out to 52 weeks [difference of 17.1 m; p <0.0001 for both],” Kosiborod said. “Improvement in walk distance was consistent across all subgroups.”

The difference in 6MWD increased further in patients with proportionately larger decreases in body weight with semaglutide from baseline to week 52 (0.1 m for <5 percent decrease, 17.1 m for a 5–10 percent decrease, 22.2 m for a 10–15 percent decrease, 24.3 m for a 15–20 percent decrease, and 34.7 m for ≥20 percent decrease).

The hierarchical composite endpoint and C-reactive protein ratio were also consistent across all tertiles of baseline 6MWD, with fewer serious and cardiac adverse events.

Multiple benefits for patients

“In patients with obesity-related HFpEF, baseline impairment in exercise function was associated with greater inflammation, congestion and adiposity,” said Kosiborod. “In this secondary analysis, semaglutide improved 6MWD as early as 20 weeks, preceding maximal weight loss, with a sustained effect at 52 weeks.”

This was in addition to improving HF-related symptoms, physical limitations and exercise function. Reductions in inflammation, congestion, and body weight were all consistent regardless of baseline exercise function, he added.