Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program (JACC Heart Failure November 2025)-Article: Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program

Article: Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program

Pdf Summary

This prespecified secondary analysis of the STEP-HFpEF Program evaluated the effects of semaglutide, a glucagon-like peptide-1 receptor agonist, on exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Exercise capacity, measured by the 6-minute walk distance (6MWD), is severely impaired in HFpEF and strongly correlates with symptoms, frailty, and outcomes. The study pooled data from two randomized, placebo-controlled trials including 1,145 patients with obesity-related HFpEF, with or without type 2 diabetes.<br /><br />At baseline, lower 6MWD was associated with older age, higher body mass index (BMI), waist circumference, systemic inflammation (C-reactive protein [CRP]), and congestion indicators (N-terminal pro–B-type natriuretic peptide [NT-proBNP], diuretic use), along with worse heart failure symptoms as measured by the Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS). Semaglutide treatment markedly improved 6MWD compared to placebo, with significant gains evident as early as 20 weeks and sustained at 52 weeks (treatment difference approximately 15-17 meters). Improvement in 6MWD was consistent across subgroups regardless of baseline exercise function, age, sex, diabetes status, or other factors, and correlated strongly with the magnitude of weight loss achieved. Each reduction of 1 unit in BMI on semaglutide corresponded to a 4.1-meter increase in 6MWD.<br /><br />Semaglutide also resulted in significant reductions in body weight, CRP, NT-proBNP, and improvements in KCCQ-CSS and a hierarchical composite endpoint including death and heart failure events, independent of baseline 6MWD. Safety profiles were favorable, with fewer serious adverse events on semaglutide compared to placebo, including in patients with the lowest baseline 6MWD.<br /><br />In sum, this analysis demonstrates that in obesity-related HFpEF, exercise limitation is linked to inflammation, congestion, and excess adiposity, and that semaglutide improves symptoms, exercise capacity, and biomarkers across the spectrum of baseline functional impairment. Benefits occurred early, ahead of maximal weight loss, and greater weight reduction was associated with larger functional gains. These findings support targeting obesity and inflammation with semaglutide to enhance exercise tolerance and clinical status in patients with obesity-related HFpEF.

Keywords

semaglutide

HFpEF

obesity-related heart failure

exercise capacity

6-minute walk distance

weight loss

glucagon-like peptide-1 receptor agonist

inflammation

NT-proBNP

Kansas City Cardiomyopathy Questionnaire