Summary: In a prespecified secondary analysis pooling the STEP-HFpEF and STEP-HFpEF DM randomised trials (n=1,145; 49.7% women), once-weekly semaglutide 2.4 mg improved heart-failure symptoms similarly in both sexes (KCCQ-CSS mean difference +7.6 in women and +7.5 in men; P interaction 0.94), while body-weight reduction was significantly greater in women (-9.6% vs -7.2%; P interaction 0.006). This is a subgroup-by-sex analysis testing effect modification, not a new efficacy trial.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF (LVEF ≥45%, BMI ≥30 kg/m², KCCQ-CSS <90), pooled from two double-blind RCTs (STEP-HFpEF and STEP-HFpEF DM) across 129 sites in 18 countries; 570 (49.7%) women. Prespecified secondary analysis examining sex as an effect modifier. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks (n=573 in the pooled semaglutide group). |
| Comparison | Matched once-weekly placebo for 52 weeks (n=572 in the pooled placebo group). |
| Outcome | KCCQ-CSS improved regardless of sex: women +7.6 points (95% CI 4.5 to 10.7), men +7.5 points (95% CI 4.3 to 10.6), P interaction 0.94. Body-weight reduction was larger in women: -9.6% (95% CI -10.9 to -8.4) vs men -7.2% (95% CI -8.4 to -6.0), P interaction 0.006. The 6-minute walk distance benefit (P interaction 0.21) and the hierarchical composite endpoint (P interaction 0.66) were consistent across sexes. Fewer serious adverse events occurred with semaglutide than placebo. No absolute risk reduction or NNT applies, as the primary endpoints were continuous and no clinical-event efficacy claim was tested. |
Semaglutide in obesity-related HFpEF: effect by sex
Pooled RCT secondary analysis · obesity-related HFpEF · 52 weeks
Semaglutide 2.4 mg improved heart-failure symptoms to a similar degree in women and men (P interaction 0.94); weight loss was greater in women (-9.6% vs -7.2%). The result shows consistency of benefit across sexes, not new efficacy.
Expert Commentary
This prespecified secondary analysis was designed to ask whether the symptomatic and weight benefits of semaglutide in obesity-related HFpEF are modified by sex, and the verdict is reassuring: heart-failure-related symptoms, physical limitations, exercise capacity, and the hierarchical composite all improved to a similar degree in women and men, with no signal of effect modification for the symptom endpoint. The one meaningful sex difference was greater weight loss in women, which is biologically plausible and consistent with broader GLP-1 receptor agonist data. The headline finding should be read as consistency of benefit across sexes rather than as fresh proof of efficacy, since efficacy was established by the parent trials and this analysis is exploratory by design, underpowered for clinical events, and at risk of residual confounding and multiplicity across the many subgroup comparisons. The trials were funded by the manufacturer, Novo Nordisk, and several authors are company employees, which warrants the usual caution even within a rigorous double-blind design. Can I use this with my patients? Yes, for a woman or man with obesity-related HFpEF and a high symptom burden, this analysis supports offering semaglutide 2.4 mg with the expectation of comparable symptomatic gains and, in women, somewhat greater weight reduction. It would be useful to see whether the larger weight loss in women translates into any difference in hard outcomes over longer follow-up.
References
Verma S, Butler J, Borlaug BA, Davies M, Kitzman DW, Shah SJ, et al. Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials. J Am Coll Cardiol. 2024;84(9):773-785. doi:10.1016/j.jacc.2024.06.001