Summary: In a prespecified secondary analysis of the pooled STEP-HFpEF and STEP-HFpEF DM trials (n=1,145; 49.7% women), once-weekly semaglutide 2.4 mg improved heart failure symptoms to a similar degree in women and men (KCCQ-CSS +7.6 vs +7.5 points; P interaction = 0.94), while body-weight reduction was greater in women than men (-9.6% vs -7.2%; P interaction = 0.006). No clinically meaningful sex-based difference in symptom benefit was observed.
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 randomised trials across 18 countries; 570 (49.7%) women. Prespecified secondary analysis by sex. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks (semaglutide group n=573 in the pooled cohort). |
| Comparison | Matched placebo for 52 weeks (placebo group n=572); treatment effect tested for interaction by sex (women vs men). |
| Outcome | KCCQ-CSS improvement: 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 change: women -9.6% (95% CI -10.9 to -8.4), men -7.2% (95% CI -8.4 to -6.0), P interaction = 0.006. 6-minute walk distance (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) improved in both sexes. Fewer serious adverse events occurred with semaglutide than placebo. No hard clinical-event outcomes (mortality, hospitalisation) were powered for this subgroup analysis. |
STEP-HFpEF: Semaglutide by Sex
RCT secondary analysis · obesity-related HFpEF · 52 weeks
Semaglutide 2.4 mg improved heart failure symptoms to a similar degree in women and men with obesity-related HFpEF. Weight loss was greater in women, but symptom benefit did not differ by sex.
Expert Commentary
This prespecified secondary analysis was undertaken to determine whether the symptomatic and weight benefits of semaglutide in obesity-related HFpEF are modified by sex, a relevant question given that women are over-represented in this phenotype. The verdict is reassuring: the improvement in heart-failure-related symptoms and physical limitations was essentially identical in women and men (P interaction = 0.94), and exercise capacity and the hierarchical composite were improved in both. The one clear sex difference was greater weight loss in women, which is consistent with the pharmacology of GLP-1 receptor agonists and is unlikely to be clinically disadvantageous. The principal limitation is that this is a subgroup analysis of pooled symptomatic endpoints over 52 weeks; it was not powered for hard cardiovascular events, and an interaction P value of 0.006 for weight does not establish a difference in the outcome that matters most to patients, namely symptoms. Sponsorship by the manufacturer and the presence of company authors warrant the usual caution, although the trials were double-blind and placebo-controlled. Can I use this with my patients? Yes, for a symptomatic woman or man with obesity-related HFpEF, this supports offering semaglutide 2.4 mg with the expectation of comparable symptom benefit regardless of sex. Clinicians should still counsel that event-reduction data remain to be confirmed and prioritise patients most likely to tolerate and adhere to therapy.
References
Verma S, Butler J, Borlaug BA, 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