Summary: In a prespecified secondary analysis of the pooled STEP-HFpEF and STEP-HFpEF DM trials (n=1,145; 45% with a history of atrial fibrillation), once-weekly semaglutide 2.4 mg over 52 weeks improved symptoms more in participants with AF (KCCQ-CSS 11.5 vs 4.3 points; P interaction=0.001). Weight, CRP, and NT-proBNP fell consistently regardless of AF status. This is a subgroup (effect-modification) finding, not a separate efficacy trial.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF (LVEF ≥45%, BMI ≥30 kg/m², KCCQ-CSS <90); pooled, multinational STEP-HFpEF and STEP-HFpEF DM trials. 518 (45%) had a history of AF (40% paroxysmal, 24% persistent, 35% permanent); 627 (55%) did not. Prespecified secondary analysis by AF history. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks, 1:1 randomisation within the parent double-blind trials. |
| Comparison | Matching placebo for 52 weeks. |
| Outcome | KCCQ-CSS improvement: 11.5 points (95% CI 8.3 to 14.8) with AF vs 4.3 points (95% CI 1.3 to 7.2) without AF; P interaction=0.001. Hierarchical composite win ratio: 2.25 (95% CI 1.79 to 2.83) with AF vs 1.30 (95% CI 1.06 to 1.59) without; P interaction<0.001. Responder rates (≥5, ≥10, ≥15, ≥20-point KCCQ-CSS gains) higher with AF (all P interaction<0.05). Body weight, CRP, and NT-proBNP reduced regardless of AF status (all P interaction not significant). Fewer serious adverse events with semaglutide than placebo. No ARR/NNT reported (continuous and hierarchical endpoints). |
Semaglutide in Obesity-HFpEF by AF Status
RCT secondary analysis · HFpEF · 52 weeks
Semaglutide improved symptoms and the hierarchical composite in obesity-related HFpEF regardless of AF, with a larger benefit in patients with AF at baseline. This is an effect-modification subgroup finding, not a randomised AF-vs-no-AF comparison.
Expert Commentary
This is a credible, prespecified secondary analysis of two well-conducted, double-blind randomised trials, and the verdict is that semaglutide 2.4 mg helps patients with obesity-related HFpEF irrespective of atrial fibrillation, with a larger symptomatic gain in those with AF at baseline. The randomised parent design protects the within-group treatment estimates, and the consistent reductions in weight, CRP, and NT-proBNP across AF strata strengthen biological plausibility. The principal limitation is that the headline message is an effect-modification claim drawn from subgroups defined by investigator-reported AF history rather than a randomised comparison of AF versus no AF; participants with AF were older, more often male, and had more advanced heart failure, so the apparently greater benefit may partly reflect a higher symptom ceiling for improvement rather than a true mechanistic interaction. Several authors are employees of the manufacturer (Novo Nordisk), which warrants the usual caution, and the analysis is a secondary one, so the interaction findings are hypothesis-supporting, not definitive. Can I use this with my patients? Yes for the core point: an ambulatory patient with obesity-related HFpEF and coexisting AF is a reasonable candidate for semaglutide on symptom and weight grounds, while recognising it is not an AF-rhythm therapy. A dedicated prospective evaluation of HFpEF phenotypes would sharpen who benefits most.
References
Verma S, Butler J, Borlaug BA, Davies MJ, Kitzman DW, Petrie MC, et al. Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program. J Am Coll Cardiol. 2024;84(17):1603-1614. doi:10.1016/j.jacc.2024.08.023