Summary: In a secondary, pooled subgroup analysis of the STEP-HFpEF and STEP-HFpEF DM trials (n=1,145), once-weekly semaglutide 2.4 mg improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) by 11.5 points (95% CI 8.3 to 14.8) in patients with a history of atrial fibrillation versus 4.3 points (95% CI 1.3 to 7.2) in those without (P interaction = 0.001). Reductions in body weight, C-reactive protein, and NT-proBNP were consistent regardless of atrial-fibrillation status.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF (LVEF ≥45%, BMI ≥30 kg/m², KCCQ-CSS <90); 518 (45%) with a history of atrial fibrillation, 627 (55%) without. Pooled secondary analysis of two randomised, double-blind, placebo-controlled, multicentre trials (STEP-HFpEF and STEP-HFpEF DM). |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks, on top of standard care (randomised 1:1). |
| Comparison | Matching placebo once weekly for 52 weeks, with outcomes assessed by baseline atrial-fibrillation history (yes/no) and AF type. |
| Outcome | KCCQ-CSS improvement was larger in the AF subgroup: 11.5 points (95% CI 8.3 to 14.8) with AF versus 4.3 points (95% CI 1.3 to 7.2) without (P interaction = 0.001). Hierarchical composite win ratio 2.25 (95% CI 1.79 to 2.83) with AF versus 1.30 (95% CI 1.06 to 1.59) without (P interaction <0.001). Reductions in body weight, CRP, and NT-proBNP were consistent across AF status (all P interaction not significant). Serious adverse events were fewer with semaglutide than placebo irrespective of AF history. As a subgroup interaction analysis, these between-group differences are associational and hypothesis-generating; no absolute risk reduction or NNT was reported. |
Semaglutide in HFpEF by atrial fibrillation status
STEP-HFpEF pooled subgroup analysis · obesity-related HFpEF · 52 weeks
Semaglutide beat placebo on the hierarchical composite in both subgroups, but the effect was markedly larger in patients with a history of atrial fibrillation (win ratio 2.25 vs 1.30, P interaction <0.001). The interaction is hypothesis-generating, not an AF-directed indication.
Expert Commentary
This secondary analysis pooled the STEP-HFpEF and STEP-HFpEF DM trials to ask whether semaglutide’s benefit in obesity-related HFpEF is modified by a history of atrial fibrillation. The signal is internally consistent: symptom and physical-limitation gains were roughly two to three times larger in the AF subgroup, and the interaction was statistically significant for the patient-reported and composite endpoints, while weight, CRP, and NT-proBNP fell similarly regardless of rhythm history. The verdict is that semaglutide remains beneficial across the cohort, with a plausibly amplified symptomatic response in those with AF, who were older and had more advanced heart failure at baseline. The principal limitation is that this is a post-hoc subgroup interaction analysis: AF was ascertained by investigator report, the comparison was not a randomisation stratum, and a single significant interaction carries real risk of chance, so the effect modification should be read as hypothesis-generating rather than established. Industry sponsorship is relevant here, as the trials and this analysis were funded by the manufacturer of semaglutide. Can I use this with my patients? Yes, for symptomatic adults with obesity-related HFpEF who already meet the trial profile, a coexisting AF history is no reason to withhold semaglutide and may predict a larger symptom benefit, though it should not be framed as an AF-directed therapy. Confirmation in prospectively stratified analyses would strengthen the case.
References
Verma S, Butler J, Borlaug BA, 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