Summary: In a prespecified subgroup analysis of the pooled STEP-HFpEF Program (n=1,145), once-weekly semaglutide 2.4 mg improved heart-failure-related symptoms in obesity-related HFpEF both with and without atrial fibrillation. The benefit was larger in participants with AF (KCCQ-CSS gain 11.5 vs 4.3 points; P interaction = 0.001), while weight, CRP, and NT-proBNP fell regardless of AF status.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF (LVEF ≥45%, BMI ≥30 kg/m², KCCQ-CSS <90); pooled STEP-HFpEF and STEP-HFpEF DM trials. 518 (45%) had a history of AF (40% paroxysmal, 24% persistent, 35% permanent); 627 (55%) did not. Multinational, double-blind RCTs; this is a secondary subgroup analysis. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks plus standard care (pooled trial arm). |
| Comparison | Matching once-weekly placebo plus standard care; subgroups defined by baseline investigator-reported AF history (yes/no), randomised 1:1 within the parent trials. |
| Outcome | KCCQ-CSS improvement (semaglutide vs placebo): 11.5 points (95% CI 8.3-14.8) with AF vs 4.3 points (95% CI 1.3-7.2) without AF; P interaction = 0.001. Hierarchical composite win ratio 2.25 (95% CI 1.79-2.83) with AF vs 1.30 (95% CI 1.06-1.59) without AF; P interaction < 0.001. Reductions in CRP, NT-proBNP, and body weight were consistent across AF status (P interaction values not significant). Fewer serious adverse events occurred with semaglutide irrespective of AF history. As a subgroup analysis, no overall ARR/NNT is reported. |
Semaglutide in Obesity-HFpEF by AF Status
STEP-HFpEF subgroup · obesity-related HFpEF · 52 weeks
Semaglutide improved HFpEF symptoms with and without AF, but the symptom and win-ratio benefits were significantly larger in those with AF. The interaction is hypothesis-generating, as AF status was investigator-reported and non-randomised.
Expert Commentary
This secondary, prespecified subgroup analysis of the pooled STEP-HFpEF Program asks a focused question: does baseline atrial fibrillation modify the response to once-weekly semaglutide 2.4 mg in obesity-related HFpEF? The parent trials were double-blind and placebo-controlled, which lends the underlying comparison credibility, yet the present report is an effect-modification analysis rather than a fresh efficacy trial, and its findings are exploratory and hypothesis-generating. The signal is internally consistent: symptom and physical-limitation gains, captured by the KCCQ-CSS and the hierarchical composite, were larger in participants with AF, while weight, CRP, and NT-proBNP were reduced irrespective of AF status. The most weighable limitation is that AF status was investigator-reported and not randomised, so the larger benefit in the AF group is observational and may reflect their more advanced heart failure and greater room to improve rather than a true biological interaction. Readers should also note that the program was funded by the manufacturer of semaglutide, with sponsor-affiliated authors. Can I use this with my patients? Cautiously yes, as supportive context when considering semaglutide for an obese HFpEF patient who also has AF, but not as standalone proof that AF predicts response. The interaction should be confirmed in dedicated, prospectively powered analyses before it guides selection.
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