Summary: In a prespecified pooled analysis of two double-blind randomised trials (n=1145) in adults with obesity-related heart failure with preserved ejection fraction, semaglutide 2.4 mg weekly improved heart failure-related symptoms and physical limitations (KCCQ-CSS +7.5 points, 95% CI 5.3 to 9.8) and reduced bodyweight (-8.4%, 95% CI -9.2 to -7.5) versus placebo at 52 weeks. These were symptom, functional, and biomarker endpoints rather than a powered test of hard cardiovascular outcomes.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1145 adults aged 18 years or older with heart failure, left ventricular ejection fraction at least 45%, BMI at least 30 kg/m2, NYHA class II to IV symptoms, and KCCQ-CSS below 90; prespecified pooled individual patient data from the STEP-HFpEF and STEP-HFpEF DM randomised, double-blind, placebo-controlled trials at 129 sites in 18 countries. |
| Intervention | Semaglutide 2.4 mg subcutaneously once weekly for 52 weeks (n=573). |
| Comparison | Matched placebo once weekly for 52 weeks (n=572). |
| Outcome | Dual primary endpoints, change from baseline to week 52: KCCQ-CSS between-group difference +7.5 points (95% CI 5.3 to 9.8; p<0.0001); bodyweight -8.4% (95% CI -9.2 to -7.5; p<0.0001). Confirmatory secondary endpoints: 6-minute walk distance +17.1 m (95% CI 9.2 to 25.0); hierarchical composite win ratio 1.65 (95% CI 1.42 to 1.91); CRP treatment ratio 0.64 (95% CI 0.56 to 0.72); all p<0.0001. Effects were largely consistent across subgroups. Serious adverse events: 161 with semaglutide versus 301 with placebo. No ARR/NNT for a hard clinical endpoint was reported, as the trials were not powered for mortality or heart failure hospitalisation. |
Semaglutide in obesity-related HFpEF
Pooled RCT analysis · obesity HFpEF · 52 weeks
Semaglutide 2.4 mg weekly improved symptoms, function, and weight in obesity-related HFpEF over 52 weeks. Endpoints were symptomatic, functional, and biomarker measures, not a powered test of hard cardiovascular outcomes.
Expert Commentary
The verdict is that semaglutide 2.4 mg produced a consistent, clinically meaningful improvement in symptoms, physical limitations, and bodyweight in obesity-related HFpEF, supported by gains in 6-minute walk distance, a favourable hierarchical composite, and lower CRP. The design is a genuine strength: prespecified pooling of individual patient data from two double-blind, placebo-controlled trials lends precision and consistency across subgroups, and the lower serious-adverse-event count argues for good tolerability. The principal limitation is that the endpoints were symptomatic, functional, and biomarker measures over 52 weeks rather than a powered assessment of hard cardiovascular outcomes such as mortality or heart failure hospitalisation; the hierarchical composite includes such events but cannot be read as a definitive outcomes trial, and the funder, Novo Nordisk, both manufactures semaglutide and conducted the analysis, which warrants the usual caution about sponsor-led interpretation. Can I use this with my patients? Yes, for the patient with obesity-related HFpEF and a high symptom burden who is seeking better function and weight control, this is reasonable evidence to support a trial of semaglutide, while being candid that a survival or hospitalisation benefit is not yet established. A dedicated, adequately powered outcomes trial in this phenotype would be the natural next step.
References
Butler J, Shah SJ, Petrie MC, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024;403(10437):1635-1648. doi:10.1016/S0140-6736(24)00469-0