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.
Level 1 - systematic review of randomized trials
Prespecified individual patient data pooled analysis of randomized controlled trials
PubMed 38599221 · doi:10.1016/S0140-6736(24)00469-0
What was done
A prespecified pooled analysis of individual participant data from two multicenter, randomised, double-blind, placebo-controlled trials (STEP-HFpEF and STEP-HFpEF DM) across 129 clinical research sites in 18 countries. Participants were aged ≥18 years with heart failure, left ventricular ejection fraction ≥45%, BMI ≥30 kg/m², NYHA class II–IV symptoms, and KCCQ-CSS <90 points. STEP-HFpEF excluded patients with diabetes (HbA1c ≥6.5%), while STEP-HFpEF DM required type 2 diabetes (HbA1c ≤10%). Participants were randomly assigned to semaglutide 2.4 mg once weekly or matched placebo for 52 weeks. Dual primary endpoints were 52-week changes in KCCQ-CSS and bodyweight. Confirmatory secondary endpoints included 6-minute walk distance, a hierarchical composite clinical endpoint, and CRP concentrations.
What was found
Across 1,145 pooled participants (573 semaglutide, 572 placebo), semaglutide resulted in significantly greater improvements than placebo at week 52: - KCCQ-CSS mean difference: 7.5 points (95% CI 5.3 to 9.8; p<0.0001) - Bodyweight mean difference: -8.4% (95% CI -9.2 to -7.5; p<0.0001) - 6-minute walk distance mean difference: 17.1 metres (95% CI 9.2 to 25.0; p<0.0001) - Hierarchical composite endpoint win ratio: 1.65 (95% CI 1.42 to 1.91; p<0.0001) - CRP treatment ratio: 0.64 (95% CI 0.56 to 0.72; p<0.0001) Efficacy was consistent across subgroups by age, sex, race, BMI, baseline CRP, and ejection fraction. Serious adverse events were reported in 161 patients in the semaglutide group versus 301 in the placebo group.
Why it matters
This pooled analysis demonstrates that semaglutide consistently improves symptom burden, physical limitations, and exercise capacity in patients with obesity-related HFpEF regardless of whether they have type 2 diabetes.
Limits
Follow-up was restricted to 52 weeks, so hard clinical outcomes such as long-term mortality and hospitalisation rates were not assessed over multi-year horizons. The study enrolled only individuals with obesity (BMI ≥30 kg/m²) and preserved ejection fraction (≥45%), precluding generalization to non-obese HFpEF or reduced ejection fraction populations.
Cited by
- supports GLP-1 receptor agonist medications prevent or improve heart failure with preserved ejection fraction (HFpEF).