Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.
Level 1 - systematic review of randomized trials
Pooled individual participant-level analysis of four randomised controlled trials
PubMed 39222642 · doi:10.1016/S0140-6736(24)01643-X
What was done
A post-hoc, participant-level pooled analysis of four randomized, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) evaluating once-weekly subcutaneous semaglutide (1.0 mg in FLOW; 2.4 mg in the other three) versus placebo. The study included all participants from the STEP-HFpEF trials and those with an investigator-reported history of heart failure with mildly reduced or preserved ejection fraction (HFpEF) from SELECT and FLOW (total n = 3,743; 1,914 semaglutide, 1,829 placebo). Key endpoints assessed by intention-to-treat were time to cardiovascular death or first worsening heart failure event (hospitalisation or urgent visit), time to first worsening heart failure event, and cardiovascular death alone.
What was found
Semaglutide significantly reduced the primary composite of cardiovascular death or worsening heart failure events compared with placebo: 5.4% (103/1,914) versus 7.5% (138/1,829), hazard ratio (HR) 0.69 (95% CI 0.53–0.89; p=0.0045). Worsening heart failure events alone were also significantly lower: 2.8% (54/1,914) versus 4.7% (86/1,829), HR 0.59 (95% CI 0.41–0.82; p=0.0019). The difference in cardiovascular death alone was not statistically significant: 3.1% (59/1,914) versus 3.7% (67/1,829), HR 0.82 (95% CI 0.57–1.16; p=0.25). Serious adverse events occurred in 29.9% (572/1,914) of patients taking semaglutide versus 38.7% (708/1,829) on placebo.
Why it matters
Extends earlier findings that semaglutide improves quality of life in HFpEF by demonstrating a concrete reduction in hard clinical worsening events and hospitalisations across broad patient populations with obesity, diabetes, and cardiovascular or kidney disease.
Limits
This was a post-hoc pooled analysis rather than a single prospective trial powered specifically for clinical events in HFpEF. HFpEF status was investigator-reported in SELECT and FLOW rather than verified by standardized echocardiographic screening criteria. Doses varied between trials (1.0 mg vs 2.4 mg weekly), and the study was funded by the manufacturer (Novo Nordisk).
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