Summary: In a post-hoc, participant-level pooled analysis of 3743 adults with heart failure with mildly reduced or preserved ejection fraction (HFpEF) drawn from four semaglutide trials, once-weekly subcutaneous semaglutide was associated with a lower risk of the composite of cardiovascular death or worsening heart failure (HR 0.69, 95% CI 0.53 to 0.89; p=0.0045) and of worsening heart failure events alone (HR 0.59, 95% CI 0.41 to 0.82; p=0.0019). The effect on cardiovascular death alone was not statistically significant (HR 0.82, 95% CI 0.57 to 1.16; p=0.25).
PICO Summary
| Element | Detail |
|---|---|
| Population | 3743 participants with an investigator-reported history of HFpEF (16.8% of 22,282 total), pooled at participant level from four randomised, placebo-controlled, multinational trials (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM). Post-hoc, intention-to-treat full analysis set. |
| Intervention | Once-weekly subcutaneous semaglutide (2.4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1.0 mg in FLOW). n=1914. |
| Comparison | Matching placebo, once weekly subcutaneous. n=1829. |
| Outcome | Composite of cardiovascular death or worsening heart failure event: 103 (5.4%) vs 138 (7.5%); HR 0.69 (95% CI 0.53 to 0.89), p=0.0045. Worsening heart failure events alone: 54 (2.8%) vs 86 (4.7%); HR 0.59 (95% CI 0.41 to 0.82), p=0.0019. Cardiovascular death alone: 59 (3.1%) vs 67 (3.7%); HR 0.82 (95% CI 0.57 to 1.16), p=0.25 (not significant). Serious adverse events: 572 (29.9%) vs 708 (38.7%). Absolute risk reduction for the composite endpoint was approximately 2.1 percentage points (NNT around 48 over the trial durations). |
Semaglutide and HF events in HFpEF
Pooled analysis · 4 RCTs · HFpEF
Semaglutide was associated with fewer composite cardiovascular death or worsening heart failure events in HFpEF, driven by the worsening heart failure component; cardiovascular death alone was not significantly reduced. Hypothesis-generating, not confirmatory.
Expert Commentary
This pooled analysis is best read as hypothesis-generating rather than confirmatory. The signal is internally consistent: the composite endpoint and the worsening heart failure component were both reduced, and serious adverse events were fewer with semaglutide, which is reassuring for a population in which therapeutic options remain limited. The verdict, however, must be tempered. The work is a post-hoc, participant-level pool of trials that were not individually designed or powered to adjudicate heart failure events in HFpEF, and HFpEF status rested on investigator-reported history in SELECT and FLOW rather than on protocolised echocardiographic confirmation. The principal limitation is therefore one of design and ascertainment: heart failure events were a secondary consideration in three of the four source trials, and event numbers were modest, so the composite is driven largely by worsening heart failure rather than by mortality, which showed no significant benefit. The analysis was funded by the manufacturer, Novo Nordisk, and several authors are company employees, which warrants the usual caution around selective framing. Can I use this with my patients? Cautiously yes, for a patient with obesity-related HFpEF or HFpEF alongside type 2 diabetes or established atherosclerotic disease who already has a guideline indication for semaglutide, where these data add supportive reassurance rather than a new mandate. A dedicated, prospectively powered outcome trial in confirmed HFpEF is needed before semaglutide can be positioned as a heart-failure therapy in its own right.
References
Kosiborod MN, Deanfield J, Pratley R, et al. 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. Lancet. 2024;404(10456):949-961. doi:10.1016/S0140-6736(24)01643-X