Time to Benefit of Incretin-Based Therapies in Adiposity-Related Heart Failure With Mildly Reduced or Preserved Ejection Fraction: a Systematic Review and Meta-Analysis.

BACKGROUND

Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF). Incretin-based therapies are associated with a reduction in worsening heart failure (HF) events for patients with HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), although the time to clinical benefit from these therapies is unknown.

METHODS

PubMed, Embase, and CENTRAL were searched until July 12, 2025, for randomized controlled trials studying incretin-based therapies (semaglutide, tirzepatide) in adults with overweight/obesity and HF with ejection fraction >40%, and ≥52-week follow-up. We extracted study-level data, from which individual participant data (IPD) were reconstructed. To estimate the time to benefit, we iteratively calculated hazard ratios (HRs) and 95% confidence intervals (CIs) with the dataset truncated for each day of follow-up. We pooled overall results with reconstructed IPD and study-level random-effects meta-analyses. Risk of bias was assessed with RoB 2, and certainty of evidence with GRADE.

RESULTS

Four trials, encompassing 4149 participants and a weighted average median follow-up of 2.47 years, were included. Risk of bias was low. Compared to placebo, incretin-based therapies reduced worsening HF or cardiovascular death (HR 0.59, 95% CI 0.45-0.78; moderate certainty). The nominal time to first statistical significance was 126 days (4.1 months), and statistical significance was sustained after day 162 (5.3 months). Incretin-based therapies reduced worsening HF events (HR 0.33, 95% CI 0.20-0.54; high certainty), with sustained significance after day 183 (6.0 months).

CONCLUSIONS

Incretin-based therapies are associated with reduced HF events in patients with overweight/obesity and HFmrEF/HFpEF, with sustained statistically significant outcome benefits observed from approximately 6 months onward.