Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events and worsening heart failure in patients with heart failure: an umbrella meta-analysis.

backgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes, have demonstrated cardiovascular benefits. However, evidence regarding their efficacy in heart failure (HF) remains conflicting due to inconsistent results from individual studies and meta-analyses.

methodsWe conducted an umbrella review of systematic reviews and meta-analyses. PubMed, Embase, and the Web of Science were searched from inception until August 2025. Methodological quality and risk of bias were assessed using AMSTAR-2 and ROBIS. Evidence certainty was evaluated using GRADE. Dual analytical approaches (a least redundant set and an all meta-analyses approach) were employed to address primary study overlap.

resultsTwelve systematic reviews (encompassing 29 unique randomized controlled trials) were included. GLP-1RAs treatment significantly reduced the risk of major adverse cardiovascular events (HR = 0.86, 95%CI: 0.66–0.98) and worsening HF (HR = 0.56, 95%CI: 0.41–0.77). It also significantly improved functional capacity as measured by the 6-minute walking test (mean difference = 14.23 m, 95%CI: 6.19 to 22.27). However, no significant benefits were observed for all-cause mortality, cardiovascular mortality, hospitalization HF, or cardiac structural parameters including left ventricular ejection fraction, left ventricular end-diastolic volume, and left ventricular end-systolic volume. Considerable overlap existed among the included reviews (Corrected Covered Area = 20.20%). The overall quality of evidence for outcomes ranged from low to moderate.

conclusionThis umbrella review suggests that GLP-1RAs may reduce MACE and worsening HF, and improve functional capacity in patients with HF. However, no benefits were observed for mortality or HF hospitalization. The positive findings were primarily driven by studies in HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), while evidence in HF with reduced ejection fraction (HFrEF) was limited and showed no benefit. Given the low-to-moderate certainty of evidence and the absence of benefit on hard clinical outcomes, these findings do not support a definitive change in clinical practice but rather highlight the urgent need for dedicated, phenotype-specific HF trials. CLINICAL TRIAL NUMBER: Not applicable.