Glucagon-Like Peptide-1 Receptor Agonists Across the Heart Failure Spectrum: A Systematic Review and Meta-Analysis

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular (CV) benefits, but their effects across the heart failure (HF) spectrum remain uncertain. We synthesized randomized evidence comparing GLP-1 RAs with placebo in adults with HF across ejection fraction phenotypes by searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of CV death and first HF hospitalization, and random-effects meta-analysis used restricted maximum likelihood (REML) estimation with the Hartung-Knapp-Sidik-Jonkman (HKSJ) adjustment. We included 14 studies (six dedicated HF trials and eight cardiovascular outcomes trials (CVOT) HF subgroup analyses) encompassing 18,184 patients. The primary composite outcome was not statistically significant (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.01; P=0.067; I²=47%). GLP-1 RAs reduced all-cause mortality (ACM; HR 0.86, 95% CI 0.79-0.95; P=0.008; low certainty according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE)) and major adverse CV events (MACE; HR 0.80, 95% CI 0.69-0.93), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) by 7.4 points and 6-minute walk distance (6MWD) by 17.6 m. However, the mortality benefit was driven by CVOT subgroups, whereas dedicated HF trials showed directional harm. GLP-1 RAs did not significantly reduce the primary composite outcome but improved quality of life and functional capacity in heart failure with preserved ejection fraction (HFpEF) and obesity. The pooled mortality reduction should be interpreted cautiously, given the divergence between indirect and direct evidence.