GLP-1 RAs show no significant reduction in composite CV death/HF hospitalization but improve quality of life and function in HFpEF.

Despite established cardiovascular (CV) benefits in obesity and heart failure with preserved ejection fraction (HFpEF), the role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) across the entire heart failure (HF) spectrum, particularly in heart failure with reduced ejection fraction (HFrEF), remains unclear. Current standard-of-care for HF often falls short in improving both hard outcomes and patient-reported quality of life, highlighting a critical gap for therapies that can address the multifaceted nature of the disease.

This systematic review and meta-analysis synthesized randomized evidence comparing GLP-1 RAs with placebo in adults with HF across ejection fraction phenotypes. Researchers searched PubMed, Cochrane CENTRAL, and ClinicalTrials.gov. The analysis included 14 studies (six dedicated HF trials and eight cardiovascular outcomes trials (CVOT) HF subgroup analyses) encompassing 18,184 patients. The primary outcome was a composite of CV death and first HF hospitalization, analyzed using random-effects meta-analysis with REML estimation and HKSJ adjustment.

The primary composite outcome of CV death and first HF hospitalization was not statistically significant (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.01; P=0.067; I²=47%). However, GLP-1 RAs significantly reduced all-cause mortality (ACM; HR 0.86, 95% CI 0.79-0.95; P=0.008) and major adverse CV events (MACE; HR 0.80, 95% CI 0.69-0.93). They also improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) by 7.4 points and 6-minute walk distance (6MWD) by 17.6 m. These benefits were primarily observed in HFpEF patients with obesity.

The observed mortality benefit was largely driven by CVOT subgroups, whereas dedicated HF trials showed a directional harm, warranting cautious interpretation.