The Efficacy of Glucagon-like Peptide-1 Based Therapies in Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis

Background/Objectives: Despite advances in heart failure (HF) pharmacotherapy, novel treatments are needed for its main subtypes: preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. Glucagon-like peptide-1 (GLP-1) based therapies have shown cardioprotective effects. We conducted a systematic review and meta-analysis (Prospero Registration Number CRD42024606997) assessing the efficacy of GLP-1 based therapies (GLP-1 receptor agonists including tirzepatide) across the spectrum of left ventricular ejection fraction on cardiovascular (CV) outcomes. Methods: The PubMed, Embase, Scopus and trial registries were searched until December 2025 for randomised controlled trials (RCTs) involving adults with HF treated with GLP-1 based therapies. Outcomes included heart failure hospitalisations (HFH), CV, and all-cause mortality. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analyses were performed by HF subtype, age, coronary artery disease (CAD) presence, and GLP-1 based therapeutic agent. Results: Fourteen RCTs (15,180 participants), at low risk of bias, were included. These agents significantly reduced HFH (RR: 0.84, 95% CI: 0.71–0.99), especially in HFpEF patients with stable CAD (RR: 0.61, 95% CI: 0.46–0.79). Limited data suggested benefits for exenatide in HFmrEF patients (RR: 0.67, 95% CI: 0.47–0.95). CV mortality was reduced in HFrEF patients <65 years old (RR: 0.71, 95% CI: 0.54–0.95). Benefit was seen in composites of HFH and CV mortality for HFpEF (RR: 0.67, 95% CI: 0.54–0.83). Conclusions: GLP-1 based therapies may reduce HFH in HFpEF and possibly lower CV mortality in younger HFrEF patients, suggesting phenotype-specific effects.