Current and Emerging Roles of GLP1 Receptor Agonists Across the Spectrum of Left Ventricular Ejection Fraction in Heart Failure

: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) have demonstrated significant cardiometabolic benefits, particularly in patients with type 2 diabetes and obesity. Their role in heart failure (HF) is gaining increasing attention, with growing evidence supporting their efficacy in HF with preserved ejection fraction (HFpEF). Recent trials have shown that semaglutide improves symptoms, functional capacity, and weight loss in patients with HFpEF. However, these trials did not demonstrate a reduction in HF hospitalizations or mortality. In contrast, tirzepatide has revealed a significant reduction in cardiovascular death and worsening HF events in patients with obesity-related HFpEF, suggesting broader cardioprotective effects. Concordantly, the benefit of GLP1-RAs in the setting of HF with reduced ejection fraction (HFrEF) remains uncertain. Although their mechanisms suggest potential advantages, particularly for patients with a cardiometabolic phenotype, clinical evidence supporting improvements in major clinical outcomes is lacking. Additionally, concerns regarding risk of increased HF hospitalizations, fluid retention and arrhythmic risk have led to a cautious approach in this population. As HF management continues to evolve, GLP1-RAs emerge as a promising yet complex therapeutic option. This review synthesizes the current evidence, highlights key knowledge gaps, and explores how these medications might be integrated into guideline-directed medical therapy (GDMT) to determine their optimal role across the LVEF spectrum in HF.