GLP-1 Receptor Agonists in Heart Failure

Heart failure (HF) is a growing public health concern, driven by the increasing prevalence of obesity, diabetes, and aging. Despite therapeutic advances, HF continues to be associated with high morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for glycemic control in type 2 diabetes, have demonstrated cardiovascular benefits in clinical trials. Recent studies, including STEP-HFpEF and SUMMIT, have shown improvement in symptoms and weight loss in patients with HF with preserved ejection fraction (HFpEF). GLP-1 RAs are involved in multiple biological pathways relevant to heart failure pathophysiology. These include pathways related to sympathetic nervous system activity, inflammatory cytokine signaling, oxidative stress, calcium handling, natriuretic peptide signaling, and cardiac metabolism. GLP-1 receptor agonists modulate vascular pathways involving nitric oxide signaling, endothelial function, and renal sodium handling, contributing to improved hemodynamics and neurohormonal balance. Together, these actions intersect with key neurohormonal and cellular processes contributing to chronic heart failure progression. This review explores the mechanistic overlap between GLP-1 receptor signaling and heart failure pathophysiology. This mechanistic overlap suggests a plausible role for these agents as adjunctive treatments in heart failure, especially in metabolically driven phenotypes. While direct cardiac effects remain incompletely defined, systemic metabolic and anti-inflammatory actions provide a mechanistic basis for observed clinical benefits.