Glucagon-Like Peptide-1 Receptor Agonists in Cardiovascular Disease: Redefining Therapy Through Cardiometabolic Substrate Modification

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have moved from the margins of diabetes care to the center of cardiovascular medicine. Although initially developed as glucose-lowering agents, their most important clinical effects arise from broader actions on body weight, vascular biology, inflammation, and metabolic stress. Randomized trials have established that several GLP-1RAs reduce major adverse cardiovascular events and mortality in patients with type 2 diabetes and, more recently, in individuals with overweight or obesity and established cardiovascular disease without diabetes. However, their cardiovascular effects are not uniform across syndromes. The clearest benefit is observed in atherosclerotic disease, whereas their role in heart failure is phenotype-specific and largely confined to obesity-associated heart failure with preserved ejection fraction. Emerging data suggest that GLP-1RAs may also influence arrhythmic risk and outcomes in selected populations, although these observations remain hypothesis-generating. Together, these findings support a unifying concept: GLP-1RAs function as cardiometabolic substrate-modifying therapies, acting through effects on weight, inflammation, vascular biology, myocardial energetics, and autonomic regulation. This framework provides a coherent explanation for their heterogeneous clinical profile and supports a phenotype-directed approach to their use in contemporary cardiovascular care.