The Cardiovascular Physiology of Glucagon-like Peptide-1 Receptor Agonists: From Macro-Level Outcomes to Micro-Level Mechanisms

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have instigated a paradigm shift in the management of cardiometabolic disease. Initially developed for glycemic control in type 2 diabetes, their therapeutic role has expanded dramatically following the demonstration of robust cardiovascular benefits in large-scale clinical trials. This review provides a comprehensive synthesis of the physiological mechanisms underlying the cardioprotective effects of GLP-1 RAs, moving beyond the clinical outcomes to explore the cellular and molecular pathways involved. This review systematically deconstructs the effects of this drug class on the vasculature, where they mitigate atherosclerosis by improving endothelial function, attenuating vascular inflammation and oxidative stress, and favorably modulating plaque composition. The review delves into the complex and controversial effects on the myocardium, addressing the debate over GLP-1 receptor expression and detailing the interplay of direct and indirect actions on cardiomyocyte metabolism, ion homeostasis, and fibrosis. A central focus is the differential impact of GLP-1 RAs on heart failure (HF) phenotypes, clarifying their established benefits in HF with preserved ejection fraction (HFpEF), largely through targeting obesity and inflammation, whilst their role in the setting of HF with reduced ejection fraction (HFrEF) remains to be definitively determined. By integrating evidence from landmark trials with cutting-edge mechanistic studies, this review illuminates how GLP-1 RAs exert their profound cardiovascular effects and identifies critical unanswered questions that will shape the future of cardiometabolic medicine.