GLP-1 Receptor Agonists: From Clinical Success to Mechanistic Insight

GLP-1R (glucagon-like peptide-1 receptor) agonists are transforming therapeutic strategies in hypertension and cardiometabolic syndrome by shifting the focus from merely controlling individual risk factors to modifying the vascular-metabolic biology that underpins these conditions. In addition to promoting weight loss and improved glycemic control, growing clinical and experimental evidence indicates their beneficial effects on endothelial dysfunction, vascular inflammation, leukocyte recruitment, atherosclerotic plaque composition, and cardiorenal pathways involved in sodium regulation and neurohumoral balance, key processes in cardiometabolic-related hypertension and associated heart failure. This review integrates rapid clinical advancements in GLP-1R agonists with emerging mechanistic insights, clarifying which findings are well-established and which remain inferential, and identifying significant translational gaps that would provide deeper insight into cardiometabolic diseases. Key priorities include determining which benefits reflect direct GLP-1R signaling within cardiovascular/renal tissues versus secondary cardiometabolic changes, establishing cell type-resolved GLP-1R localization in human heart and kidney, and developing response biomarkers for cardiovascular and heart failure outcomes. Addressing these issues through detailed trial phenotyping, advanced mechanistic imaging, and relevant experimental models will facilitate personalized application of existing therapies and inform the development of next-generation incretin-based strategies aimed at durable vascular protection and blood pressure regulation for better cardiovascular health.