The Expanding Role of GLP‐1RAs Beyond Diabetes: Cardiovascular and Renal Protection—A Narrative Review

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), developed for glycemic control in type 2 diabetes (T2DM), also confer cardiovascular and renal protection, including in people without diabetes. This narrative review summarizes evidence and mechanisms underlying these cardiorenal benefits. Methods Major cardiovascular outcome trials (LEADER, SUSTAIN‐6, REWIND, EXSCEL, ELIXA, SELECT, and SOUL), renal studies including FLOW, and STEP‐HFpEF and STEP‐HFpEF DM trials were reviewed. Results Meta‐analyses show that GLP‐1 RAs reduce major adverse cardiovascular events (MACE) by approximately 12%–14%, with reductions in cardiovascular death, myocardial infarction, stroke, and heart‐failure hospitalization. Renal benefits include reduced new‐onset macroalbuminuria (approximately 22%–23%) and slower eGFR decline (approximately 16%–24%). In FLOW, semaglutide reduced progression to kidney failure by 24% in patients with T2DM and chronic kidney disease. SELECT demonstrated a 20% reduction in MACE with semaglutide in overweight or obese adults with established cardiovascular disease but without diabetes. STEP‐HFpEF and STEP‐HFpEF DM showed improvements in heart‐failure symptoms, physical function, and weight in obesity‐related HFpEF, with and without diabetes. Mechanisms Cardiorenal protection involves improved endothelial function, anti‐inflammatory and metabolic effects, natriuresis, hemodynamic modulation, attenuation of glomerular hyperfiltration, and inhibition of profibrotic pathways. Conclusions GLP‐1 RAs have emerged as cardiorenal therapies beyond glycemic control, with benefits extending across the glycemic spectrum. Further research is needed to define optimal patient selection, combination therapy, and long‐term outcomes.