Abstract
PURPOSE OF REVIEW: This review provides a comprehensive and scholarly examination of glucagon-like peptide-1 receptor (GLP-1R) agonists, tracing their evolution from glycemic control agents in diabetes mellitus (DM) to multifaceted therapeutics with expanding indications in cardiovascular, renal, and metabolic health. We explore the underlying biological mechanisms, summarize clinical trial evidence, and highlight emerging applications in non-diabetic populations. Recent developments underscore the relevance of GLP-1R agonists in addressing the complex interplay of cardiovascular-kidney-metabolic (CKM) syndrome, microvascular dysfunction, and metabolic-associated steatohepatitis (MASH). We also discuss combination therapies and strategies to mitigate muscle mass loss during treatment and calls for targeted research, improved clinical education, and policy reforms to optimize the translational potential of GLP-1R agonists in both individualized care and population health. RECENT FINDINGS: Diabetes mellitus currently affects over 422 million individuals worldwide, with projections indicating a rise to 783 million by 2045, representing 10.5% of the global adult population. Common comorbidities include chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD), which collectively impact nearly one-third of individuals with DM. The growing prevalence of metabolic disease, CKD, and ASCVD have prompted investigation into the role of GLP-1R agonists in mitigating cardiovascular and metabolic risks, particularly within the framework of Cardiovascular-Kidney-Metabolic (CKM) Syndrome, irrespective of diabetic status. Emerging evidence, foundational science, and transformative knowledge of mechanisms of action further support the expansion of therapeutic indications for this drug class. Although GLP-1R agonists were originally developed for glycemic control in DM, their mechanistic versatility has enabled broader application across a spectrum of cardiovascular, cerebrovascular and metabolic disorders. This review traces the trajectory of their development and highlights opportunities for more expansive translational use in both clinical and population health settings. We also address current barriers to implementation and evidence-based use, ongoing clinical trials, and future directions, including combination therapies that may enhance efficacy and patient outcomes.