GLP-1 Receptor Agonists Evolve from Glycemic Control to Multisystem Therapies for Cardiometabolic Disease

Initially developed for type 2 diabetes mellitus (T2DM), glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated therapeutic effects far beyond glycemic control. Despite their established efficacy in T2DM, obesity, and cardiometabolic disease, a comprehensive understanding of their broader multisystem benefits and the strength of evidence supporting them across various organ systems has been needed. This review addresses the gap by synthesizing the diverse clinical and mechanistic evidence for GLP-1RA applications.

This narrative review synthesized evidence from a broad range of study types to evaluate the multisystem effects of GLP-1RAs. Researchers critically appraised data from randomized controlled trials, cardiovascular and kidney outcome studies, meta-analyses, and real-world data. The review also incorporated relevant mechanistic and translational studies. Evidence was assessed across various organ systems, considering study design, outcome relevance, heterogeneity, and overall clinical certainty to provide a comprehensive overview.

GLP-1 receptor agonists consistently induce clinically meaningful weight loss and significantly reduce major adverse cardiovascular events (MACE). They also effectively slow the progression of chronic kidney disease in both diabetic and non-diabetic populations. These benefits are supported by large outcome trials and appear only partially attributable to improvements in glycemic control or body weight alone. In contrast, evidence supporting additional effects in metabolic liver disease and obstructive sleep apnea is moderate but evolving. > Data on immune modulation, skeletal health, neuroprotection, and neuropsychiatric outcomes are largely derived from mechanistic, biomarker-based, observational, or preclinical studies and remain heterogeneous, requiring cautious interpretation.