GLP-1 receptor agonists as multisystem therapies: from glycemic control to cardiorenal, neuroimmune, and metabolic disease

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were initially developed as incretin-based therapies for the management of type 2 diabetes mellitus. Over the past decade, robust clinical and mechanistic evidence has demonstrated that their therapeutic effects extend beyond glycemic control, leading to expanding use in obesity and cardiometabolic disease. This narrative review synthesizes evidence from randomized controlled trials, cardiovascular and kidney outcome studies, meta-analyses, and real-world data, complemented by mechanistic and translational studies where relevant. Evidence across organ systems was critically appraised with attention to study design, outcome relevance, heterogeneity, and clinical certainty. GLP-1RAs consistently induce clinically meaningful weight loss and reduce major adverse cardiovascular events, while slowing 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, whereas data on immune modulation, skeletal health, neuroprotection, and neuropsychiatric outcomes are largely derived from mechanistic, biomarker-based, observational, or preclinical studies and remain heterogeneous. GLP-1 receptor agonists have transitioned from glucose-lowering therapies to cornerstone agents in cardiometabolic disease management. While their efficacy in obesity, cardiovascular risk reduction, and kidney protection is well established, proposed benefits in other organ systems should be interpreted cautiously and in the context of variable evidence strength. Future research should prioritize long-term safety, durability of benefit, and adequately powered trials designed to clarify disease-modifying potential beyond established cardiometabolic indications.