Pleiotropic effects of GLP-1 receptor agonists — a narrative review of extra-metabolic outcomes in adults

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established therapies for obesity and type 2 diabetes, with increasing evidence of benefits extending beyond glycemic control. As their clinical use expands, understanding their extra-metabolic effects has become increasingly relevant. This narrative review summarizes current evidence on non-metabolic outcomes associated with GLP-1 RAs in adults, focusing on cardiovascular, renal, hepatic, musculoskeletal, neurobehavioral, and inflammatory effects, as well as safety. Material and methods: We synthesized data from randomized controlled trials, large cardiovascular outcome trials, mechanistic studies, and systematic reviews evaluating extra-metabolic effects of GLP-1-based therapies in adults with or without metabolic disease. Results: Large, randomized trials consistently demonstrate significant cardiovascular risk reduction with GLP-1 RAs, including a 12–26% relative decrease in major adverse cardiovascular events in high-risk populations. Evidence supports renal benefits, particularly reduced albuminuria, with emerging data suggesting potential slowing of kidney function decline. In hepatic disease, GLP-1 RAs reduce steatosis and liver enzymes, with promising findings in biopsy-proven NASH. Musculoskeletal effects appear largely secondary to weight loss, without consistent adverse impact on bone density. GLP-1 RAs also exert anti-inflammatory and immunomodulatory actions, and growing evidence suggests neuromodulatory and neuroprotective effects. Safety is generally favorable, dominated by gastrointestinal symptoms and increased gallbladder-related events, while serious adverse events remain uncommon. Conclusions: GLP-1-based therapies demonstrate broad extra-metabolic benefits across multiple organ systems. Further long-term studies are needed to clarify their impact on inflammation, neuroprotection, musculoskeletal integrity, and hepatic fibrosis progression.