GLP-1 Receptor Agonists in Modern Endocrinology: Mechanisms, Therapeutic Expansion Beyond Glycemic Control, and Emerging Safety Considerations — A Narrative Review
Keywords:
GLP-1 receptor agonists, semaglutide, tirzepatide, obesity, type 2 diabetes, cardiovascular outcomes, chronic kidney disease, MASH, endocrinologyAbstract
Background. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved from glucose-lowering agents for type 2 diabetes mellitus (T2DM) into multi-system therapeutics with substantiated benefits across cardiovascular, renal, hepatic, and neurodegenerative domains. Objective. To synthesise contemporary evidence on the mechanisms, expanding therapeutic indications, comparative efficacy, and safety profile of GLP-1 RAs and dual incretin agonists. Methods. A structured narrative review of peer-reviewed publications from 2016 to 2025, including pivotal randomised controlled trials, mechanistic studies, meta-analyses, and regulatory documents. Results. Phase 3 trials demonstrate weight reductions of 14.9–22.5%, a 14–26% reduction in major adverse cardiovascular events, a 24% reduction in composite kidney outcomes, and resolution of metabolic dysfunction-associated steatohepatitis in 62.9% of treated participants. Emerging signals support efficacy in obstructive sleep apnoea, addiction, and possibly neurodegeneration. Gastrointestinal adverse events remain the principal tolerability barrier, and rare risks involving thyroid C-cells, biliary disease, and perioperative aspiration require vigilance. Conclusion. GLP-1 RAs represent a paradigm shift in endocrine pharmacotherapy, transitioning from glucose-centred therapy to integrated cardiometabolic disease management. Long-term real-world data, equitable access, and head-to-head comparative trials remain priorities.
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