Emerging Frontiers in GLP-1 Therapeutics: A Comprehensive Evidence Base (2025)

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved from glucose-lowering agents to transformative therapies across multiple organ systems. This comprehensive review synthesizes current evidence on the mechanisms, established applications, and emerging therapeutic frontiers of GLP-1 RAs. Methods: We conducted a systematic literature search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception through May 2025, using controlled vocabulary and free-text terms related to GLP-1 RAs, their mechanisms, and clinical applications. Results: GLP-1 RAs demonstrate pleiotropic effects through fundamental cellular mechanisms, including enhanced mitochondrial function, anti-inflammatory actions, improved cellular quality control, and comprehensive metabolic regulation. Established applications demonstrate robust efficacy in diabetes management (HbA1c reductions of 1.5–2.0%), obesity treatment (weight loss of 7–24%), and cardiovascular protection (14–20% reduction in major adverse cardiovascular events, or MACE). Emerging applications span neurological disorders, dermatological conditions, respiratory diseases, and novel applications in addiction medicine and autoimmune disorders. Conclusions: GLP-1 RAs represent a paradigmatic shift toward multi-system therapeutic intervention, with expanding evidence supporting their role as comprehensive metabolic modulators.