GLP-1 receptor biology and the therapeutic role of incretin-based agonists in metabolic diseases.

Type 2 diabetes (T2DM) and obesity represent a growing global health burden, sharing underlying pathophysiological mechanisms such as impaired insulin signalling and chronic low-grade inflammation. The discovery of the incretin effect opened the way for agonist therapies targeting the glucagon-like peptide-1 receptor (GLP-1R) as therapies capable of addressing the metabolic dysregulation common to both diseases simultaneously. This review examines the biology of GLP-1 and the incretin system, with a focus on the structure and signalling mechanisms of GLP-1R, including biased agonism and receptor trafficking. The clinical effectiveness of stable, long-acting GLP-1RAs is evaluated across three therapeutic domains: T2DM management, obesity treatment, and emerging cardiovascular protection. Current evidence demonstrates that GLP-1RAs, which induce insulin secretion and suppress appetite, achieve superior glycaemic control and significant weight reduction compared with conventional therapies, with emerging cardiovascular benefits now extending to non-diabetic patients as well. The shift towards dual and triple receptor agonists, such as tirzepatide and retatrutide, together with biased agonist design, is a promising development for further improvements in effectiveness. Progress in oral formulations of GLP-1RAs may also improve tolerability and patient adherence. Nevertheless, important challenges remain, including gastrointestinal side effects, weight regain upon discontinuation, loss of lean body mass, and unresolved questions regarding long-term safety. In conclusion, while GLP-1R-based therapies represent a major therapeutic advancement, particularly for T2DM patients, their broader application in obesity management requires careful patient selection, continued long-term safety monitoring, and integration with lifestyle interventions.