Personalization of incretin therapy: can GLP-1 and GIP receptor polymorphisms influence therapy response?

OBJECTIVE: Incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide and the dual GLP-1/GIP receptor agonist tirzepatide-have transformed the management of type 2 diabetes (T2D) and obesity. However, substantial interindividual variability in therapeutic response remains incompletely explained by clinical factors alone. METHODS: A systematic search of PubMed, SciSpace, and Google Scholar was conducted (through May 2026) using terms including GLP1R, GIPR, polymorphisms, pharmacogenomics, semaglutide, tirzepatide, and Italian population. Relevant original studies, genome-wide association studies, and reviews were included. RESULTS: Common GLP1R variants-notably rs6923761 (Gly168Ser) and rs10305492 (Ala316Thr)-modulate receptor expression, G-protein coupling efficiency, and downstream cAMP signaling, translating to differential HbA1c reduction and weight loss with GLP-1RAs. GIPR rs1800437 (Glu354Gln), present at ∼20% frequency in Europeans, is associated with altered incretin effect and increased nausea/vomiting risk with tirzepatide (OR 1.83). Geographic analyses reveal significant allele frequency variation between European, East Asian, and African populations; Italian-specific data remain limited but suggest frequencies consistent with broader Southern European patterns. CONCLUSION: Pharmacogenomic profiling of GLP1R and GIPR variants holds promise for personalizing incretin therapy. Prospective studies in Italian and broader Mediterranean cohorts are needed to define clinically actionable genotype-phenotype relationships and inform precision endocrinology practice.