Personalization of Incretin Therapy: Can GLP-1 and GIP Receptor Polymorphisms Influence Therapy Response?

Context 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 inter-individual variability in therapeutic response remains incompletely explained by clinical factors alone. Evidence Acquisition 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. Evidence Synthesis 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. Conclusions 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.