Personalization of incretin therapy: can GLP-1 and GIP receptor polymorphisms influence therapy response?
Level 5 - mechanism / opinion, no new human data
Review synthesizing observational genetic studies, GWAS, and mechanistic data without a meta-analysis
PubMed 42487666 · doi:10.1210/jendso/bvag149
What was done
The authors conducted a systematic literature search in PubMed, SciSpace, and Google Scholar through May 2026 for original studies, genome-wide association studies, and reviews. They evaluated the impact of GLP1R and GIPR polymorphisms on therapeutic responses to GLP-1 receptor agonists (such as semaglutide) and dual GLP-1/GIP agonists (tirzepatide), focusing on mechanistic pathways, clinical efficacy, adverse events, and population allele frequencies.
What was found
GLP1R variants rs6923761 (Gly168Ser) and rs10305492 (Ala316Thr) alter receptor expression, G-protein coupling, and cAMP signaling, modifying HbA1c reduction and weight loss. GIPR rs1800437 (Glu354Gln), present at approximately 20% frequency in Europeans, was linked to an altered incretin effect and increased risk of nausea and vomiting with tirzepatide (OR 1.83). Allele frequencies varied across European, East Asian, and African ancestries, with limited specific data reported for Italian populations.
Why it matters
Identifying incretin receptor polymorphisms helps explain interindividual variability in efficacy and gastrointestinal tolerability, laying the groundwork for personalized selection of GLP-1 and dual GLP-1/GIP receptor agonists.
Limits
The abstract does not report the total number of studies or patients included. The evidence relies on heterogeneous observational and mechanistic studies rather than randomized pharmacogenomic trials, and actionable genotype-guided prescribing rules remain unvalidated in prospective clinical cohorts.
Cited by
- supports A study found genetic differences in individuals that influence their therapeutic responsiveness and nausea severity when taking GLP-1 receptor agonists.