Influence of GLP1 receptor rs6923761 and rs761387 genetic variants on oral semaglutide response in patients with type 2 diabetes

Glucagon-like peptide-1 receptor (GLP-1R) has become one of the most promising ligand-receptor systems to target for type 2 diabetes mellitus (T2DM) treatment. Over the last two decades, several GLP-1 receptor agonists (GLP-1RAs) have been developed and semaglutide is the first and only GLP-1RA available as an oral formulation. GLP1R single nucleotide polymorphisms may affect GLP-1R response to oral semaglutide. Here we aimed to evaluate the impact of rs6923761 and rs761387 GLP1R polymorphisms on the response to oral semaglutide. This is a retrospective cohort study including adult patients with T2DM who had been treated with oral semaglutide for at least one year. Patients were enrolled between November 2023 and April 2024, and then genotyped. We selected 210 adult patients with a median age of 71 years. Their median BMI was 29.1 kg/m2, HbA1c was 7.2% (55 mmol/mol), duration of diabetes was 12 years. After a median follow-up of 18 months, oral semaglutide reduced HbA1c by −0.3% (−3 mmol/mol), BMI by −1.1 kg/m2, SBP by −5 mmHg, total cholesterol by -8 mg/dL, triglycerides by -6.5 mg/dL. In addition, a reduction of ACR by −44.02 mg/g was observed in patients with baseline ACR > 30 mg/g, along with a decrease of liver transaminases in patients with baseline levels ≥ 35 U/L. Multivariate linear regression did not show any significant association between rs6923761 or rs761387 GLP1R genotypes and changes in HbA1c, BMI, SBP and DBP. Our findings confirm the effectiveness of oral semaglutide in improving metabolic control and providing cardiorenal protection in different clinical scenarios. Conversely, they fail to show a clear benefit of GLP1R genotyping to guide treatment decisions, at least in patients with HbA1c < 7.5% (< 58 mmol/mol). Further studies are needed to confirm and extend our findings.