A GLP1R gene variant and sex influence the response to semaglutide treatment in patients with severe obesity

Abstract Objective The objective of this study is to identify whether the glucagon‐like peptide‐1 receptor ( GLP1R ) gene variant rs6923761G→A has an influence on semaglutide response in individuals with severe obesity. Methods From March 2023 to July 2024, we prospectively genotyped 112 patients treated with semaglutide 2.4 mg weekly. All patients had been treated over 4 months for grade 3 obesity (BMI ≥ 40 kg/m 2 ). Results The frequency of the rs6923761 AA variant was 9 out of 112 patients (8%), GA was 42 out of 112 (37.5%), and GG was 61 out of 112 (54.5%). The mean weight loss kinetics was 1.64% (SD 0.78%) per month in homozygotes of variant A in comparison with a mean weight loss of 1.04% (SD 0.79%) per month in carriers of at least one G variant ( p = 0.03). Multivariate analysis demonstrated that rs6923761G→A and sex were independent predictors of weight loss. The rate of weight loss in women homozygous for the A allele was more than double that observed in men carrying the G allele: mean (SD) 1.89% (0.75%) per month versus 0.7% (0.7%) per month ( p = 0.0009). No woman homozygous for the A allele was a nonresponder, compared with 56% (21 out of 37) of the men carrying the G allele. Conclusions The rs6923761G→A gene variant and sex profoundly affect weight loss in response to semaglutide in patients with severe obesity.