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

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). 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.