Influence of BMI-associated genetic variants and metabolic risk factors on weight loss with semaglutide: a longitudinal clinico-genomic cohort study

BackgroundIndividual weight loss response to the GLP-1 receptor agonist semaglutide varies considerably, with many possible contributing factors. Leveraging multiple clinico-genomic cohorts, we analyzed differences in weight loss trajectories according to patient characteristics, including a polygenic score (PGS) and metabolic risk factors, in semaglutide initiators with BMI [&ge;]27 kg/m2. MethodsThis longitudinal study utilized clinical-grade exome sequencing and electronic health record data from six U.S. cohorts within the Helix Research Network (n=134,806). A BMI PGS was calculated using 26,941 variants. Twelve-month weight loss trajectories were modeled using mixed effects models, and associations with demographics, PGS, comorbidities, medications, and laboratory results were evaluated. FindingsAmong 1,923 semaglutide users, the mean pretreatment BMI was 38.4 kg/m2. For those on doses [&ge;]1.7 mg, the mean body weight reduction was 7.3% at 6 months and 9.9% at 12 months. Over 12 months, low PGS was associated with an adjusted 1.5% and 1.8% additional weight loss compared to intermediate and high PGS, respectively (both p<0.01). Male sex, type 2 diabetes, hypertension, obstructive sleep apnea, and non-alcoholic fatty liver disease were each associated with 1.2%-1.9% less weight loss (all p<0.05). In type 2 diabetes, each 1%-increase in pretreatment hemoglobin A1c was associated with 0.6% less weight loss (p=0.0019). InterpretationAmong adults with overweight or obesity, a lower genetic predisposition to obesity is linked to greater weight loss on semaglutide. Additionally, metabolic health significantly impacts the drugs effectiveness. These findings underscore the importance of precision medicine in obesity management. FundingRenown Health Foundation. Nevada Governors Office of Economic Development. HealthPartners.