Background: Individual 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 ≥27 kg/m2. Methods: This 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. Findings: Among 1,923 semaglutide users, the mean pretreatment BMI was 38.4 kg/m2. For those on doses ≥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). Interpretation: Among 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 drug's effectiveness. These findings underscore the importance of precision medicine in obesity management.

M.E.L., N.T., K.M.S.B., A.B., N.L.W., W.L., and E.T.C. are employees of Helix. M.E.L. reports contracted research from Pfizer and Novavax. No other competing interests were reported.

Funding was provided to the Desert Research Institute by the Renown Institute for Health Innovation and the Renown Health Foundation. Funding was provided to DRI by the Nevada Governor's Office of Economic Development. Funding was provided to the myGenetics program by HealthPartners.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Helix Research Network cohorts were approved by the Salus IRB (reliance on Salus for all sites; approval number 21143), the WCG IRB (Western Institutional Review Board, WIRB-Copernicus Group; approval number 20224919), the MUSC Institutional Review Board for Human Research (approval number Pro00129083), and the University of Nevada, Reno Institutional Review Board (approval number 7701703417). All participants provided written informed consent prior to participation. All data used for research were de-identified.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The Helix Research Network (HRN) data are available to qualified researchers upon reasonable request and with permission of the HRN Steering Committee and Helix. Researchers who would like to obtain the raw genotype data related to this study will be presented with a Data Use Agreement which requires that participants will not be reidentified and that no data will be shared between individuals, third parties, or uploaded onto public domains. The HRN encourages collaboration with scientific researchers on an individual basis. Examples of restrictions that will be considered in requests to access data include but are not limited to: 1) whether the request comes from an academic institution in good standing and will collaborate with our team to protect the privacy of the participants and the security of the data requested; 2) type and amount of data requested; 3) feasibility of the research suggested; and 4) amount of resource allocation for Helix and HRN member institutions required to support a collaboration.