Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery

Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of -3.93% or -6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced -21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., P = 1.24 × 10<sup>-4</sup>), but the effect attenuated in sensitivity analyses. Our findings suggest known genetic factors have limited impact on GLP1-RA effectiveness with respect to weight change and confirm treatment efficacy across ancestry groups.

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Publication Details

Journal
Nature Medicine
Published
2025-04-18
DOI
https://doi.org/10.1038/s41591-025-03645-3
Citations
26
Primary Topic
Diabetes Treatment and Management
Type
article
Field-Weighted Citation Impact
33.67

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article

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery

Yi Ding, Anthony Philippakis, Akintunde O. Akinkuolie, Ruth J. F. Loos et al.
26 citations
Nature Medicine
Diabetes Treatment and Management
33.67
article

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery

Yi Ding, Anthony Philippakis, Akintunde O. Akinkuolie, Ruth J. F. Loos, Tatiana Cajuso, Kadri Arumäe, Henrike Heyne, Jiwoo Lee, J German, Yasser Al‐Sarraj, Andrea Corbetta, Uku Vainik, Chadi Saad, Pradeep Natarajan, Hamdi Mbarek, Łukasz Szczerbiński, Roelof A. J. Smit, Bogdan Paşaniuc, Samuli Ripatti, Sarah Urbut, Adrian Janucik, Andrea Ganna, Rania Abdellatif, Zoltán Kutalik, Mattia Cordioli, Josephine H. Li, Alexandra Barry, Veronica Tozzo, Moza Al Hail, Andrea Eoli, Zhe Wang, Shaban Mohammed
article en
26 citations

Abstract

Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of -3.93% or -6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced -21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., P = 1.24 × 10<sup>-4</sup>), but the effect attenuated in sensitivity analyses. Our findings suggest known genetic factors have limited impact on GLP1-RA effectiveness with respect to weight change and confirm treatment efficacy across ancestry groups.

Nature MedicineVol. 31(7)
Broad Institute (US), University of Copenhagen (DK), SIB Swiss Institute of Bioinformatics (CH), University of Helsinki (FI), Harvard University (US), Hasso Plattner Institute (DE), Medical University of Białystok (PL), University of California, Los Angeles (US), University of Potsdam (DE), Novo Nordisk Foundation (DK), Foundation Center (US), University of Alabama at Birmingham (US), Massachusetts General Hospital (US), Novo Nordisk (United States) (US), Human Technopole (IT), Dana-Farber Cancer Institute (US), Institute for Molecular Medicine Finland (FI), Mass General Brigham (US), Hamad Medical Corporation (QA), McGill University (CA), University of Tartu (EE), University of Pennsylvania (US), Qatar Foundation (QA), Politecnico di Milano (IT), University of Lausanne (CH), Icahn School of Medicine at Mount Sinai (US)
American Diabetes Association, Massachusetts General Hospital, University of Pennsylvania, Helsingin Yliopisto, UCLA Health System, Helsingin ja Uudenmaan Sairaanhoitopiiri, McGill University, Broad Institute, Eesti Teadusagentuur, Université de Lausanne, Tartu Ülikool, Agencja Badań Medycznych, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Institute of Diabetes and Digestive and Kidney Diseases, David Geffen School of Medicine, University of California, Los Angeles, Clinical and Translational Science Institute, University of California, Los Angeles
Good health and well-being
Openalex Percentile: Top 0%
Diabetes Treatment and Management
33.67
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