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Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation\/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/joe-25-0174","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T15:38:18Z","timestamp":1759505898000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":9,"title":["RISING STARS: Effects of a GLP-1 receptor polymorphism on responses to liraglutide"],"prefix":"10.1530","volume":"267","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0331-2395","authenticated-orcid":true,"given":"Mona","family":"Mashayekhi","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism 1 , , ,","place":["Nashville, Tennessee, USA"]},{"name":"Department of Veterans Affairs, Tennessee Valley Healthcare System 2 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilgunay Ilkin","family":"Safa","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism 1 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Nian","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Biostatistics 3 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K","family":"Devin","sequence":"additional","affiliation":[{"name":"UCHealth Endocrinology, Yampa Valley Medical Center 4 , , ,","place":["Steamboat Springs, Colorado, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge L","family":"Gamboa","sequence":"additional","affiliation":[{"name":"The University of Alabama at Birmingham, School of Medicine, Division of Nephrology 5 , , ,","place":["Birmingham, Alabama, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Yu","sequence":"additional","affiliation":[{"name":"NYU Grossman School of Medicine, Department of Population Health 6 , , ,","place":["New York, New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Department of Molecular Physiology and Biophysics 7 , , ,","place":["Nashville, Tennessee, USA"]},{"name":"Vanderbilt University Medical Center, Vanderbilt Genetics Institute 8 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A","family":"Beckman","sequence":"additional","affiliation":[{"name":"UTSouthwestern Medical Center, Department of Internal Medicine, Division of Vascular Medicine 9 , , ,","place":["Dallas, Texas, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R","family":"Koethe","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs, Tennessee Valley Healthcare System 2 , , ,","place":["Nashville, Tennessee, USA"]},{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases 10 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi J","family":"Silver","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs, Tennessee Valley Healthcare System 2 , , ,","place":["Nashville, Tennessee, USA"]},{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition 11 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Niswender","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism 1 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M","family":"Luther","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Clinical Pharmacology 12 , , ,","place":["Nashville, Tennessee, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J","family":"Brown","sequence":"additional","affiliation":[{"name":"Yale School of Medicine 13 , , ,","place":["New Haven, Connecticut, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"2026070806123889700_bib1","article-title":"Association between allelic variants in the glucagon-like peptide 1 and cholecystokinin receptor genes with gastric emptying and glucose 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