{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T07:50:42Z","timestamp":1794124242992,"version":"4.8.0"},"reference-count":292,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have revolutionized the management of not only type 2 diabetes but also obesity. However, even with rapid therapeutic advances in GLP-1RAs, questions regarding the fundamental principles of GLP-1-mediated weight loss and the enhanced efficacy of next-generation therapies remain. In this comprehensive review article, we first examine the milestones of GLP-1, from its initial discovery and biological characterization to its successful translation into clinical therapy. Furthermore, this review highlights the latest clinical trial data, specifically HbA1c reduction, weight-loss efficacy, and safety profiles, while exploring current pipelines of major pharmaceutical companies. Additionally, we delineate the mechanistic principles underlying the efficacy of GLP-1 single- and multi-receptor agonists and address challenges in mitigating side effects of GLP-1RAs. Finally, we analyze the rapidly evolving landscape of next-generation, incretin-based combination therapies. With an abundance of GLP-1- related therapies already available or in development, we assess how future GLP-1 multi-receptor agonists can achieve enhanced efficacy and how leveraging weight-loss biology, such as set-point theory, can improve therapeutic outcomes.<\/jats:p>","DOI":"10.3390\/biology15161395","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T13:12:56Z","timestamp":1786713176000},"page":"1395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["For Weight Loss: Why Do GLP-1 Agonists Work, and How Can We Make Them Work Better?"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3851-2929","authenticated-orcid":false,"given":"Charlise","family":"Giang","sequence":"first","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"College of Natural Sciences and Mathematics, University of Houston, Houston, TX 77004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3829-9648","authenticated-orcid":false,"given":"Jieyi","family":"Meng","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud Ali","family":"Mohammad","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5077-0941","authenticated-orcid":false,"given":"Zhenqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinle","family":"Wu","sequence":"additional","affiliation":[{"name":"Research and Development Center, Sciwind Biosciences, San Ramon, CA 94583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1650-1363","authenticated-orcid":false,"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2024). 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