GLP-1 RECEPTOR AGONISTS IN METABOLIC HEALTH: EXPANDING APPLICATIONS, WEIGHT MANAGEMENT, AND EMERGING SAFETY CONSIDERATIONS
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6416Keywords:
GLP-1 Receptor Agonists, Off-Label Use, Adverse Effects, Safety ProfileAbstract
GLP-1 receptor agonists (GLP-1 RAs) have transformed the treatment of type 2 diabetes mellitus (T2DM) and obesity and have recently gained an additional approved indication for metabolic dysfunction-associated steatohepatitis (MASH). Their expanding clinical use has also increased interest in off-label applications and their evolving safety profile. This narrative review summarizes current evidence regarding the off-label use of GLP-1 RAs and evaluates both well-established and emerging adverse effects. A literature search was performed using the PubMed database, and relevant studies addressing approved and off-label applications, efficacy, and safety were qualitatively analyzed. Current evidence suggests that GLP-1 RAs have therapeutic potential beyond approved indications, particularly in polycystic ovary syndrome, antipsychotic-induced weight gain, prediabetes, binge eating disorder, and disorders involving dysregulation of reward-related behavior. The most common adverse effects are gastrointestinal symptoms and gallbladder disorders, whereas emerging safety concerns include weight regain following treatment discontinuation, changes in body composition, hair loss, non-arteritic anterior ischemic optic neuropathy (NAION), and a theoretical risk of medullary thyroid carcinoma in susceptible individuals. Although these findings are promising, the available evidence remains heterogeneous. Further high-quality studies are required to establish the efficacy and long-term safety of off-label applications. Careful patient selection, appropriate monitoring, and integration of pharmacotherapy with lifestyle modification remain essential for optimizing clinical outcomes.
References
Zheng, Z., Zong, Y., Ma, Y., et al. (2024). Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, 9, 234. https://doi.org/10.1038/s41392-024-01931-z
Mademlis, C., Patoulias, D., Koufakis, T., Teperikidis, E., Giouleme, O., & Doumas, M. (2025). Semaglutide for the treatment of MASH: Reaching into the ESSENCE of cardio-metabolic health? Expert Review of Clinical Pharmacology, 18(10), 1–5. https://doi.org/10.1080/17512433.2025.2573785
Morello, C. M., Mnatzaganian, C. L., & Painter, N. A. (2026). Emerging and off-label uses of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists. Journal of the American Board of Family Medicine, 39(1), 157891. https://doi.org/10.3122/jabfm.2025.250158R1
Monney, M., Mavromati, M., Leboulleux, S., & Gariani, K. (2025). Endocrine and metabolic effects of GLP-1 receptor agonists on women with polycystic ovary syndrome: A narrative review. Endocrine Connections, 14(5), e240529. https://doi.org/10.1530/EC-24-0529
Vasiliu, O. (2023). Therapeutic management of atypical antipsychotic-related metabolic dysfunctions using glucagon-like peptide-1 receptor agonists: A systematic review. Experimental and Therapeutic Medicine, 26(1), 355. https://doi.org/10.3892/etm.2023.12054
Bergmann, N. C., Davies, M. J., Lingvay, I., & Knop, F. K. (2023). Semaglutide for the treatment of overweight and obesity: A review. Diabetes, Obesity and Metabolism, 25(1), 18–35. https://doi.org/10.1111/dom.14863
Balantekin, K. N., Kretz, M. J., & Mietlicki-Baase, E. G. (2024). The emerging role of glucagon-like peptide-1 in binge eating. Journal of Endocrinology, 262(1), e230405. https://doi.org/10.1530/JOE-23-0405
Klausen, M. K., Thomsen, M., Wortwein, G., & Fink-Jensen, A. (2022). The role of glucagon-like peptide-1 (GLP-1) in addictive disorders. British Journal of Pharmacology, 179(4), 625–641. https://doi.org/10.1111/bph.15677
Tan, H. C., Dampil, O. A., & Marquez, M. M. (2022). Efficacy and safety of semaglutide for weight loss in obesity without diabetes: A systematic review and meta-analysis. Journal of the ASEAN Federation of Endocrine Societies, 37(2), 65–72. https://doi.org/10.15605/jafes.037.02.14
Chiang, C. H., Jaroenlapnopparat, A., Colak, S. C., Yu, C. C., Xanthavanij, N., Wang, T. H., et al. (2025). Glucagon-like peptide-1 receptor agonists and gastrointestinal adverse events: A systematic review and meta-analysis. Gastroenterology, 169(6), 1268–1281. https://doi.org/10.1053/j.gastro.2025.06.003
Ismaiel, A., Scarlata, G. G. M., Boitos, I., Leucuta, D. C., Popa, S. L., Al Srouji, N., et al. (2025). Gastrointestinal adverse events associated with GLP-1 receptor agonists in non-diabetic patients with overweight or obesity: A systematic review and network meta-analysis. International Journal of Obesity, 49(10), 1946–1957. https://doi.org/10.1038/s41366-025-01859-6
Ja'arah, D., Al Zoubi, M. S., Abdelhady, G., Rabi, F., & Tambuwala, M. M. (2021). Role of glucagon-like peptide-1 receptor agonists in hypoglycemia. Clinical Medicine Insights: Endocrinology and Diabetes, 14, 11795514211051697. https://doi.org/10.1177/11795514211051697
Qian, D., Zhang, T., Tan, X., Zheng, P., Liang, Z., Xie, J., et al. (2018). Comparison of antidiabetic drugs added to sulfonylurea monotherapy in patients with type 2 diabetes mellitus: A network meta-analysis. PLoS ONE, 13(8), e0202563. https://doi.org/10.1371/journal.pone.0202563
Wilding, J. P. H., Batterham, R. L., Davies, M., Van Gaal, L. F., Kandler, K., Konakli, K., et al. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obesity and Metabolism, 24(8), 1553–1564. https://doi.org/10.1111/dom.14725
Duca, F. A., Katebzadeh, S., & Covasa, M. (2015). Impaired GLP-1 signaling contributes to reduced sensitivity to duodenal nutrients in obesity-prone rats during high-fat feeding. Obesity, 23(11), 2260–2268. https://doi.org/10.1002/oby.21231
Noronha, J. C., Van Gaal, L. F., Neeland, I. J., Fitch, A., Pfeiffer, A. F., Chiavaroli, L., et al. (2025). Optimizing GLP-1 therapies for obesity and diabetes management. Obesity Pillars, 16, 100222. https://doi.org/10.1016/j.obpill.2025.100222
Kadowaki, Y., Aoyama, T., Hada, Y., et al. (2025). Effects of rapid weight loss on body composition and pathophysiological mechanisms involved in obesity. Endocrine Journal, 72(3), 307–317. https://doi.org/10.1507/endocrj.EJ24-0315
Daneshgaran, G., Shauly, O., & Gould, D. J. (2025). “Ozempic face” in plastic surgery: A systematic review of the literature on glucagon-like peptide-1 receptor agonist-mediated weight loss and analysis of public perceptions. Aesthetic Surgery Journal Open Forum, 7, ojaf056. https://doi.org/10.1093/asjof/ojaf056
Paschou, I. A., Sali, E., Paschou, S. A., Tsamis, K. I., Peppa, M., Psaltopoulou, T., et al. (2025). GLP-1 receptor agonists and the possible skin aging. Endocrine, 89(3), 680–685. https://doi.org/10.1007/s12020-025-04293-w
Alsuwailem, O. A., Alanazi, R., Almutairi, H. M., Asiree, R. H., Almutairi, W., Almutairi, T. M., Zamandar, A., & Alkhames, S. (2025). Hair loss associated with glucagon-like peptide-1 receptor agonist use: A systematic review. Cureus, 17(9), e92454. https://doi.org/10.7759/cureus.92454
Toro-Tobon, D., Singh Ospina, N., & Brito, J. P. (2025). Thyroid cancer risk with glucagon-like peptide-1 receptor agonists: Evidence, knowledge gaps, and the path forward. Thyroid, 35(1), 3–5. https://doi.org/10.1089/thy.2024.0690
Hsu, A. Y., Wang, Y. H., Lin, C. J., Hsia, N. Y., Shao, Y. C., Chiang, C. C., et al. (2025). NAION risk with semaglutide: What we know so far. Eye, 39(9), 1655–1656. https://doi.org/10.1038/s41433-025-03833-y
Hathaway, J. T., Shah, M. P., Hathaway, D. B., Zekavat, S. M., Krasniqi, D., Gittinger, J. W., Jr., et al. (2024). Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmology, 142(8), 732–739. https://doi.org/10.1001/jamaophthalmol.2024.2296
Berry, S., Lin, W. V., Sadaka, A., & Lee, A. G. (2017). Nonarteritic anterior ischemic optic neuropathy: Cause, effect, and management. Eye and Brain, 9, 23–28. https://doi.org/10.2147/EB.S125311
Willard, F. S., Douros, J. D., Gabe, M. B., Showalter, A. D., Wainscott, D. B., Suter, T. M., et al. (2020). Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight, 5(17), e140532. https://doi.org/10.1172/jci.insight.140532
Lempesis, I. G., & Dalamaga, M. (2026). Obesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators: Perspectives and controversies. Metabol Open, 30, 100463. https://doi.org/10.1016/j.metop.2026.100463
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Natalia Kostecka, Katarzyna Otrębska, Aleksandra Szredzka, Dominika Lewandowska, Aleksandra Makulec, Aleksandra Jóźwik-Szymańska, Laura Mikuła, Zuzanna Bogdan-Groszyk, Jan Kucharski
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
