INCRETIN-BASED PHARMACOTHERAPY FOR OBESITY: A COMPARATIVE NARRATIVE REVIEW OF GLP-1, DUAL AND TRIPLE AGONISTS AND COMBINATION THERAPIES
Abstract
Background: Incretin-based pharmacotherapy has emerged as a central component in modern obesity management. Recent developments include ont only GLP-1 receptor agosnists byt albo dual GIP/GLP-1 agonists, triple multi-rceptor agnosits and combination regimens integrating complementary hormonal pathways.
Aim: The narrative review provides a comparative analysis of current incretin-based therapies for obesity, summarizing clinical evidence on their efficacy, safety and mechanisms of action.
Methods: A structured literature search was conducted using PubMed, Scopus and Web of Science. The review included randomized controlled trials, original research articles, meta-analyses and selected narrative reviews addressing GLP-1 receptor agonists, dual GIP/GLP-1 agonists, triple agonists and combination therapies. Case reports, small uncontrolled studies and non-peer-reviewed sources were excluded.
Results: GLP-1 receptor agonists, such as liraglutide and semaglutide, demonstrate consistent weight-reducing effects and metabolic benefits. Dual agonists, particularly tirzepatide, show enhanced efficacy, likely due to synergistic modulation of GIP and GLP-1 pathways. Triple receptor agonists, such as retatrutide, achieve the most pronounced reductions in body weight reported to date in pharmacotherapy. Combination therapy with semaglutide and cagrilintide provides clinically meaningful weight loss comparable to multi-receptor agonists. Across therapeutic classes, gastrointestinal adverse events remain the most common limitation.
Conclusions: Incretin-based therapies represent a rapidly evolving field, with multi-receptor agonists and combination approaches offering the strongest therapeutic potential. Long-term studies are required to evaluate durability of outcomes and to better define patient phenotypes best suited for specific treatment strategies.
References
Aronne, L. J., Sattar, N., Horn, D. B., Bays, H. E., Wharton, S., Lin, W. Y., Ahmad, N. N., Zhang, S., Liao, R., Bunck, M. C., Jouravskaya, I., & Murphy, M. A. (2024). Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA, 331(1), 38–48. https://doi.org/10.1001/JAMA.2023.24945
Davies, M. J., Bajaj, H. S., Broholm, C., Eliasen, A., Garvey, W. T., le Roux, C. W., Lingvay, I., Lyndgaard, C. B., Rosenstock, J., & Pedersen, S. D. (2025). Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. New England Journal of Medicine, 393(7), 648–659. https://doi.org/10.1056/nejmoa2502082
Davies, M. J., Bergenstal, R., Bode, B., Kushner, R. F., Lewin, A., Skjøth, T. V., Andreasen, A. H., Jensen, C. B., DeFronzo, R. A., Valensi, P., Levy, M., Benabdallah, S., Serusclat, P., Courreges, J. P., Gouet, D., Clavel, S., Cariou, B., Tyler, K., Hanefeld, M., … Zimmerman, T. S. (2015). Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA, 314(7), 687–699. https://doi.org/10.1001/JAMA.2015.9676
Frias, J. P., Deenadayalan, S., Erichsen, L., Knop, F. K., Lingvay, I., Macura, S., Mathieu, C., Pedersen, S. D., & Davies, M. (2023). Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. The Lancet, 402(10403), 720–730. https://doi.org/10.1016/S0140-6736(23)01163-7
Garvey, W. T., Blüher, M., Osorto Contreras, C. K., Davies, M. J., Winning Lehmann, E., Pietiläinen, K. H., Rubino, D., Sbraccia, P., Wadden, T., Zeuthen, N., & Wilding, J. P. H. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 393(7), 635–647. https://doi.org/10.1056/nejmoa2502081
Garvey, W. T., Frias, J. P., Jastreboff, A. M., le Roux, C. W., Sattar, N., Aizenberg, D., Mao, H., Zhang, S., Ahmad, N. N., Bunck, M. C., Benabbad, I., Zhang, X. M., Abalos, F. H., Manghi, F. C. P., Zaidman, C. J., Vico, M. L., Costanzo, P. R., Serra, L. P., MacKinnon, I. J., … Jones, T. (2023). Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet, 402(10402), 613–626. https://doi.org/10.1016/S0140-6736(23)01200-X
Htike, Z. Z., Zaccardi, F., Papamargaritis, D., Webb, D. R., Khunti, K., & Davies, M. J. (2017). Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis. Diabetes, Obesity and Metabolism, 19(4), 524–536. https://doi.org/10.1111/dom.12849
Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., & Stefanski, A. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine, 387(3), 205–216. https://doi.org/10.1056/nejmoa2206038
Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., & Hartman, M. L. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine, 389(6), 514–526. https://doi.org/10.1056/nejmoa2301972
Knudsen, L. B., & Lau, J. (2019). The discovery and development of liraglutide and semaglutide. In Frontiers in Endocrinology (Vol. 10, Issue APR). Frontiers Media S.A. https://doi.org/10.3389/fendo.2019.00155
Lau, D. C. W., Erichsen, L., Francisco, A. M., Satylganova, A., le Roux, C. W., McGowan, B., Pedersen, S. D., Pietiläinen, K. H., Rubino, D., & Batterham, R. L. (2021). Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. The Lancet, 398(10317), 2160–2172. https://doi.org/10.1016/S0140-6736(21)01751-7
Lau, J., Bloch, P., Schäffer, L., Pettersson, I., Spetzler, J., Kofoed, J., Madsen, K., Knudsen, L. B., McGuire, J., Steensgaard, D. B., Strauss, H. M., Gram, D. X., Knudsen, S. M., Nielsen, F. S., Thygesen, P., Reedtz-Runge, S., & Kruse, T. (2015). Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of Medicinal Chemistry, 58(18), 7370–7380. https://doi.org/10.1021/ACS.JMEDCHEM.5B00726
Montanya, E., & Sesti, G. (2009). A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. In Clinical Therapeutics (Vol. 31, Issue 11, pp. 2472–2488). https://doi.org/10.1016/j.clinthera.2009.11.034
Mu, Y., Bao, X., Eliaschewitz, F. G., Hansen, M. R., Kim, B. T., Koroleva, A., Ma, R. C. W., Yang, T., Zu, N., & Liu, M. (2024). Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial. The Lancet Diabetes and Endocrinology, 12(3), 184–195. https://doi.org/10.1016/S2213-8587(23)00388-1
O’Neil, P. M., Birkenfeld, A. L., McGowan, B., Mosenzon, O., Pedersen, S. D., Wharton, S., Carson, C. G., Jepsen, C. H., Kabisch, M., & Wilding, J. P. H. (2018). Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. The Lancet, 392(10148), 637–649. https://doi.org/10.1016/S0140-6736(18)31773-2
Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., Lau, D. C. W., le Roux, C. W., Violante Ortiz, R., Jensen, C. B., & Wilding, J. P. H. (2015). A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. New England Journal of Medicine, 373(1), 11–22. https://doi.org/10.1056/nejmoa1411892
Rubino, D. M., Greenway, F. L., Khalid, U., O’Neil, P. M., Rosenstock, J., Sørrig, R., Wadden, T. A., Wizert, A., Garvey, W. T., Investigators, S. 8, Arauz-Pacheco, C., Cannon, K., Downey, H. J., Fitz-Patrick, D., Geohas, J., Gerety, G., Gilbert, J., Hollander, P., Klein, E., … Toth, P. (2022). Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA, 327(2), 138–150. https://doi.org/10.1001/JAMA.2021.23619
Sanyal, A. J., Kaplan, L. M., Frias, J. P., Brouwers, B., Wu, Q., Thomas, M. K., Harris, C., Schloot, N. C., Du, Y., Mather, K. J., Haupt, A., & Hartman, M. L. (2024). Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine, 30(7), 2037–2048. https://doi.org/10.1038/s41591-024-03018-2
Sinha, R., Papamargaritis, D., Sargeant, J. A., & Davies, M. J. (2023). Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management. In Journal of Obesity and Metabolic Syndrome (Vol. 32, Issue 1, pp. 25–45). Korean Society for the Study of Obesity. https://doi.org/10.7570/jomes22067
Wadden, T. A., Hollander, P., Klein, S., Niswender, K., Woo, V., Hale, P. M., & Aronne, L. (2013). Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. International Journal of Obesity (2005), 37(11), 1443–1451. https://doi.org/10.1038/IJO.2013.120
World Health Organization. (2025). Obesity and Overweight: WHO Fact Sheet.
Views:
13
Downloads:
5
Copyright (c) 2025 Łukasz Krzystek, Karolina Buć, Paweł Buć, Michał Mazurek, Jagoda Józefczyk, Konrad Zieliński, Karolina Ganczar, Stanisław Jurkowski, Marianna Rudzińska, Mikołaj Zalewski
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.
