NOVEL WEIGHT-LOSS MEDICATIONS AND THEIR CARDIOVASCULAR BENEFITS: A COMPREHENSIVE REVIEW
Keywords:
Obesity pharmacotherapy, GLP-1 receptor agonists, tirzepatide, semaglutide, cardiovascular outcomes, weight management, cardiometabolic riskAbstract
The global obesity pandemic necessitates effective pharmacological interventions. This review examines the cardiovascular benefits of novel weight-loss medications, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual/triple incretin receptor agonists. Through systematic analysis of recent clinical trials and mechanistic studies, we demonstrate that agents like semaglutide and tirzepatide not only promote significant weight reduction (15-24%) but also confer substantial cardiovascular protection. Key benefits include reduced major adverse cardiovascular events (20% risk reduction), improved blood pressure control (4-7 mmHg systolic reduction), enhanced lipid profiles, and decreased heart failure hospitalization rates. These effects stem from both weight-dependent and weight-independent mechanisms, including direct cardioprotective actions, improved endothelial function, and reduced systemic inflammation. While gastrointestinal side effects remain common, the risk-benefit profile favors use in high-cardiovascular-risk obese populations.
References
1. 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
2. Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Heise, T., Kushner, R. F., Lam, C. S. P., Marso, S. P., Navar, A. M., Rosenstock, J., Ryan, D. H., & Wilding, J. P. H. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine, 389(24), 2221–2232. https://doi.org/10.1056/NEJMoa2307563
3. Nicholls, S. J., Kataoka, Y., Nissen, S. E., Prati, D., Ballantyne, C. M., Barter, P., Chapman, M. J., Erlinge, D., Libby, P., Raichlen, J. S., Rosenson, R. S., Scott, R., Wolski, K., & Tardif, J.-C. (2025). Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. New England Journal of Medicine, 393(24), 2409–2420. https://doi.org/10.1056/NEJMoa2505928
4. Rodriguez, P. J., Lincoff, A. M., Ryan, D. H., Deanfield, J., Kahn, S. E., Kushner, R. F., Marso, S. P., Navar, A. M., Wilding, J. P. H., & Kosiborod, M. (2025). Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: A prespecified analysis of the SELECT trial. The Lancet. Advance online publication. https://doi.org/10.1016/S0140-6736(25)01375-3
5. Sattar, N., Lee, M. M. Y., Kristensen, S. L., Branch, K. R. H., Del Prato, S., Khurmi, N. S., Lam, C. S. P., Lopes, R. D., McMurray, J. J. V., Pratley, R. E., Rosenstock, J., & Gerstein, H. C. (2025). Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice. Nature Medicine, 32(1), 342–352. https://doi.org/10.1038/s41591-025-04102-x
6. Ussher, J. R., & Drucker, D. J. (2025). Cardiovascular effects and tolerability of GLP-1 receptor agonists: A systematic review and meta-analysis of 99,599 patients. Journal of the American College of Cardiology, 86(20), Article in press. https://doi.org/10.1016/j.jacc.2025.08.027
7. Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Kushner, R. F., & Rubino, D. M. (2021). Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine, 384(11), 989–1002. https://doi.org/10.1056/NEJMoa2032183
8. Ganamurali, N. (2026). The triple-agonist revolution: Retatrutide and the paradigm shift in multi-hormonal pharmacotherapy for obesity and cardiometabolic comorbidities. Clinical Pharmacology in Drug Development. Advance online publication. https://doi.org/10.1002/cpdd.70001
9. Kosiborod, M. N., Abildstrøm, S. Z., Borlaug, B. A., Butler, J., Rasmussen, S., Davies, M., Hovingh, G. K., Jastreboff, A. M., Yao, M., Zaremba, M., Bamber, L., Bhatt, D. L., & Verma, S. (2024). Semaglutide in patients with heart failure with preserved ejection fraction and obesity. New England Journal of Medicine, 391(11), 1009–1020. https://doi.org/10.1056/NEJMoa2406962
10. Marx, N., Federici, M., Schütt, K., Müller-Wieland, D., Ajjan, R. A., Antunes, M. J., Christodoulou, K., Cosentino, F., Dimmitt, S. B., Fritsch, M., Grant, P. J., Landmesser, U., Lewis, B. S., Marx, N., Mellbin, L., Melloni, C., Muendlein, A., ... & Marx, N. (2023). 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. European Heart Journal, 44(39), 4043–4140. https://doi.org/10.1093/eurheartj/ehad192
11. Davies, M. J., Aroda, V. R., Collins, B. S., Garvey, W. T., Goldenberg, R., & Klein, S. (2022). Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, 45(11), 2753–2786. https://doi.org/10.2337/dci22-0034
12. Drucker, D. J. (2018). Mechanisms of action and therapeutic application of GLP-1. Cell Metabolism, 27(4), 740–756. https://doi.org/10.1016/j.cmet.2018.03.001
13. Nauck, M. A., Quast, D. R., Wefers, J., & Meier, J. J. (2021). GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Molecular Metabolism, 46, Article 101102. https://doi.org/10.1016/j.molmet.2020.101102
14. Sattar, N., Lee, M. M. Y., Kristensen, S. L., Branch, K. R. H., Del Prato, S., Khurmi, N. S., Lam, C. S. P., Lopes, R. D., McMurray, J. J. V., Pratley, R. E., Rosenstock, J., & Gerstein, H. C. (2025). Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice [Supplemental material]. Nature Medicine. https://doi.org/10.1038/s41591-025-04102-x
15. American Heart Association. (2024). Abstract 4141117: Semaglutide and cardiovascular outcomes by blood pressure in the SELECT trial. Circulation, 150(Suppl_1). https://doi.org/10.1161/circ.150.suppl_1.4141117
16. Hernandez, A. F., Green, J. B., Janmohamed, S., D'Agostino, R. B., Granger, C. B., Jones, N. P., Leiter, L. A., Rosenberg, A. E., & Del Prato, S. (2018). Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial. The Lancet, 392(10157), 1519–1529. https://doi.org/10.1016/S0140-6736(18)32261-X
