Rachel Kurian

Background:  Obesity is a growing global health concern, with adult prevalence roughly doubling since 1990.¹ Recently, anti‑obesity medications such as semaglutide and tirzepatide have produced weight loss of approximately 15–20% of initial body weight.^{2, 3} Semaglutide, a glucagon‑like peptide‑1 (GLP‑1) receptor agonist (RA), enhances glucose‑dependent insulin secretion and suppresses glucagon, thereby lowering blood glucose.⁴ Tirzepatide is a dual GLP‑1 and glucose‑dependent insulinotropic polypeptide (GIP) RA that functions similarly but generally produces greater weight loss than GLP‑1 monoagonists.² Obesity substantially increases risk for acute cardiovascular events, including myocardial infarction and stroke. Lifestyle interventions used to treat obesity improve cardiovascular risk factors, but obesity and cardiovascular disease are usually treated with parallel pharmacologic regimens. Emerging evidence shows that agents originally approved for type 2 diabetes, such as semaglutide and tirzepatide,⁴ can reduce cardiometabolic event rates.^5-8 This review examines whether GLP‑1/GIP RAs should be incorporated into routine care for cardiometabolic conditions.

Methods: Google Scholar and PubMed were searched for recent studies addressing cardiometabolic outcomes with GLP‑1/GIP RAs. Search terms included “GLP‑1 receptor agonists,” “GIP agonists,” “cardiometabolic outcomes,” “cardiovascular outcomes,” “semaglutide,” “tirzepatide,” and “obesity.” Peer‑reviewed articles published from 2021 onward were included.

Results:  In SELECT, once‑weekly semaglutide in patients with obesity, established cardiovascular disease, and no diabetes reduced the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 20% versus placebo.⁵ In FLOW, semaglutide in type 2 diabetes with chronic kidney disease lowered risk of a composite kidney outcome (kidney failure, ≥50% eGFR decline, or kidney‑ or cardiovascular‑related death), reduced cardiovascular mortality, and slowed eGFR decline compared with placebo.⁶ In SUMMIT, tirzepatide in participants with obesity, heart failure with preserved ejection fraction, and preserved ejection fraction reduced worsening heart failure events and cardiovascular death versus placebo.⁷ A large retrospective analysis found that, in type 2 diabetes, tirzepatide was associated with lower hazards of all‑cause mortality, major adverse cardiovascular events, acute kidney injury, and major adverse kidney events than treatment with GLP‑1 RAs.⁸

Conclusions:  GLP‑1 and dual GLP‑1/GIP agonists show substantial promise for cardiometabolic risk reduction. Across diverse high‑risk populations, semaglutide and tirzepatide not only induce robust weight loss but also slow kidney disease progression and lower cardiovascular event and mortality rates.^5-8 These findings support considering GLP‑1/GIP‑based obesity pharmacotherapy as part of long‑term management and prevention strategies for chronic cardiometabolic disease.

Works Cited

1. Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism. 2019;92(92):6-10. doi:https://doi.org/10.1016/j.metabol.2018.09.005
2. Wilding JPH, Batterham RL, Calanna S. Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine. 2021;384(11):989-1002. doi:https://doi.org/10.1056/NEJMoa2032183
3. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. 2022;387(3):205-216. doi:https://doi.org/10.1056/nejmoa2206038
4. Tan HC, Dampil OA, Marquez MM. 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. 2022;37(2):65-72. doi:https://doi.org/10.15605/jafes.037.02.14
5. A. Michael Lincoff, Kirstine Brown‐Frandsen, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. 2023;389(24). doi:https://doi.org/10.1056/nejmoa2307563
6. Perkovic V, Tuttle K, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. New England journal of medicine/The New England journal of medicine. 2024;391(2). doi:https://doi.org/10.1056/nejmoa2403347
7. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. New England Journal of Medicine. 2024;392(5). doi:https://doi.org/10.1056/nejmoa2410027
8. Chuang MH, Chen JY, Wang HY, Jiang ZH, Wu VC. Clinical Outcomes of Tirzepatide or GLP-1 Receptor Agonists in Individuals With Type 2 Diabetes. JAMA Network Open. 2024;7(8):e2427258-e2427258. doi:https://doi.org/10.1001/jamanetworkopen.2024.27258