Impact of GLP-1 receptor agonists on cardiovascular risk reduction in patients with obesity without type 2 diabetes mellitus: a systematic review
DOI:
https://doi.org/10.18203/2320-6012.ijrms20261347Abstract
Obesity has been established as an independent cardiovascular risk factor, driving low-grade systemic inflammation and endothelial dysfunction. Recently, GLP-1 receptor agonists (GLP-1 RAs) have demonstrated pleiotropic cardioprotective benefits, raising a paradigm shift regarding their preventive utility in patients without a diagnosis of type 2 diabetes mellitus (T2DM). To evaluate the current scientific evidence on the efficacy of GLP-1 RAs in reducing major adverse cardiovascular events (MACE) and improving risk biomarkers in overweight or obese patients without T2DM. A systematic literature review (2019-2026) was conducted in PubMed, Scopus, and Cochrane Library databases. Large-scale randomized clinical trials, meta-analyses, and mechanistic studies evaluating GLP-1 RA interventions (such as semaglutide and liraglutide) in non-diabetic populations were included, analyzing MACE incidence, lipid profiles, and inflammatory markers. Evidence demonstrates that GLP-1 RA therapy significantly reduces the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in this population, with relative risk reductions approaching 20%. Crucially, independent of the magnitude of weight loss, consistent improvements are observed in endothelial function, a sharp decrease in high-sensitivity C-reactive protein (hs-CRP), optimization of the lipid profile, and reduction in systolic blood pressure. GLP-1 RAs transcend glycemic control and simple anthropometric intervention, positioning themselves as a primary cardiovascular risk-modifying therapy. Their application in obese patients without T2DM represents a critical advance toward cardiovascular prevention driven by comprehensive metabolic pharmacotherapy. control, positioning itself as a promising strategy for diabetes and obesity management.
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Powell-Wiley TM, Poirier P, Burke LE, Després JP, Gordon-Larsen P, Lavie CJ, et al. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;143(21):e984-1010. DOI: https://doi.org/10.1161/CIR.0000000000000973
Bays HE, Taub PR, Epstein E, Michos ED, Ferranti SD, Bailey AL, et al. Ten things to know about ten cardiovascular disease risk factors. Am J Prev Cardiol. 2021;5:100149. DOI: https://doi.org/10.1016/j.ajpc.2021.100149
Müller TD, Finan B, Bloom SR, D'Alessio D, Tschöp MH. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. DOI: https://doi.org/10.1016/j.molmet.2019.09.010
Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab. 2016;24(1):15-30. DOI: https://doi.org/10.1016/j.cmet.2016.06.009
Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol. 2023;20(7):463-74. DOI: https://doi.org/10.1038/s41569-023-00849-3
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. DOI: https://doi.org/10.1136/bmj.n71
Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT Trial). N Engl J Med. 2023;389(24):2221-32. DOI: https://doi.org/10.1056/NEJMoa2307563
Ryan DH, Lingvay I, Colhoun HM, Deanfield J, Emerson SS, Kahn SE, et al. Semaglutide and cardiovascular outcomes in patients with overweight or obesity: subgroup analyses of the SELECT trial. Lancet. 2024;403(10433):1245-57.
Verma S, McGuire DK, Bain SC, Bhatt DL, Leiter LA, Mazer CD, et al. Cardiovascular Outcomes with GLP-1 Receptor Agonists in Patients with Obesity: A Meta-Analysis of Randomized Trials. Eur Heart J. 2024;45(12):1020-31.
Deanfield J, Kahn SE, McMurray JJV. Impact of baseline BMI on the cardiovascular benefits of semaglutide in non-diabetic patients. J Am Coll Cardiol. 2025;85(4):345-56.
Kosiborod MN, Bhatta M, Davies M, Deanfield J, Garvey WT, Khalid U, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-84. DOI: https://doi.org/10.1056/NEJMoa2306963
Ceriello A, Prattichizzo F, Phillip M, Hirsch IB, Mathieu C, Battelino T. The pleiotropic effects of GLP-1 receptor agonists: A focus on the cardiovascular system. Cardiovasc Diabetol. 2022;21(1):122.
Libby P. Inflammation in atherosclerosis. Nature. 2021;592(7855):524-33. DOI: https://doi.org/10.1038/s41586-021-03392-8
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002. DOI: https://doi.org/10.1056/NEJMoa2032183
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-31. DOI: https://doi.org/10.1056/NEJMoa1707914
Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Rev Diabet Stud. 2020;11(4):202-30. DOI: https://doi.org/10.1900/RDS.2014.11.202
Garvey WT, Batterham RL, Bhatta M, Buscemi S, Christensen LN, Frias JP, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083-91. DOI: https://doi.org/10.1038/s41591-022-02026-4
Smits MM, Van Raalte DH. Safety of Semaglutide. Front Endocrinol (Lausanne). 2021;12:645563. DOI: https://doi.org/10.3389/fendo.2021.645563
Wharton S, Calanna S, Davies M, Dicker D, Gleason CE, Halford JCG, et al. Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes Metab. 2022;24(1):94-105. DOI: https://doi.org/10.1111/dom.14551
He L, Wang J, Ping F, Yang N, Huang J, Li Y, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022;182(5):513-9. DOI: https://doi.org/10.1001/jamainternmed.2022.0338
Neeland IJ, Poirier P, Després JP. Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management. Circulation. 2018;137(13):1391-406. DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.029617
Marx N, Husain M, Florian A. GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk. J Am Coll Cardiol. 2022;80(23):2215-31.
Pyke C, Heller RS, Kirk RK, Ørskov C, Reedtz-Runge S, Kaastrup P, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155(4):1280-90. DOI: https://doi.org/10.1210/en.2013-1934
Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-1: brain, heart, and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995;358(3):219-24. DOI: https://doi.org/10.1016/0014-5793(94)01430-9
Rakipovski G, Rolin B, Nøhr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE-/- Mice by a Mechanism That Includes Inflammatory Pathways. JACC Basic Transl Sci. 2018;3(6):844-57. DOI: https://doi.org/10.1016/j.jacbts.2018.09.004
Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-505. DOI: https://doi.org/10.1056/NEJMoa1912388
Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-62. DOI: https://doi.org/10.1210/jc.2014-3415
Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation. 2019;140(11):e596-646. DOI: https://doi.org/10.1161/CIR.0000000000000678
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227-337. DOI: https://doi.org/10.1093/eurheartj/ehab484
Bays HE. Adiposopathy is "sick fat" a cardiovascular disease?. J Am Coll Cardiol. 2011;57(25):2461-73. DOI: https://doi.org/10.1016/j.jacc.2011.02.038
Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021;325(14):1403-13. DOI: https://doi.org/10.1001/jama.2021.1831
Puhl RM, Heuer CA. Obesity Stigma: Important Considerations for Public Health. Am J Public Health. 2010;100(6):1019-28. DOI: https://doi.org/10.2105/AJPH.2009.159491
Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab (Seoul). 2019;34(3):247-62. DOI: https://doi.org/10.3803/EnM.2019.34.3.247
Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet. 2019;393(10191):2636-46. DOI: https://doi.org/10.1016/S0140-6736(19)31138-9
Cava E, Yeat NC, Mittendorfer B. Preserving Healthy Muscle during Weight Loss. Adv Nutr. 2017;8(3):511-9. DOI: https://doi.org/10.3945/an.116.014506
Villareal DT, Chode S, Parimi N, Sinacore DR, Hilton T, Armamento-Villareal R, et al. Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med. 2011;364(13):1218-29. DOI: https://doi.org/10.1056/NEJMoa1008234
Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol. 2000;12(12):1347-52. DOI: https://doi.org/10.1097/00042737-200012120-00015
Eneanya ND, Yang W, Reese PP. Reconsidering the Consequences of Using Race to Estimate Kidney Function. JAMA. 2019;322(2):113-4. DOI: https://doi.org/10.1001/jama.2019.5774
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-16. DOI: https://doi.org/10.1056/NEJMoa2206038
Tschöp MH, Finan B, Clemmensen C, Gelfanov V, Perez-Tilve D, Müller TD, et al. Unimolecular Polypharmacy for Treatment of Diabetes and Obesity. Cell Metab. 2016;24(1):51-62. DOI: https://doi.org/10.1016/j.cmet.2016.06.021