Cardiovascular effects of semaglutide and tirzepatide and their potential for cardioprevention

Obesity and diabetes mellitus lead to metabolic changes that cause morphological and functional transformations in the cardiovascular system. The pathogenesis of cardiovascular damage in obesity is multifaceted. Cardiovascular complications associated with obesity are caused by processes involving hormones and peptides, when inflammation, insulin resistance, endothelial dysfunction, coronary calcification, activation of coagulation, renin-angiotensin-aldosterone and sympathetic nervous systems are included, leading to the development of heart failure with both preserved ejection fraction and reduced ejection fraction. Initiation of effective, safe and affordable therapeutic interventions may be crucial for managing cardiometabolic health. This review aims to summarize the results of studies confirming the efficacy and safety of drugs with incretin activity – one of the most prescribed drugs from the class of glucagon-like peptide 1 receptor agonists – semaglutide and the first dual agonist of glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptors – tirzepatide. Pathogenesis mechanisms of cardiovascular damage in obesity are considered in detail based on the latest fundamental studies and the mechanisms implemented in the heart and blood vessels by glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide. Emphasis is placed on the capabilities of incretin mimetics, in addition to the hypoglycemic effect, to reduce vascular inflammation, adipose tissue mass and contribute to the improvement of the lipid profile, which demonstrates their metabolism-modifying properties. Incretins can be classified as disease-modifying therapy drugs, since they affect the cardiovascular system, improving the functional state of the endothelium, reducing blood pressure, slowing platelet aggregation, inhibiting cardiomyocyte apoptosis, improving glucose utilization, and exerting a vasodilating effect. This explains the reduction in the risk of cardiovascular complications observed in clinical studies, and in experimental studies, a decrease in the necrosis zone during modeling of myocardial infarction and the use of incretin mimetics.

1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–781. https://doi.org/10.1016/S0140-6736(14)60460-8.

2. GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017;377(1):13–27. https://doi.org/10.1056/NEJMoa1614362.

3. GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1223–1249. https://doi.org/10.1016/S0140-6736(20)30752-2.

4. Mamatov A, Orozmatov T, Madaminov J, Abdymanap Kyzy A, Chubasheva N. Obesity And The Risk Of Developing Cardiovascular Diseases: A Look At The Current Problem. The Scientific Heritage. 2021;(64):35–42. (In Russ.) https://doi.org/10.24412/9215-0365-2021-64-2-35-42.

5. Bogers RP, Bemelmans WJ, Hoogenveen RT, Boshuizen HC, Woodward M, Knekt P et al.; BMI-CHD Collaboration Investigators. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300 000 persons. Arch Intern Med. 2007;167(16):1720–1728. https://doi.org/10.1001/archinte.167.16.1720.

6. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983;67(5):968–977. https://doi.org/10.1161/01.cir.67.5.968.

7. The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects); Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants. Lancet. 2014;383(9921):970–983. https://doi.org/10.1016/S0140-6736(13)61836-X.

8. Wilson PW, Bozeman SR, Burton TM, Hoaglin DC, Ben-Joseph R, Pashos CL. Prediction of first events of coronary heart disease and stroke with consideration of adiposity. Circulation. 2008;118(2):124–130. https://doi.org/10.1161/CIRCULATIONAHA.108.772962.

9. Caleyachetty R, Thomas GN, Toulis KA, Mohammed N, Gokhale KM, Balachandran K, Nirantharakumar K. Metabolically Healthy Obese and Incident Cardiovascular Disease Events Among 3.5 Million Men and Women. J Am Coll Cardiol. 2017;70(12):1429–1437. https://doi.org/10.1016/j.jacc.2017.07.763.

10. Cholesterol Treatment Trialists’ (CTT) Collaboration; Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753): 1670–1681. https://doi.org/10.1016/S0140-6736(10)61350-5.

11. SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103–2116. https://doi.org/10.1056/NEJMoa1511939.

12. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis. JAMA Cardiol. 2021;6(2):148–158. https://doi.org/10.1001/jamacardio.2020.4511.

13. Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and metaanalysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653–662. https://doi.org/10.1016/S2213-8587(21)00203-5.

14. Ma C, Avenell A, Bolland M, Hudson J, Stewart F, Robertson C et al. Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. BMJ. 2017;359:j4849. https://doi.org/10.1136/bmj.j4849.

15. Look AHEAD Research Group; Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–154. https://doi.org/10.1056/NEJMoa1212914.

16. Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary treatment goal for type 2 diabetes: Time to reframe the conversation. Lancet. 2022;399(10322):394–405. https://doi.org/10.1016/S0140-6736(21)01919-X.

17. Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab. 2016;24(1):15–30. https://doi.org/10.1016/j.cmet.2016.06.009.

18. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372(14):1333–1341. https://doi.org/10.1056/NEJMoa1406656.

19. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G et al. Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1–25. https://doi.org/10.1016/j.jacc.2017.04.052.

20. Murphy SL, Xu J, Kochanek KD, Arias E. Mortality in the United States, 2017. NCHS Data Brief. 2018;(328):1–8. Available at: https://pubmed.ncbi.nlm.nih.gov/30500322.

21. Sidney S, Sorel ME, Quesenberry CP, Jaffe MG, Solomon MD, NguyenHuynh MN et al. Comparative Trends in Heart Disease, Stroke, and AllCause Mortality in the United States and a Large Integrated Healthcare Delivery System. Am J Med. 2018;131(7):829–836.e1. https://doi.org/10.1016/j.amjmed.2018.02.014.

22. Bombelli M, Facchetti R, Fodri D, Brambilla G, Sega R, Grassi G, Mancia G. Impact of body mass index and waist circumference on the cardiovascular risk and all-cause death in a general population: data from the PAMELA study. Nutr Metab Cardiovasc Dis. 2013;23(7):650–656. https://doi.org/10.1016/j.numecd.2012.01.004.

23. Druzhilov MA, Druzhilova OYu, Beteleva YuE, Kuznetsova TYu. Obesity as cardiovascular risk factor: accent on quality and functional activity of adipose tissue. Russian Journal of Cardiology. 2015;(4):111–117. (In Russ.) https://doi.org/10.15829/1560-4071-2015-4-111-117.

24. Jindal A, Whaley-Connell A, Sowers JR. Obesity and heart failure as a mediator of the cerebrorenal interaction. Contrib Nephrol. 2013;179:15–23. https://doi.org/10.1159/000346718.

25. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–1278. https://doi.org/10.1016/S0140-6736(05)67394-1.

26. Lawler PR, Bhatt DL, Godoy LC, Lüscher TF, Bonow RO, Verma S, Ridker PM. Targeting cardiovascular inflammation: next steps in clinical translation. Eur Heart J. 2021;42(1):113–131. https://doi.org/10.1093/eurheartj/ehaa099.

27. Mechanick JI, Farkouh ME, Newman JD, Garvey WT. Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(5):525–538. https://doi.org/10.1016/j.jacc.2019.11.044.

28. Mechanick JI, Garber AJ, Grunberger G, Handelsman Y, Garvey WT. Dysglycemia-based chronic disease: an American Association of Clinical Endocrinologists position statement. Endocr Pract. 2018;24(11):995–1011. https://doi.org/10.4158/PS-2018-0139.

29. Piché ME, Poirier P. Obesity, ectopic fat and cardiac metabolism. Expert Rev Endocrinol Metab. 2018;13(4):213–221. https://doi.org/ 10.1080/17446651.2018.1500894.

30. Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K et al.; EMPEROR-Reduced Trial Committees and Investigators. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail. 2019;21(10):1270–1278. https://doi.org/10.1002/ejhf.1536.

31. Koliaki CC, Katsilambroset NL. Are the Modern Diets for the Treatment of Obesity Better than the Classical Ones? Endocrines. 2022;(3):603–623. https://doi.org/10.3390/endocrines3040052.

32. Savji N, Meijers WC, Bartz TM, Bhambhani V, Cushman M, Nayor M et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Heart Fail. 2018;6:701–709. https://doi.org/10.1016/j.jchf.2018.05.018.

33. Liu L, Lima JAC, Post WS, Szklo M. Associations of time-varying obesity and metabolic syndrome with risk of incident heart failure and its subtypes: Findings from the Multi-Ethnic Study of Atherosclerosis. Int J Cardiol. 2021;338:127–135. https://doi.org/10.1016/j.ijcard.2021.05.051.

34. Filiniuk PY, Shishkin AN, Pchelin IY, Khudyakova NV, Volovnikova VA, Kulibaba TG. Some Features of Correction of Adipose Tissue Dysfunction. Juvenis Scientia. 2023;9(6):6–17. (In Russ.) https://doi.org/10.32415/jscientia2023966-17.

35. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol. 2009;53:1925–1932. https://doi.org/10.1016/j.jacc.2008.12.068.

36. Ashrafian H, le Roux CW, Darzi A, Athanasiou T. Effects of Bariatric Surgery on Cardiovascular Function. Circulation. 2008;118(20):2091–2102. https://doi.org/10.1161/CIRCULATIONAHA.107.721027.

37. Ebong IA, Goff DC, Rodriges CJ, Chen H, Bertoni AG. Mechanisms of Heart Failure in Obesity. Obes Res Clin Pract. 2014;8(6):540–548. https://doi.org/10.1016/j.orcp.2013.12.005.

38. Kim M, Oh JK, Sakata S, Liang I, Park W, Hajjar RJ, Lebeche D et al. Role of resistin in cardiac contractility and hypertrophy. J Mol Cell Cardiol. 2008;45(2):270–280. https://doi.org/10.1016/j.yjmcc.2008.05.006.

39. Dedov II, Aleksandrov AA, Kukharenko SS. Heart and obesity. Obesity and Metabolism. 2006;3(1):14–20. (In Russ.) https://doi.org/10.14341/2071-8713-4938.

40. Dreval AV, Nechaeva OA, Dreval OA, Britvin TA, Gabrielyan AR. Metabolic medicine. RMJ. Medical Review. 2024;8(9):518–525. (In Russ.) https://doi.org/10.32364/2587-6821-2024-8-9-3.

41. Baggio LL, Drucker DJ: Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–2157. https://doi.org/10.1053/j.gastro.2007.03.054.

42. Anagnostis P, Athyros VG, Adamidou F, Panagiotou A, Kita M, Karagiannis A, Mikhailidis DP. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diab Obes Metab. 2011;13:302–312. https://doi.org/10.1111/j.1463-1326.2010.01345.x.

43. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340–2350. https://doi.org/10.1161/CIRCULATIONAHA.107.739938.

44. Erdogdu O, Nathanson D, Sjöholm A, Nyström T, Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKAand PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol. 2010;325(1-2):26–35. https://doi.org/10.1016/j.mce.2010.04.022.

45. Green BD, Hand KV, Dougan JE, McDonnell BM, Cassidy RS, Grieve DJ. GLP1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP. Arch Biochem Biophys. 2008;478(2):136–142. https://doi.org/10.1016/j.abb.2008.08.001.

46. Kuc RE, Maguire JJ, Siew K, Patel S, Derksen DR, Margaret Jackson V et al. Characterization of [¹²⁵I]GLP-1(9-36), a novel radiolabeled analog of the major metabolite of glucagon-like peptide 1 to a receptor distinct from GLP1-R and function of the peptide in murine aorta. Life Sci. 2014;102(2):134–138. https://doi.org/10.1016/j.lfs.2014.03.011.

47. Eriksson L, Nystrom T. Antidiabetic agents and endothelial dysfunction – beyond glucose control. Basic Clin Pharmacol Toxicol. 2015;117(1):15–25. https://doi.org/10.1111/bcpt.12402.

48. Ha SJ, Kim W, Woo JS. Preventive effects of exenatide on endothelial dysfunction induced by ischemia-reperfusion injury via KATP channels. Arterioscler Thromb Vasc Biol. 2012;32(2):474−480. https://doi.org/10.1161/atvbaha.110.222653.

49. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab. 2007;293(5):1289−1295. https://doi.org/10.1152/ajpendo.00373.2007.

50. Tyurenkov IN, Bakulin DA, Kurkin DV, Volotova EV. Cardiovascular Effects of Incretin-Based Therapies and Their Therapeutic Potential. Annals of the Russian Academy of Medical Sciences. 2017;72(1):66–75. (In Russ.) https://doi.org/10.15690/vramn732.

51. Xiao-Yun X, Zhao-Hui M, Ke C. Glucagon-like peptide-1 improves proliferation and differentiation of endothelial progenitor cells via upregulating VEGF generation. Med Sci Monit. 2011;17(2):BR35−41. https://doi.org/10.12659/msm.881383.

52. Hogan AE, Gaoatswe G, Lynch L, Corrigan MA, Woods C, O’Connell J, O’Shea D. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014;57(4):781–784. https://doi.org/10.1007/s00125-013-3145-0.

53. Lorber D. GLP-1 Receptor Agonists: Effects on Cardiovascular Risk Reduction. Cardiovasc Ther. 2013;31(4):238–249. https://doi.org/10.1111/1755-5922.12000.

54. Tate M, Chong A, Robinson E, Green BD, Grieve DJ. Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes. Br J Pharmacol. 2015;172(3):721–736. https://doi.org/10.1111/bph.12943.

55. Cameron-Vendrig A, Reheman A, Siraj MA, Xu XR, Wang Y, Lei X et al. Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes. 2016;65(6):1714−1723. https://doi.org/10.2337/db15-1141.

56. Khedr RM, Ahmed AAE, Kamel R, Raafat EM. Sitagliptin attenuates intestinal ischemia/reperfusion injury via cAMP/PKA, PI3K/Akt pathway in a glucagon-like peptide 1 receptor-dependent manner. Life Sci. 2018;211:31–39. https://doi.org/10.1016/j.lfs.2018.09.013.

57. Shestakova EA, Il’in AV, Shestakova MV, Dedov II. Glucose-dependent insulinotropic polypeptide – a new link in the development of obesity. Obesity and Metabolism. 2015;12(1):16–19. (In Russ.) https://doi.org/10.14341/omet2015116-19.

58. Holst JJ. On the physiology of GIP and GLP-1. Horm Metab Res. 2004;36(11-12): 747–754. https://doi.org/10.1055/s-2004-826158.

59. Vergès B. Do antiobesity medical treatments have a direct effect on adipose tissue? Ann Endocrinol. 2024;85(3):179–183. https://doi.org/10.1016/j.ando.2024.05.021.

60. Lorber D. GLP-1 Receptor Agonists: Effects on Cardiovascular Risk Reduction. Cardiovasc Ther. 2013;31(4):238–249. https://doi.org/10.1111/1755-5922.12000.

61. Manna P, Jain SK. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies. Metab Syndr Relat Disord. 2015;13(10):423–444. https://doi.org/10.1089/met.2015.0095.

62. Dedov II, Shestakova MV, Melnichenko GA, Mazurina NV, Andreeva EN, Bondarenko IZ et al. Interdisciplinary clinical practice guidelines “management of obesity and its comorbidities”. Obesity and Metabolism. 2021;18(1):5–99. (In Russ.) https://doi.org/10.14341/omet12714.

63. Biryukova EV, Markina NV, Garbuzova MA. Effective and flexible pharmacotherapy of obesity today is the key to successful prevention of type 2 diabetes in the future. Diabetes Mellitus. 2007;10(4):23–28. (In Russ.) https://doi.org/10.14341/2072-0351-5862.

64. Valenzuela PL, Carrera-Bastos P, Castillo-García A, Lieberman DE, SantosLozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol. 2023;20:475–494. https://doi.org/10.1038/s41569-023-00847-5.

65. Дедов ИИ, Мокрышева НГ, Мельниченко ГА, Трошина ЕА. Ожирение у взрослых: клинические рекомендации. 2024. Режим доступа: https://diseases.medelement.com/disease/ожирение-у-взрослых-кр-рф-2024/18475?ysclid=mdr0saztbl647599587.

66. Tsygankova OV, Veretyuk VV, Ametov AS. Incretins today: multiple effects and therapeutic potential. Diabetes Mellitus. 2019;22(1):70–78. (In Russ.) https://doi.org/10.14341/DM9841.

67. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844. https://doi.org/10.1056/NEJMoa1607141.

68. Blundell J, Finlayson G, Axelsen M, Flint A, Gibbons C, Kvist T, Hjerpsted JB. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab. 2017;19(9):1242–1251. https://doi.org/10.1111/dom.12932.

69. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S et al.; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221–2232. https://doi.org/10.1056/NEJMoa2307563.

70. Birkeland KI, Bodegard J, Eriksson JW Norhammar A, Haller H, Linssen GCM et al. Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study. Diabetes Obes Metab. 2020;22(9):1607–1618. https://doi.org/10.1111/dom.14074.

71. Wang Q, Cao H, Li P, Li C, Shi Z, Ren J. New approach to heart failure: Integrated traditional Chinese with Western medicine. Advanced Chinese Medicine. 2024;1(1):19–39. https://doi.org/10.1002/acm4.10.

72. Demidova TYu, Izmailova MYa, Alieva MA. Cardiovascular effects of semaglutide: Multifaceted mechanisms of systemic organoprotection. FOCUS Endocrinology. 2025;6(2):47–56. (In Russ.) https://doi.org/10.62751/27130177-2025-6-2-06.

73. Ferrari R, Curello SA. Pathophysiology of serve ischemic myocardial injury. Netherlands: Kluwer Academic Publishers; 1990, pp. 221–238. https://doi.org/10.1007/978-94-009-0475-0.

74. Ryan DH, Lingvay I, Colhoun HM, Deanfield J, Emerson SS, Kahn SE et al. Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design. Am Heart J. 2020;229:61–69. https://doi.org/10.1016/j.ahj.2020.07.008.

75. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M et al.; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069–1084. https://doi.org/10.1056/NEJMoa2306963.

76. Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies M, Hovingh G et al.; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024;390(15):1394–13407. https://doi.org/10.1056/NEJMoa2313917.

77. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: Standards of Care in Diabetes-2025. Diabetes Care. 2025;48(Suppl. 1):S181–S206. https://doi.org/10.2337/dc25-S009.

78. Yaribeygi H, Maleki M, Jamialahmadi T, Sahebkar A. Anti-inflammatory benefits of semaglutide: State of the art. J Clin Transl Endocrinol. 2024;36:100340. https://doi.org/10.1016/j.jcte.2024.100340.

79. Lam S. American Diabetes Association – 77th Scientific Sessions (June 9–13, 2017 – San Diego, California, USA). Drugs Today. 2017;53(7):405–413. https://doi.org/10.1358/dot.2017.53.7.2669148.

80. Katsurada K, Nandi SS, Sharma NM Zheng H, Liu X, Patel KP. Does glucagon-like peptide-1 induce diuresis and natriuresis by modulating afferent renal nerve activity? Am J Physiol Renal Physiol. 2019;317(4):F1010–F1021. https://doi.org/10.1152/ajprenal.00028.2019.

81. Tchang BG, Knight MG, Adelborg K, Clements JN, Iversen AT, Traina A. Effect of semaglutide 2.4 mg on use of antihypertensive and lipidlowering treatment in five randomized controlled STEP trials. Obesity. 2025;33(2):267–277. https://doi.org/10.1002/oby.24202.

82. Ogbu IR, Ngwudike C, Lal K, Danielian A, Daoud SN. Role of glucagon-like peptide-1 agonist in patients undergoing percutaneous coronary intervention or coronary artery bypass grafting: A meta-analysis. Am Heart J Plus. 2021;11:100063. https://doi.org/10.1016/j.ahjo.2021.100063.

83. Tarasova AP, Pokrovsky MV, Danilenko LM. Incretin peptides: new targets in correction of ischemic-reperfusion myocardial damages. Kursk Scientific and Practical Bulletin “Man and His Health”. 2020;(1):29–36. (In Russ.) https://doi.org/10.21626/vestnik/2020-1/04.

84. Gallwitz B. Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity. Front Endocrinol. 2022;13:1004044. https://doi.org/10.3389/fendo.2022.1004044.

85. Tall Bull S, Nuffer W, Trujillo JM. Tirzepatide: A novel, first-in-class, dual GIP/GLP-1 receptor agonist. J Diabetes Complications. 2022;36(12):108332. https://doi.org/10.1016/j.jdiacomp.2022.108332.

86. Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, Tsapas A, Bekiari E. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia. 2022;65(8):1251–1261. https://doi.org/10.1007/s00125-022-05715-4.

87. Titova VV, Ushanova FO, Demidova TYu. Drug therapy of obesity: modern approaches and prospects. FOCUS Endocrinology. 2024;5(4):40–48. (In Russ.) https://doi.org/10.62751/2713-0177-2024-5-4-18.

88. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B et al.; SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216. https://doi.org/10.1056/NEJMoa2206038.

89. Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D et al.; SURMOUNT-2 investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomized, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613–626. https://doi.org/10.1016/S0140-6736(23)01200-X.

90. Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023;29(11):2909–2918. https://doi.org/10.1038/s41591-023-02597-w.

91. Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY et al.; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024;331(1):38–48. https://doi.org/10.1001/jama.2023.24945.

92. Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V et al.; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025;392(5):427–437. https://doi.org/10.1056/NEJMoa2410027.

93. Borlaug BA, Zile MR, Kramer CM, Baum SJ, Hurt K, Litwin SE et al. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med. 2025;31(2):544–551. https://doi.org/10.1038/s41591-024-03374-z.

94. Taktaz F, Scisciola L, Fontanella RA, Pesapane A, Ghosh P, Franzese M et al. Evidence that tirzepatide protects against diabetes-related cardiac damages. Cardiovasc Diabetol. 2024;23(1):112. https://doi.org/10.1186/s12933-024-02203-4.

95. Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a prespecified meta-analysis. Nat Med. 2022;28(3):591–598. https://doi.org/10.1038/s41591-022-01707-4.

96. Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D et al.; SURMOUNT-2 investigators. 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. Lancet. 2023;402(10402):613–626. https://doi.org/10.1016/S0140-6736(23)01200-X.

97. Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V et al.; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025;392(5):427–437. https://doi.org/10.1056/NEJMoa2410027.

98. Borlaug BA, Zile MR, Kramer CM, Baum SJ, Hurt K, Litwin SE et al. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med. 2025;31(2):544–551. https://doi.org/10.1038/s41591-024-03374-z.

99. Mori Y, Matsui T, Hirano T, Yamagishi SI. GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease-A Systematic Review. Int J Mol Sci. 2020;21(4):1509. https://doi.org/10.3390/ijms21041509.

100. Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis K, Tousoulis D. The Anti-Inflammatory Effect of Novel Antidiabetic Agents. Life. 2022;12(11):1829. https://doi.org/10.3390/life12111829.

101. Liu Q, Zhu J, Kong B, Shuai W, Huang H. Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway. Int Immunopharmacol. 2023;120:110311. https://doi.org/10.1016/j.intimp.2023.110311.

102. Fisman EZ, Tenenbaum A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc Diabetol. 2021;20(1):225. https://doi.org/10.1186/s12933-021-01412-5.

103. Kido K, Carey B, Caccamo M, Bianco C, Sokos G. Call to action for drug interactions between tirzepatide and heart failure guideline-directed medical therapy. J Am Pharm Assoc. 2024;64(1):169–173. https://doi.org/10.1016/j.japh.2023.09.011.

104. Kanbay M, Copur S, Siriopol D, Yildiz AB, Gaipov A, van Raalte DH, Tuttle KR. Effect of tirzepatide on blood pressure and lipids: A metaanalysis of randomized controlled trials. Diabetes Obes Metab. 2023;25(12):3766–3778. https://doi.org/10.1111/dom.15272.

105. Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A et al.; SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med. 2024;391(13):1193–1205. https://doi.org/10.1056/NEJMoa2404881.

106. Zanozina OV, Sorokina YuA, Kalugina EV, Zhuk SD, Plastova NN, Taradayko NYu et al. Russian-made pharmpreparation semaglutide in true clinical practice. Effective Pharmacotherapy. 2024;20(52):6–12. (In Russ.) https://doi.org/10.33978/2307-3586-2024-20-52-6-12.

107. Demidova TYu, Ushanova FO, Bogacheva TL. Semaglutide in type 2 diabetes management: review of current evidence from concept to date. FOCUS Endocrinology. 2023;4(3):13–28. (In Russ.) https://doi.org/10.15829/2713-0177-2023-3-11.

108. Noskov SM, Arefeva AN, Banko VV, Radaeva КS, Gefen ML, Archakova OA et al. Semaglutide for the treatment of obesity: Results of two open rand-omized pharmacokinetic studies. Meditsinskiy Sovet. 2024;18(16):216–222. (In Russ.) https://doi.org/10.21518/ms2024-346.

109. Karonova TL, Murasheva AV, Timkina NV, Fuks OS, Shlyakhto EV. Comparative study of the neuroprotective potential of semaglutide injectable preparations in experimental ischemic stroke. Meditsinskiy Sovet. 2024;18(16):163–170. (In Russ.) https://doi.org/10.21518/ms2024-404.