Diversity of pleiotropic effects of semaglutide: From potential mechanisms to real clinical outcomes

The new cardio-reno-metabolic strategy in the monitoring and treatment of patients with type 2 diabetes mellitus (T2DM) obliges the clinician to increasingly prefer early combination therapy, which provides not only reliable and safe glycemic control, but also protection against cardio-renal complications of T2DM. The drugs that meet these requirements are sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, which have shown not only a high efficacy and safety profile, but also a reduced risk of major cardiovascular diseases, chronic kidney disease and mortality. Moreover, it is currently known that the pleiotropic effects of these drugs are not limited to cardio-renal protection. This article discusses the latest data on the effects of GLP-1 receptor agonists, which open up completely unexpected prospects for the use of these drugs, such as the treatment of heart failure, non-alcoholic fatty liver disease, steatohepatitis and neurodegenerative diseases.

1. Демидова Т.Ю., Измайлова М.Я., Лобанова К.Г. Эволюция представлений о диагностике и лечении различных фенотипов хронической сердечной недостаточности при сахарном диабете 2 типа. FOCUS Эндокринология. 2023; 4(4): 52–63. doi: 10.15829/2713-0177-2023-4-27

2. Kalra S, Das AK, Sahay RK et al.. Consensus recommendations on GLP-1 RA use in the management of type 2 diabetes mellitus: South Asian Task Force. Diabetes Ther. 2019; 10(5): 1645–717. doi: 10.1007/s13300-019-0669-4.

3. Crajoinas RO, Oricchio FT, Pessoa TD et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol. 2011; 301(2): F355–63. doi: 10.1152/ajprenal.00729.2010.

4. Amaro A, Skolnik NS, Sugimoto D. Cardiometabolic risk factors efficacy of semaglutide in the STEP program. Postgrad Med. 2022; 134(sup1): 18–27. doi: 10.1080/00325481.2022.2147325.

5. Marso SP, Bain SC, Consoli A et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375(19): 1834–44.doi: 10.1056/NEJMoa1607141.

6. Husain M, Birkenfeld AL, Donsmark M et al; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; 381(9): 841–51.doi: 10.1056/NEJMoa1901118.

7. Lincoff AM, Brown-Frandsen K, Colhoun HM et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023; 389(24): 2221–32. doi: 10.1056/NEJMoa2307563.

8. Kosiborod MN, Abildstrom SZ, Borlaug BA 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): 1069–84. doi: 10.1056/NEJMoa2306963.

9. Kosiborod MN, Petrie MC, Borlaug BA et al. J; 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): 1394–407. doi: 10.1056/NEJMoa2313917.

10. Pratley RE, Tuttle KR, Rossing P et al.; FLOW Trial Committees and Investigators. Effects of semaglutide on heart failure outcomes in diabetes and chronic kidney disease in the FLOW trial. J Am Coll Cardiol. 2024; 84(17): 1615–28. doi: 10.1016/j.jacc.2024.08.004.

11. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2025. Diabetes Care. 2025; 48(Supplement_1): S181–206. doi: 10.2337/dc25-S009.

12. Bandyopadhyay S, Das S, Samajdar SS, Joshi SR. Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Diabetes Metab Syndr. 2023; 17(10): 102849. doi: 10.1016/j.dsx.2023.102849.

13. Volpe S, Lisco G, Fanelli M et al. Once-weekly subcutaneous semaglutide improves fatty liver disease in patients with type 2 diabetes: A 52-week prospective real-life study. Nutrients. 2022; 14(21): 4673. doi: 10.3390/nu14214673.

14. Nomoto H, Takahashi Y, Takano Y et al. Effect of switching to once-weekly semaglutide on non-alcoholic fatty liver disease: The SWITCH-SEMA 1 subanalysis. Pharmaceutics. 2023; 15(8): 2163. doi: 10.3390/pharmaceutics15082163.

15. Sattar N, Lee MMY, Kristensen SL et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021; 9(10): 653–62. doi: 10.1016/S2213-8587(21)00203-5.

16. Cummings JL, Atri A, Feldman HH et al. Evoke and Evoke+: Design of two largescale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease. Alzheimers Res Ther. 2025; 17(1). doi: 10.1186/s13195-024-01666-7.

17. Hщlscher C. Glucagon-like peptide-1 class drugs show clear protective effects in Parkinson's and Alzheimer's disease clinical trials: A revolution in the making? Neuropharmacology. 2024; 253: 109952. doi: 10.1016/j.neuropharm.2024.109952.

18. Носков С.М., Арефьева А.Н., Банко В.В. с соавт. Препарат семаглутида для лечения ожирения: результаты двух открытых рандомизированных исследований фармакокинетики. Медицинский совет. 2024; 18(16): 216–222. doi: 10.21518/ms2024-346.