Церебральные расстройства и сахарный диабет: центральные эффекты ингибиторов натрий-глюкозных котранспортеров

Сахарный диабет (СД) ассоциирован с повышенным риском нарушений мозгового кровообращения и худшего исхода инсульта, а также характеризуется большой частотой когнитивных нарушений. Уязвимость головного мозга перед метаболическими и сосудистыми повреждающими факторами, сопровождающими течение СД, определяет необходимость понимания механизмов патологического процесса в условиях коморбидности, поиска и имплементации мер церебропротекции. Лечение СД включает модификацию образа жизни, контроль гликемии и оптимизацию остальных факторов риска сердечно-сосудистых заболеваний. Интенсификация гликемического контроля позволяет добиться снижения риска микроваскулярных диабетический осложнений, но не доказала свою эффективность в профилактике сосудистых заболеваний головного мозга и КН. Новейший класс антигипергликемических препаратов – ингибиторы натрий-глюкозного котранспортера-2 (иНГЛТ-2) – занял прочное место в терапии СД 2 типа (СД2). Появляется все больше подтверждений того, что применение иНГЛТ-2 может влиять на снижение риска инсульта у пациентов с СД2, а также способствовать сохранению когнитивных функций.

1. Танашян М.М., Антонова К.В. Цереброметаболическое здоровье. Анналы клинической и экспериментальной неврологии. 2025;19(2):62–73. doi: 10.17816/ACEN.1359.

2. GBD 2021 Stroke Risk Factor Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024;23(10):973–1003. doi: 10.1016/S1474-4422(24)00369-7.

3. Emerging Risk Factors Collaboration; Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative metaanalysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22. doi: 10.1016/S0140-6736(10)60484-9.

4. Mosenzon O, Cheng AY, Rabinstein AA, Sacco S. Diabetes and stroke: What are the connections? J Stroke. 2023;25(1):26–38. doi: 10.5853/jos.2022.02306.

5. Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms. Can J Cardiol. 2018;34(5):575–84. doi: 10.1016/j.cjca.2017.12.005.

6. Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: A meta-analysis of prospective observational studies. J Diabetes Investig. 2013;4(6):640–50. doi: 10.1111/jdi.12087.

7. You Y, Liu Z, Chen Y, Xu Y, Qin J, Guo S et al. The prevalence of mild cognitive impairment in type 2 diabetes mellitus patients: A systematic review and metaanalysis. Acta Diabetol. 2021;58(6):671–85. doi: 10.1007/s00592-020-01648-9.

8. Kunutsor SK, Balasubramanian VG, Zaccardi F, Gillies CL, Aroda VR, Seidu S, Khunti K. Glycaemic control and macrovascular and microvascular outcomes: A systematic review and meta-analysis of trials investigating intensive glucoselowering strategies in people with type 2 diabetes. Diabetes Obes Metab. 2024;26(6):2069–81. doi: 10.1111/dom.15511.

9. Gerstein HC, Hart R, Colhoun HM, Diaz R, Lakshmanan M, Botros FT et al. The effect of dulaglutide on stroke: An exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol. 2020;8(2):106–14. doi: 10.1016/S2213-8587(19)30423-1.

10. Arnott C, Li Q, Kang A, Neuen BL, Bompoint S, Lam CSP, Rodgers A, et al. Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2020 Feb 4;9(3):e014908. doi: 10.1161/JAHA.119.014908.

11. Zhou Z, Jardine MJ, Li Q, Neuen BL, Cannon CP, de Zeeuw D et al.; CREDENCE Trial Investigators. Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis. Stroke. 2021;52(5):1545–56. doi: 10.1161/STROKEAHA.120.031623.

12. Pasqualotto E, Rodrigues FR, E Silva Ribeiro GB, de Oliveira Almeida G, Kabariti JC, Ferreira ROM et al. The effect of sodium-glucose transporter 2 inhibitors on stroke in patients with type 2 diabetes: A meta-analysis. J Stroke Cerebrovasc Dis. 2024;33(8):107730. doi: 10.1016/j.jstrokecerebrovasdis.2024.107730.

13. Chang SN, Chen JJ, Huang PS, Wu CK, Wang YC, Hwang JJ, Tsai CT. Sodium-glucose cotransporter-2 inhibitor prevents stroke in patients with diabetes and atrial fibrillation. J Am Heart Assoc. 2023;12(10):e027764. doi: 10.1161/JAHA.122.027764.

14. Patel SM, Kang YM, Im K, Neuen BL, Anker SD, Bhatt DL et al. Sodium-glucose cotransporter-2 inhibitors and major adverse cardiovascular outcomes: A SMART-C collaborative meta-analysis. Circulation. 2024;149(23):1789–801. doi: 10.1161/CIRCULATIONAHA.124.069568.

15. Wang F, Li C, Cui L, Gu S, Zhao J, Wang H. Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and cerebrovascular diseases: A meta-analysis of controlled clinical trials. Front Endocrinol (Lausanne). 2024;15:1436217. doi: 10.3389/fendo.2024.1436217.

16. Park CH, Lee B, Han M, Rhee WJ, Kwak MS, Yoo TH, Shin JS. Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells. Cell Death Discov. 2022;8(1):12. doi: 10.1038/s41420-021-00801-9.

17. D'Onofrio N, Sardu C, Trotta MC, Scisciola L, Turriziani F, Ferraraccio F et al. Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment. Mol Metab. 2021;54:101337. doi: 10.1016/j.molmet.2021.101337.

18. Moustafa B, Trifan G. The role of diabetes and SGLT2 inhibitors in cerebrovascular diseases. Curr Neurol Neurosci Rep. 2025;25(1):37. doi: 10.1007/s11910-025-01425-7.

19. Niu Y, Zhang Y, Zhang W, Lu J, Chen Y, Hao W et al. Canagliflozin ameliorates NLRP3 inflammasome-mediated inflammation through inhibiting NF-κB signaling and upregulating Bif-1. Front Pharmacol. 2022;13:820541. doi: 10.3389/fphar.2022.820541.

20. Rahadian A, Fukuda D, Salim HM, Yagi S, Kusunose K, Yamada H et al. Canagliflozin prevents diabetes-induced vascular dysfunction in ApoE-deficient mice. J Atheroscler Thromb. 2020;27(11):1141–51. doi: 10.5551/jat.52100.

21. Sa-Nguanmoo P, Tanajak P, Kerdphoo S, Jaiwongkam T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Toxicol Appl Pharmacol. 2017;333:43–50. doi: 10.1016/j.taap.2017.08.005.

22. Youn YJ, Kim S, Jeong HJ, Ah YM, Yu YM. Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: A systematic review and meta-analysis. Front Neuroendocrinol. 2024;73:101131. doi: 10.1016/j.yfrne.2024.101131.

23. Gyimesi G, Pujol-Gimenez J, Kanai Y, Hediger MA. Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: From molecular discovery to clinical application. Pflugers Arch. 2020;472(9):1177–206. doi: 10.1007/s00424-020-02433-x.

24. Pawlos A, Broncel M, Wozniak E, Gorzelak-Pabis P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26(23):7213. doi: 10.3390/molecules26237213.

25. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N et al.; CANVAS Program Collaborative Group. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323–34. doi: 10.1161/CIRCULATIONAHA.117.032038.

26. Rosenthal N, Meininger G, Ways K, Polidori D, Desai M, Qiu R et al. Canagliflozin: A sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. Ann N Y Acad Sci. 2015;1358:28–43. doi: 10.1111/nyas.12852.

27. Dong M, Chen H, Wen S, Yuan Y, Yang L, Li Yet al. The neuronal and non-neuronal pathways of sodium-glucose cotransporter-2 inhibitor on body weightloss and insulin resistance. Diabetes Metab Syndr Obes. 2023;16:425–35. doi: 10.2147/DMSO.S399367.

28. Razaghizad A, Ni J, Marques P, Mavrakanas TA, Tsoukas MA, Possik E et al. Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial. Diabetes Obes Metab. 2024;26(11):5025–35. doi: 10.1111/dom.15768.

29. Arafa NMS, Ali EHA, Hassan MK. Canagliflozin prevents scopolamine-induced memory impairment in rats: Comparison with galantamine hydrobromide action. Chem Biol Interact. 2017;277:195–203. doi: 10.1016/j.cbi.2017.08.013.

30. Abdelaziz AM, Rasheed NOA, Zaki HF, et al. Canagliflozin attenuates neurodegeneration and ameliorates dyskinesia through targeting the NLRP3/ Nurr1/GSK-3β/SIRT3 pathway and autophagy modulation in rotenone-lesioned rats. Int Immunopharmacol. 2025;146:113839. doi:10.1016/j.intimp.2024.113839.

31. Taylor AIP, Xu Y, Wilkinson M, Chakraborty P, Brinkworth A, Willis LF et al. Kinetic steering of amyloid formation and polymorphism by canagliflozin, a type-2 diabetes drug. J Am Chem Soc. 2025;147(14):11859–78. doi: 10.1021/jacs.4c16743.

32. Garza-Lombo C, Schroder A, Reyes-Reyes EM, Franco R. mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. Curr Opin Toxicol. 2018;8:102–110. doi: 10.1016/j.cotox.2018.05.002.

33. Jiang E, Dinesh A, Jadhav S, Miller RA, Garcia GG. Canagliflozin shares common mTOR and MAPK signaling mechanisms with other lifespan extension treatments. Life Sci. 2023;328:121904. doi: 10.1016/j.lfs.2023.121904.

34. Мурашева А.В., Каронова Т.Л., Фукс О.С., Тимкина Н.В., Федотова А.Д., Гринева Е.Н., Шляхто Е.В. Сравнительное исследование нейропротективных свойств ингибиторов натрий-глюкозного котранспортера-2 и агонистов рецепторов глюкагоноподобного пептида-1 у пациентов с сахарным диабетом 2 типа. Сахарный диабет. 2025;28(2):187–197. doi: 10.14341/DM13255.

35. Кокин А.С., Суплотова Л.А. Нейропротекторный потенциал глифлозинов. Сахарный диабет. 2023;26(6):596–602. doi: 10.14341/DM13085.