Протективный потенциал ингибиторов натрий-глюкозного котранспортера 2 типа в клинике внутренних болезней (часть 2)

Ингибиторы натрий-глюкозного котранспортера 2-го типа (SGLT2i) открывают новые горизонты в клинике внутренних болезней благодаря многообразию своих протективных эффектов. Во второй части данного обзора мы анализируем потенциал SGLT2i в области гепатологии, неврологии, офтальмологии и онкологии, рассматривая механизмы действия таких препаратов, как дапаглифлозин, эмпаглифлозин, канаглифлозин и др., а также их влияние на различные органы и системы.

1. Vafa RG, Sabahizadeh A, Mofarrah R. Guarding the heart: how SGLT-2 inhibitors protect against chemotherapy-induced cardiotoxicity: SGLT-2 inhibitors and chemotherapy-induced cardiotoxicity. Curr Probl Cardiol. 2024;49(3):102350. PMID: 38128634. https://doi.org/10.1016/j.cpcardiol.2023.102350

2. Lin L, Zhong S, Zhou Y, et al. Dapagliflozin improves the dysfunction of human umbilical vein endothelial cells (HUVECs) by downregulating high glucose/high fat-induced autophagy through inhibiting SGLT-2. J Diabetes Complications. 2025;39(1):108907. PMID: 39580877. https://doi.org/10.1016/j.jdiacomp.2024.108907

3. AvagimyanAA, Sheibani M, Trofimenko AI, et al. Protective potential of sodium-glucose cotransporter 2 inhibitors in internal medicine (part 1). Innovative Medicine of Kuban. 2024;9(4):126– 135. https://doi.org/10.35401/2541-9897-2024-9-4-126-135

4. Bhanushali KB, Asnani HK, Nair A, Ganatra S, Dani SS. Pharmacovigilance study for SGLT 2 inhibitors- safety review of real-world data & randomized clinical trials. Curr Probl Cardiol. 2024;49(9):102664. https://doi.org/10.1016/j.cpcardiol.2024.102664

5. Pouwels S, Sakran N, Graham Y, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord. 2022;22(1):63. PMID: 35287643. PMCID: PMC8919523. https://doi.org/10.1186/s12902-022-00980-1

6. Nassir F. NAFLD: mechanisms, treatments, and biomarkers. Biomolecules. 2022;12(6):824. PMID: 35740949. PMCID: PMC9221336. https://doi.org/10.3390/biom12060824

7. Nakano D, Akiba J, Tsutsumi T, et al. Hepatic expression of sodium-glucose cotransporter 2 (SGLT2) in patients with chronic liver disease. Med Mol Morphol. 2022;55(4):304–315. PMID: 36131166. PMCID: PMC9606064. https://doi.org/10.1007/s00795-022-00334-9

8. Cusi K, Bril F, Barb D, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21(4):812– 821. PMID: 30447037. https://doi.org/10.1111/dom.13584

9. Calapkulu M, Cander S, Gul OO, Ersoy C. Lipid profile in type 2 diabetic patients with new dapagliflozin treatment; actual clinical experience data of six months retrospective lipid profile from single center. Diabetes Metab Syndr. 2019;13(2):1031–1034. PMID: 31336439. https://doi.org/10.1016/j.dsx.2019.01.016

10. Akuta N, Watanabe C, Kawamura Y, et al. Effects of a sodium-glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: preliminary prospective study based on serial liver biopsies. Hepatol Commun. 2017;1(1):46–52. PMID: 29404432. PMCID: PMC5747031. https://doi.org/10.1002/hep4.1019

11. Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2020;65(2):623–631. PMID: 30684076. https://doi.org/10.1007/s10620-019-5477-1

12. Bellanti F, Lo Buglio A, Dobrakowski M, et al. Impact of sodium glucose cotransporter-2 inhibitors on liver steatosis/fibrosis/inflammation and redox balance in non-alcoholic fatty liver disease. World J Gastroenterol. 2022;28(26):3243–3257. PMID: 36051336. PMCID: PMC9331534. https://doi.org/10.3748/wjg.v28.i26.3243

13. Arai T, Atsukawa M, Tsubota A, et al. Antifibrotic effect and long-term outcome of SGLT2 inhibitors in patients with NAFLD complicated by diabetes mellitus. Hepatol Commun. 2022;6(11):3073–3082. PMID: 36039537. PMCID: PMC9592771. https://doi.org/10.1002/hep4.2069

14. Sakurai S, Jojima T, Iijima T, Tomaru T, Usui I, Aso Y. Empagliflozin decreases the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: association with improvement of fibrinolysis. J Diabetes Complications. 2020;34(11):107703. PMID: 32883567. https://doi.org/10.1016/j.jdiacomp.2020.107703

15. Arai T, Atsukawa M, Tsubota A, et al. Effect of sodiumglucose cotransporter 2 inhibitor in patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus: a propensity score-matched analysis of real-world data. Ther Adv Endocrinol Metab. 2021;12:20420188211000243. PMID: 33815743. PMCID: PMC7989116. https://doi.org/10.1177/20420188211000243

16. Xing B, Zhao Y, Dong B, Lv W, Zhao W. Effects of sodium-glucose cotransporter 2 inhibitors on non-alcoholic fatty liver disease in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. J Diabetes Investig. 2020;11(5):1238– 1247. PMID: 32083798. PMCID: PMC7477503. https://doi.org/10.1111/jdi.13237

17. Simental-Mendía M, Sánchez-García A, Rodríguez-Ramírez M, Simental-Mendía LE. Effect of sodium-glucose co-transporter 2 inhibitors on hepatic parameters: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2021;163:105319. PMID: 33246172. https://doi.org/10.1016/j.phrs.2020.105319

18. Zhou P, Tan Y, Hao Z, et al. Effects of SGLT2 inhibitors on hepatic fibrosis and steatosis: a systematic review and metaanalysis. Front Endocrinol (Lausanne). 2023;14:1144838. PMID: 36936142. PMCID: PMC10014961. https://doi.org/10.3389/fendo.2023.1144838

19. Kalantari E, Zolbanin NM, Ghasemnejad-Berenji M. Protective effects of empagliflozin on methotrexate induced hepatotoxicity in rats. Biomed Pharmacother. 2024;170:115953. PMID: 38064971. https://doi.org/10.1016/j.biopha.2023.115953

20. Satyam SM, Bairy LK, Rehman A, et al. Dapagliflozin: a promising strategy to combat cisplatin-induced hepatotoxicity in Wistar rats. Biology (Basel). 2024;13(9):672. PMID: 39336099. PMCID: PMC11428795. https://doi.org/10.3390/biology13090672

21. Тешев А.Ф., Малышев А.В., Головин А.С. Пролиферативная диабетическая ретинопатия тяжёлых стадий: современные подходы к диагностике и лечению (систематический обзор). Российский медицинский журнал. 2024;30(1):77–85. https://doi.org/10.17816/medjrf624868.

22. Wong TY, Sabanayagam C. Strategies to tackle the global burden of diabetic retinopathy: from epidemiology to artificial intelligence. Ophthalmologica. 2020;243(1):9–20. PMID: 31408872. https://doi.org/10.1159/000502387

23. Lahoti S, Nashawi M, Sheikh O, Massop D, Mir M, Chilton R. Sodium-glucose co-transporter 2 inhibitors and diabetic retinopathy: insights into preservation of sight and looking beyond. Cardiovasc Endocrinol Metab. 2020;10(1):3–13. PMID: 33634250. PMCID: PMC7901818. https://doi.org/10.1097/XCE.0000000000000209

24. Nadelmann JB, Miller CG, McGeehan B, Yu Y, Vander-Beek BL. SGLT2 inhibitors and diabetic retinopathy progression. Graefes Arch Clin Exp Ophthalmol. 2024;262(3):753–758. PMID: 37847267. PMCID: PMC11196159. https://doi.org/10.1007/s00417-023-06273-0

25. Yen FS, Wei JC, Yu TS, Hung YT, Hsu CC, Hwu CM. Sodium-glucose cotransporter 2 inhibitors and risk of retinopathy in patients with type 2 diabetes. JAMA Netw Open. 2023;6(12):e2348431. PMID: 38117497. PMCID: PMC10733799. https://doi.org/10.1001/jamanetworkopen.2023.48431

26. Benlarbi-Ben Khedher M, Hajri K, Dellaa A, et al. Astaxanthin inhibits aldose reductase activity in Psammomys obesus, a model of type 2 diabetes and diabetic retinopathy. Food Sci Nutr. 2019;7(12):3979–3985. PMID: 31890176. PMCID: PMC6924305. https://doi.org/10.1002/fsn3.1259

27. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–412. PMID: 10938048. PMCID: PMC27454. https://doi.org/10.1136/bmj.321.7258.405

28. American Diabetes Association. 1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S7–S13. PMID: 31862744. https://doi.org/10.2337/dc20-S001

29. Ott C, Jumar A, Striepe K, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017;16(1):26. PMID: 28231831. PMCID: PMC5324272. https://doi.org/10.1186/s12933-017-0510-1

30. Yoshizumi H, Ejima T, Nagao T, Wakisaka M. Recovery from diabetic macular edema in a diabetic patient after minimal dose of a sodium glucose co-transporter 2 inhibitor. Am J Case Rep. 2018;19:462–466. PMID: 29670074. PMCID: PMC5928754. https://doi.org/10.12659/ajcr.909708

31. Straznicky NE, Grima MT, Eikelis N, et al. The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components. J Clin Endocrinol Metab. 2011;96(3):E503–E508. PMID: 21177786. https://doi.org/10.1210/jc.2010-2204

32. Thorp AA, Schlaich MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res. 2015;2015:341583. PMID: 26064978. PMCID: PMC4430650. https://doi.org/10.1155/2015/341583

33. Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35(10):2059–2068. PMID: 28598954. https://doi.org/10.1097/HJH.0000000000001434

34. Cunningham C, Jabri A, Alhuneafat L, Aneja A. A comprehensive guide to sodium glucose cotransport inhibitors. Curr Probl Cardiol. 2023;48(10):101817. PMID: 37211299. https://doi.org/10.1016/j.cpcardiol.2023.101817

35. Wang S, Xu L, Jonas JB, et al. Major eye diseases and risk factors associated with systemic hypertension in an adult Chinese population: the Beijing Eye Study. Ophthalmology. 2009;116(12):2373–2380. PMID: 19815279. https://doi.org/10.1016/j.ophtha.2009.05.041

36. Zhang HY, Wang JY, Ying GS, Shen LP, Zhang Z. Serum lipids and other risk factors for diabetic retinopathy in Chinese type 2 diabetic patients. J Zhejiang Univ Sci B. 2013;14(5):392–399. PMID: 23645176. PMCID: PMC3650453. https://doi.org/10.1631/jzus.B1200237

37. Filippas-Ntekouan S, Tsimihodimos V, Filippatos T, Dimitriou T, Elisaf M. SGLT-2 inhibitors: pharmacokinetics characteristics and effects on lipids. Expert Opin Drug Metab Toxicol. 2018;14(11):1113–1121. PMID: 30360662. https://doi.org/10.1080/17425255.2018.1541348

38. Li JX, Hung YT, Bair H, Hsu SB, Hsu CY, Lin CJ. Sodiumglucose co-transporter 2 inhibitor add-on therapy for metformin delays diabetic retinopathy progression in diabetes patients: a population-based cohort study. Sci Rep. 2023;13(1):17049. PMID: 37816862. PMCID: PMC10564914. https://doi.org/10.1038/s41598-023-43893-2

39. Pascale RM, Calvisi DF, Simile MM, Feo CF, Feo F. The Warburg effect 97 years after its discovery. Cancers (Basel). 2020;12(10):2819. PMID: 33008042. PMCID: PMC7599761. https://doi.org/10.3390/cancers12102819

40. Wang Y, Patti GJ. The Warburg effect: a signature of mitochondrial overload. Trends Cell Biol. 2023;33(12):1014– 1020. PMID: 37117116. PMCID: PMC10600323. https://doi.org/10.1016/j.tcb.2023.03.013

41. Naeimzadeh Y, Tajbakhsh A, Nemati M, Fallahi J. Exploring the anti-cancer potential of SGLT2 inhibitors in breast cancer treatment in pre-clinical and clinical studies. Eur J Pharmacol. 2024;978:176803. PMID: 38950839. https://doi.org/10.1016/j.ejphar.2024.176803

42. Basak D, Gamez D, Deb S. SGLT2 inhibitors as potential anticancer agents. Biomedicines. 2023;11(7):1867. PMID: 37509506. PMCID: PMC10376602. https://doi.org/10.3390/biomedicines11071867

43. Dhas Y, Biswas N, M R D, Jones LD, Ashili S. Repurposing metabolic regulators: antidiabetic drugs as anticancer agents. Mol Biomed. 2024;5(1):40. PMID: 39333445. PMCID: PMC11436690. https://doi.org/10.1186/s43556-024-00204-z

44. Masoudkabir F, Mohammadifard N, Mani A, et al. Shared lifestyle-related risk factors of cardiovascular disease and cancer: evidence for joint prevention. ScientificWorldJournal. 2023;2023:2404806. PMID: 37520844. PMCID: PMC10386903. https://doi.org/10.1155/2023/2404806

45. Phoomak C, Vaeteewoottacharn K, Silsirivanit A, et al. High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation. Sci Rep. 2017;7:43842. PMID: 28262738. PMCID: PMC5338328. https://doi.org/10.1038/srep43842

46. Zhou J, Zhu J, Yu SJ, et al. Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. Biomed Pharmacother. 2020;132:110821. PMID: 33068934. https://doi.org/10.1016/j.biopha.2020.110821

47. Villani LA, Smith BK, Marcinko K, et al. The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. Mol Metab. 2016;5(10):1048–1056. PMID: 27689018. PMCID: PMC5034684. https://doi.org/10.1016/j.molmet.2016.08.014

48. Kennedy SP, O’Neill M, Cunningham D, et al. Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer. Oncogene. 2020;39(14):3028–3040. PMID: 32042115. PMCID: PMC7118022. https://doi.org/10.1038/s41388-020-1202-y

49. Nakano D, Kawaguchi T, Iwamoto H, Hayakawa M, Koga H, Torimura T. Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). PLoS One. 2020;15(4):e0232283. PMID: 32343721. PMCID: PMC7188283. https://doi.org/10.1371/journal.pone.0232283

50. Yu N, Kakunda M, Pham V, et al. HSP105 recruits protein phosphatase 2A to dephosphorylate β-catenin. Mol Cell Biol. 2015;35(8):1390–1400. PMID: 25645927. PMCID: PMC4372692. https://doi.org/10.1128/MCB.01307-14

51. Puglisi S, Rossini A, Poli R, et al. Effects of SGLT2 inhibitors and GLP-1 receptor agonists on renin-angiotensin-aldosterone system. Front Endocrinol (Lausanne). 2021;12:738848. PMID: 34745006. PMCID: PMC8567993. https://doi.org/10.3389/fendo.2021.738848

52. Cappetta D, De Angelis A, Bellocchio G, et al. Sodium-glucose cotransporter 2 inhibitors and heart failure: a bedside-to-bench journey. Front Cardiovasc Med. 2021;8:810791. PMID: 35004918. PMCID: PMC8733295. https://doi.org/10.3389/fcvm.2021.810791

53. Liu T, Wu J, Shi S, et al. Dapagliflozin attenuates cardiac remodeling and dysfunction in rats with β-adrenergic receptor overactivation through restoring calcium handling and suppressing cardiomyocyte apoptosis. Diab Vasc Dis Res. 2023;20(4):14791641231197106. PMID: 37589258. PMCID: PMC10437211. https://doi.org/10.1177/14791641231197106

54. Avagimyan A, Kakturskiy L, Heshmat-Ghahdarijani K, Pogosova N, Sarrafzadegan N. Anthracycline associated disturbances of cardiovascular homeostasis. Curr Probl Cardiol. 2022;47(5):100909. PMID: 34167841. https://doi.org/10.1016/j.cpcardiol.2021.100909

55. Авагимян А.А., Трофименко А.И., Шейбани М. и др. Сравнительная характеристика кардиопротекторных эффектов дапаглифлозина и триметазидина на модели доксорубицин-циклофосфамидной кардиотоксичности. Инновационная медицина Кубани. 2023;8(4):6–14. https://doi.org/10.35401/2541-9897-2023-8-4-6-14.

56. Avagimyan A, Kakturskiy L, Pogosova N, Ottaviani G, Rizzo M, Sarrafzadegan N. Doxorubicin and cyclophosphamide mode of chemotherapy-related cardiomyopathy: review of preclinical model. Curr Probl Cardiol. 2025;50(1):102882. PMID: 39427867. https://doi.org/10.1016/j.cpcardiol.2024.102882

57. Avagimyan A, Pogosova N, Kakturskiy L, et al. Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury. Cardiovasc Pathol. 2024;73:107683. PMID: 39111556. https://doi.org/10.1016/j.carpath.2024.107683

58. Avagimyan A, Sheibani M, Pogosova N, et al. Possibilities of dapagliflozin-induced cardioprotection on doxorubicin+cyclophosphamide mode of chemotherapy-induced cardiomyopathy. Int J Cardiol. 2023;391:131331. PMID: 37666280. https://doi.org/10.1016/j.ijcard.2023.131331

59. Симаненкова А.В., Фукс О.С., Тимкина Н.В. и др. Высокоселективный ингибитор натрий-глюкозного котранспортера 2 типа эмпаглифлозин как средство защиты головного мозга в условиях хронической недостаточности мозгового кровообращения (клинико-экспериментальное исследование). Проблемы эндокринологии. 2024;70(4):44–56. https://doi.org/10.14341/probl13336.

60. Youssef ME, Yahya G, Popoviciu MS, Cavalu S, Abd-Eldayem MA, Saber S. Unlocking the full potential of SGLT2 inhibitors: expanding applications beyond glycemic control. Int J Mol Sci. 2023;24(7):6039. PMID: 37047011. PMCID: PMC10094124. https://doi.org/10.3390/ijms24076039

61. Mone P, Varzideh F, Jankauskas SS, et al. SGLT2 inhibition via empagliflozin improves endothelial function and reduces mitochondrial oxidative stress: insights from frail hypertensive and diabetic patients. Hypertension. 2022;79(8):1633–1643. PMID: 35703100. PMCID: PMC9642044. https://doi.org/10.1161/HYPERTENSIONAHA.122.19586

62. Zügner E, Yang HC, Kotzbeck P, et al. Differential in vitro effects of SGLT2 inhibitors on mitochondrial oxidative phosphorylation, glucose uptake and cell metabolism. Int J Mol Sci. 2022;23(14):7966. PMID: 35887308. PMCID: PMC9319636. https://doi.org/10.3390/ijms23147966

63. Pawlos A, Broncel M, Woźniak E, Gorzelak-Pabiś P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26(23):7213. PMID: 34885795. PMCID: PMC8659196. https://doi.org/10.3390/molecules26237213

64. Shaikh S, Rizvi SM, Shakil S, Riyaz S, Biswas D, Jahan R. Forxiga (dapagliflozin): plausible role in the treatment of diabetes-associated neurological disorders. Biotechnol Appl Biochem. 2016;63(1):145–150. PMID: 25402624. https://doi.org/10.1002/bab.1319

65. Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13:363. PMID: 31440144. PMCID: PMC6692714. https://doi.org/10.3389/fncel.2019.00363

66. Liu J, Shi X, Shao Y. Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: a Mendelian randomization study. Brain Behav. 2024;14(7):e3624. PMID: 39010704. PMCID: PMC11250420. https://doi.org/10.1002/brb3.3624

67. Lardaro A, Quarta L, Pagnotta S, et al. Impact of sodium glucose cotransporter 2 inhibitors (SGLT2i) therapy on dementia and cognitive decline. Biomedicines. 2024;12(8):1750. PMID: 39200215. PMCID: PMC11351143. https://doi.org/10.3390/biomedicines12081750

68. Shourav MMI, Anisetti B, Meschia J, Lin M. Effects of sodium-glucose co-transporter 2 inhibitors on cognition in patients with diabetes: a systematic review and meta-analysis (P11-9.002). Neurology. 2024;102(17_supplement_1). https://doi.org/10.1212/wnl.0000000000205318

69. 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. PMID: 38367940. https://doi.org/10.1016/j.yfrne.2024.101131.