Влияние ипраглифлозина на компоненты метаболического синдрома и неалкогольную жировую болезнь печени

Ингибиторы натрий-глюкозного котранспортера-2 являются новыми препаратами для лечения сахарного диабета 2-го типа, механизм действия которых сводится к увеличению экскреции глюкозы с мочой за счет ингибирования реабсорбции в проксимальных канальцах почек, что приводит к снижению уровня глюкозы в крови. Эти препараты также обладают плейотропными эффектами, которые включают снижение массы тела и артериального давления, улучшение липидного профиля (повышение уровня холестерина липопротеинов высокой плотности и снижение уровня триглицеридов), а также снижение риска сердечно-сосудистой смерти и  нефропротекцию. Зарегистрированный в  России новый представитель класса ингибиторов натрий-глюкозного котранспортера-2 – препарат ипраглифлозин – показал свою эффективность в отношении гликемического контроля, снижая уровни гликированного гемоглобина и гликемии плазмы натощак как при монотерапии, так и в сочетании с другими сахароснижающими препаратами. Исследования PRIME-V и ILLUMINATE продемонстрировали, что ипраглифлозин способствует снижению инсулинорезистентности, массы тела, ИМТ и  окружности талии, общего и  ЛПНП-холестерина. Положительное влияние ипраглифлозина на массу и функцию β-клеток поджелудочной железы было показано в исследованиях на  животных. В  ряде исследований изучались положительные эффекты ипраглифлозина на  течение неалкогольной жировой болезни печени у пациентов с СД 2-го типа. Было показано значительное снижение уровней АЛТ и ГГТ и уменьшение абсолютного процента содержания жира в  печени. Исследования на  животных подтвердили влияние ипраглифлозина на гистологические характеристики НАЖБП. В обзоре представлены данные об эффективности ипраглифлозина в отношении компонентов метаболического синдрома у пациентов с СД 2-го типа, а также рассмотрены вероятные механизмы положительного влияния препарата на течение НАЖБП при СД 2-го типа. 

1. Scheen A.J. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16(10):556– 577. https://doi.org/10.1038/s41574-020-0392-2.

2. Ghosh R.K., Bandyopadhyay D., Hajra A., Biswas M., Gupta A. Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies. Int J Cardiol. 2016;212:29–36. https://doi.org/10.1016/j.ijcard.2016.02.134.

3. Wu J.H., Foote C., Blomster J., Toyama T., Perkovic V., Sundström J. et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: A systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411–419. https://doi.org/10.1016/S2213-8587(16)00052-8.

4. Zelniker T.A., Wiviott S.D., Raz I., Im K., Goodrich E.L., Furtado R.H.M. et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019; 139(17):2022–2031. https://doi.org/10.1161/CIRCULATIONAHA.118.038868.

5. Zelniker T.A., Braunwald E. Mechanisms of cardiorenal effects of sodiumglucose cotransporter 2 inhibitors: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(4):422–434. https://doi.org/10.1016/j.jacc.2019.11.031.

6. Buse J.B., Wexler D.J., Tsapas A., Rossing P., Mingrone G., Mathieu C. et al. 2019 Update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of diabetes (EASD). Diabetes Care. 2020;43(2):487–493. https://doi.org/10.2337/dci19-0066.

7. Elgebaly A., Abdelazeim N., Abdelazeim B., El Ashal G., Mattar O., Namous L. et al. Tolerability and efficacy of ipragliflozin in the management of inadequately controlled type 2 diabetes mellitus: a systematic review and meta-analysis. Exp Clin Endocrinol Diabetes. 2021;129(1):56–72. https://doi.org/10.1055/a-0579-7860.

8. Idris I., Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabet Obes Metab. 2009;11(2):79– 88. https://doi.org/10.1111/j.1463-1326.2008.00982.x.

9. Kashiwagi A., Takahashi H., Ishikawa H., Yoshida S., Kazuta K., Utsuno A. et al. A randomized, double-blind, placebo-controlled study on long-term ecacy and safety of ipragliozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes Obes Metab. 2015;17(2):152–160. https://doi.org/10.1111/dom.12403.

10. Nakamura I., Maegawa H., Tobe K., Tabuchi H., Uno S. Safety and efficacy of ipragliflozin in Japanese patients with type 2 diabetes in realworld clinical practice: interim results of the STELLA-LONG TERM post-marketing surveillance study. Expert Opin Pharmacother. 2018;19(3):189–201. https://doi.org/10.1080/14656566.2017.1408792.

11. Kashiwagi A., Kazuta K., Goto K., Yoshida S., Ueyama E., Utsuno A. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2015;17(3):304–308. https://doi.org/10.1111/dom.12331.

12. Shestakova M.V., Wilding J.P.H., Wilpshaar W., Tretter R., Orlova V.L., Verbovoy A.F. A phase 3 randomized placebo-controlled trial to assess the efficacy and safety of ipragliflozin as an add-on therapy to metformin in Russian patients with inadequately controlled type 2 diabetes mellitus. Diabetes Research Clin Pract. 2018;146:240–250. https://doi.org/10.1016/j.diabres.2018.10.018.

13. Ishihara H., Yamaguchi S., Nakao I., Okitsu A., Asahina S. Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a multi-centre, randomized, placebocontrolled, double-blind study. Diabetes Obes Metab. 2016;18(12):1207– 1216. https://doi.org/10.1111/dom.12745.

14. Semple R.K., Savage D.B., Cochran E.K., Gorden P., O’Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev. 2011;32(4):498–514. https://doi.org/10.1210/er.2010-0020.

15. Kolterman O.G., Gray R.S., Griffin J., Burstein P., Insel J., Scarlett J.A. et al. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981;68(4):957– 969. https://doi.org/10.1172/jci110350.

16. Bollag G.E., Roth R.A., Beaudoin J., Mochly-Rosen D., Koshland D.E. Jr. Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci USA.1986;83(16):5822–5824. https://doi.org/10.1073/pnas.83.16.5822.

17. Freidenberg G.R., Reichart D., Olefsky J.M., Henry R.R. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulindependent diabetes mellitus. Effect of weight loss. J Clin Invest. 1988;82(4):1398–1406. https://doi.org/10.1172/JCI113744.

18. Takayama S., White M.F., Kahn C.R. Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem. 1988;263(7):3440–3447. Available at: https://pubmed.ncbi.nlm.nih.gov/3125181/

19. Kashiwagi A., Kazuta K., Goto K., Yoshida S., Ueyama E., Utsuno A. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2015;17(3):304–308. https://doi.org/10.1111/dom.12331.

20. Tsurutani Y., Nakai K., Inoue K., Azuma K., Mukai S., Maruyama S. et al. Comparative study of the effects of ipragliflozin and sitagliptin on multiple metabolic variables in Japanese patients with type 2 diabetes: A multicentre, randomized, prospective, open-label, active-controlled study. Diabetes Obes Metab. 2018;20(11):2675–2679. https://doi.org/10.1111/dom.13421.

21. Koshizaka M., Ishikawa K., Ishibashi R., Maezawa Y., Sakamoto K., Uchida D. et al. Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study). Diabetes Obes Metab. 2019;21(8):1990–1995. https://doi.org/10.1111/dom.13750.

22. Тakasu T., Takakura S. Protective effect of ipragliflozin on pancreatic islet cells in obese type 2 diabetic db/db mice. Biol Pharm Bull. 2018;41(5):761–769. https://doi.org/10.1248/bpb.b17-01007.

23. Aronne L.J., Segal R.K. Adiposity and fat distribution outcome measures: assessment and clinial implications. Obes Res. 2002;10(1 Suppl.):14–21. https://doi.org/10.1038/oby.2002.184.

24. Bailey C.J. The challenge of managing coexistent type 2 diabetes and obesity. BMJ. 2011;342:d1996. https://doi.org/10.1136/bmj.d1996.

25. Kashiwagi A., Kazuta K., Yoshida S., Nagase I. Randomized, placebo-controlled, double-blind glycemic control trial of novel sodium dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2014;5(4):382–391. https://doi.org/10.1111/jdi.12156.

26. Лазебник Л.Б., Голованова Е.В., Туркина С.В., Райхельсон К.Л., Оковитый С.В., Драпкина О.М. и др. Неалкогольная жировая болезнь печени у взрослых: клиника, диагностика, лечение. Рекомендации для терапевтов, третья версия. Экспериментальная и клиническая гастроэнтерология. 2021;1(1): 4–52. https://doi.org/10.31146/1682-8658-ecg-185-1-4-52.

27. Lonardo A., Bellentani S., Argo C.K., Ballestri S., Byrne C.D., Caldwell S.H. et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis. 2015;47(12):997–1006. https://doi.org/10.1016/j.dld.2015.08.004.

28. Younossi Z.M. Non-alcoholic fatty liver disease – A global public health perspective. J Hepatol. 2019;70(3):531–544. https://doi.org/10.1016/j.jhep.2018.10.033.

29. Lomonaco R., Ortiz-Lopez C., Orsak B., Finch J., Webb A., Bril F. et al. Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis. Hepatology. 2011;54(3):837–845. https://doi.org/10.1002/hep.24483.

30. Younossi Z., Anstee Q.M., Marietti M., Hardy T., Henry L., Eslam M. et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20. https://doi.org/10.1038/nrgastro.2017.109.

31. Targher G., Lonardo A., Byrne C.D. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018;14(2):99–114. https://doi.org/10.1038/nrendo.2017.173.

32. Mantovani A., Scorletti E., Mosca A., Alisi A., Byrne C.D., Targher G. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism. 2020;111S:154170. https://doi.org/10.1016/j.metabol.2020.154170.

33. Doycheva I., Patel N., Peterson M., Loomba R. Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes. J Diabetes Complications. 2013;27(3):293–300. https://doi.org/10.1016/j.jdiacomp.2012.10.008.

34. Budd J., Cusi K. Role of agents for the treatment of diabetes in the management of nonalcoholic fatty liver disease. Curr Diab Rep. 2020;20:59. https://doi.org/10.1007/s11892-020-01349-1.

35. Sanyal A.J. NASH: A global health problem. Hepatol Res. 2011;41(7):670– 674. https://doi.org/10.1111/j.1872-034X.2011.00824.x.

36. Jang H.R., Kang D., Sinn D.H., Gu S., Cho S.J., Lee J.E. et al. Nonalcoholic fatty liver disease accelerates kidney function decline in patients with chronic kidney disease: A cohort study. Sci Rep. 2018;8(1):4718. https://doi.org/10.1038/s41598-018-23014-0.

37. Medina J., Fernández-Salazar L.I., García-Buey L., Moreno-Otero R. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diabetes Care. 2004;27(8):2057–2066. https://doi.org/10.2337/diacare.27.8.2057.

38. Xu L., Ota T. Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: Focus on fat browning and macrophage polarization. Adipocyte. 2018;7(2):121–128. https://doi.org/10.1080/21623945.2017.1413516.

39. Mavrogiannaki A.N., Migdalis I.N. Nonalcoholic fatty liver disease, diabetes mellitus and cardiovascular disease: newer data. Int J Endocrinol. 2013;2013:450639. https://doi.org/10.1155/2013/450639.

40. Barb D., Portillo‐Sanchez P., Cusi K. Pharmacological management of nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1183–1195. https://doi.org/10.1016/j.metabol.2016.04.004.

41. Portillo‐Sanchez P., Cusi K. Treatment of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus. Clin Diabetes Endocrinol. 2016;2:9. https://doi.org/10.1186/s40842-016-0027-7.

42. Mantovani A., Byrne C.D., Scorletti E., Mantzoros C.S., Targher G. Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials. Diabetes Metab. 2020;46(6):427–441. https://doi.org/10.1016/j.diabet.2019.12.007.

43. Cusi K. A diabetologist’s perspective of non-alcoholic steatohepatitis (NASH): Knowledge gaps and future directions. Liver Int. 2020;40(Suppl. 1): 82–88. https://doi.org/10.1111/liv.14350.

44. Hsiang J.C., Wong V.W. SGLT2 Inhibitors in liver patients. Clin Gastroenterol Hepatol. 2020;18(10):2168–2172.e2. https://doi.org/10.1016/j.cgh.2020.05.021.

45. Dougherty J.A., Guirguis E., Thornby K.A. A systematic review of newer antidiabetic agents in the treatment of nonalcoholic fatty liver disease. Ann Pharmacother. 2021;55(1):65–79. https://doi.org/10.1177/1060028020935105.

46. Pyper S.R., Viswakarma N., Yu S., Reddy J.K. PPARα: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal. 2010;8:e002. https://doi.org/10.1621/nrs.08002.

47. Hong F., Xu P., Zhai Y. The opportunities and challenges of peroxisome proliferator-activated receptors ligands in clinical drug discovery and development. Int J Mol Sci. 2018;19(8):2189. https://doi.org/10.3390/ijms19082189.

48. Yamane M., Matono T., Okano J.I., Nagahara R., Matsuki Y., Okamoto T. et al. Protective effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on a non-alcoholic steatohepatitis mouse model. Yonago Acta Med. 2019;62(1):30–35. https://doi.org/10.33160/yam.2019.03.005.

49. Mantovani A., Petracca G., Csermely A., Beatrice G., Targher G. Sodiumglucose cotransporter-2 inhibitors for treatment of nonalcoholic fatty liver disease: A meta-analysis of randomized controlled trials. Metabolites. 2020;11(1):22. https://doi.org/10.3390/metabo11010022.

50. Tobe K., Maegawa H., Nakamura I., Uno S. Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM). Endocr J. 2021. https://doi.org/10.1507/endocrj.EJ20-0765.

51. Komiya C., Tsuchiya K., Shiba K., Miyachi Y., Furuke S., Shimazu N. et al. Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction. PLoS ONE. 2016;11(3):e0151511. https://doi.org/10.1371/journal.pone.0151511.

52. Honda Y., Imajo K., Kato T., Kessoku T., Ogawa Y., Tomeno W. et al. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS ONE. 2016;11(1):e0146337. https://doi.org/10.1371/journal.pone.0146337.