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Ингибиторы натрий-глюкозного котранспортера 2: механизмы кардиоренальной защиты
Леонова М.В. Ингибиторы натрий-глюкозного котранспортера 2: механизмы кардиоренальной защиты. Consilium Medicum. 2024;26(4):225–231. DOI: 10.26442/20751753.2024.4.202763
© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.
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Leonova MV. Sodium-glucose cotransporter 2 inhibitors: mechanisms of cardiorenal protection: A review. Consilium Medicum. 2024;26(4):225–231. DOI: 10.26442/20751753.2024.4.202763
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Аннотация
Ингибиторы натрий-глюкозного котранспортера 2 (иНГЛТ-2) – новый класс гипогликемических препаратов, которые первоначально одобрены для лечения сахарного диабета (СД) 2-го типа. В настоящее время 5 препаратов класса иНГЛТ-2 одобрены Управлением по контролю пищевых продуктов и лекарств в США для контроля гликемии: канаглифлозин, дапаглифлозин, эмпаглифлозин, эртуглифлозин и сотаглифлозин. Однако вскоре установлена их эффективность в снижении риска хронической сердечной недостаточности и прогрессирования хронической болезни почек вне зависимости от статуса СД. Кроме того, по данным ряда метаанализов рандомизированных клинических исследований, у пациентов с кардиометаболическими и почечными заболеваниями применение иНГЛТ-2 снижает сердечно-сосудистую и общую смертность и количество серьезных нежелательных сердечных событий и почечных исходов у пациентов с СД или без него, что нашло отражение в показаниях к их применению. Представлены научные данные в обсуждении механизмов кардиопротективных и ренопротективных эффектов класса иНГЛТ-2, многие из которых рассматривают как плейотропные эффекты, не связанные с влиянием на уровень гликемии.
Ключевые слова: ингибиторы натрий-глюкозного котранспортера 2, кардиоренопротекция, сердечная недостаточность, хроническая болезнь почек, диабет
Ключевые слова: ингибиторы натрий-глюкозного котранспортера 2, кардиоренопротекция, сердечная недостаточность, хроническая болезнь почек, диабет
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Sodium-glucose cotransporter 2 inhibitors (SGLT-2) are a new class of hypoglycemic drugs that were initially approved for the treatment of type 2 diabetes. Currently, 5 drugs in the SGLT-2 class of drugs are approved by the FDA for glycemic control: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin and sotagliflozin. However, their effectiveness in reducing the risk of heart failure and progression of chronic kidney disease was soon established, regardless of diabetes status. In addition, according to a number of meta-analyses of RCTs in patients with cardiometabolic and renal diseases, the use of SGLT-2 reduces cardiovascular and overall mortality and the number of serious adverse cardiac events and renal outcomes in patients with or without diabetes, which is reflected in the indications to their use. Scientific data are presented in a discussion of the mechanisms of cardioprotective and renoprotective effects of the SGLT-2 class, many of which are considered as pleiotropic effects not related to the effect on glycemic levels.
Keywords: sodium-glucose cotransporter 2 inhibitors, cardiorenoprotection, heart failure, chronic kidney disease, diabetes
Полный текст
Список литературы
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21. Sano M, Goto S. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation. 2019;139:1985-7. DOI:10.1161/CIRCULATIONAHA.118.038881
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27. Chen-Izu Y, Shaw RM, Pitt GS, et al. Na+ channel function, regulation, structure, trafficking and sequestration. J Physiol. 2015;593(6):1347-60. DOI:10.1113/jphysiol.2014.281428
28. Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 inhibitors and their mode of action in heart failure – has the mystery been unravelled? Curr Heart Fail Rep. 2021;18(5):315-28. DOI:10.1007/s11897-021-00529-8
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2. Giugliano D, Longo M, Scappaticcio L, et al. SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs. Cardiovasc Diabetol. 2021;20(1):236. DOI:10.1186/s12933-021-01430-3
3. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400:757-67. DOI:10.1016/S0140-6736(22)01429-5
4. Li N, Lv D, Zhu X, et al. Effects of SGLT2 inhibitors on renal outcomes in patients with chronic kidney disease: a meta-analysis. Front Med (Lausanne). 2021;8:728089. DOI:10.3389/fmed.2021.728089
5. Teo YH, Teo YN, Syn NL, et al. Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus: a systematic review and meta-analysis of randomized-controlled trials. J Am Heart Assoc. 2021;10(5):e019463. DOI:10.1161/JAHA.120.019463
6. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-9. DOI:10.1016/S0140-6736(18)32590-X
7. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11-26. DOI:10.1038/nrneph.2016.170
8. Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:422-34. DOI:10.1016/J.JACC.2019.11.031
9. Bjornstad P, Greasley PJ, Wheeler DC, et al. The potential roles of osmotic and nonosmotic sodium handling in mediating the effects of sodium-glucose cotransporter 2 inhibitors on heart failure. J Card Fail. 2021;27(12):1447-55. DOI:10.1016/j.cardfail.2021.07.003
10. Cherney DZI, Cooper ME, Tikkanen I, et al. Pooled analysis of phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93(1):231-44. DOI:10.1016/j.kint.2017.06.017
11. Osataphan S, Macchi C, Singhal G, et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight. 2019;4(5):e123130. DOI:10.1172/jci.insight.123130
12. Sato T, Aizawa Y, Yuasa S, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018;17(1):6. DOI:10.1186/s12933-017-0658-8
13. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5(6):632-44. DOI:10.1016/j.jacbts.2020.02.004
14. Adam CA, Anghel R, Marcu DTM, et al. Impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on arterial stiffness and vascular aging – what do we know so far? (A narrative review). Life (Basel). 2022;12(6):803. DOI:10.3390/life12060803
15. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-17. DOI:10.1007/s00125-018-4670-7
16. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-93. DOI:10.1111/dom.12572
17. Pfeifer M, Townsend RR, Davies MJ, et al. Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis. Cardiovasc Diabetol. 2017;16(1):29. DOI:10.1186/s12933-017-0511-0
18. Baker WL, Buckley LF, Kelly MS, et al. Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J Am Heart Assoc. 2017;6(5):e005686. DOI:10.1161/JAHA.117.005686
19. Zhang Q, Zhou S, Liu L. Efficacy and safety evaluation of SGLT2i on blood pressure control in patients with type 2 diabetes and hypertension: a new meta-analysis. Diabetol Metab Syndr. 2023;15(1):118. DOI:10.1186/s13098-023-01092-z
20. Silva Dos Santos D, Polidoro JZ, Borges-Júnior FA, Girardi ACC. Cardioprotection conferred by sodium-glucose cotransporter 2 inhibitors: a renal proximal tubule perspective. Am J Physiol Cell Physiol. 2020;318(2):C328-36. DOI:10.1152/ajpcell.00275.2019
21. Sano M, Goto S. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation. 2019;139:1985-7. DOI:10.1161/CIRCULATIONAHA.118.038881
22. Maruyama T, Takashima H, Oguma H, et al. Canagliflozin improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technol Ther. 2019;21(12):713-20. DOI:10.1089/dia.2019.0212
23. Tran DH, Wang ZV. Glucose metabolism in cardiac hypertrophy and heart failure. J Am Heart Assoc. 2019;8(12):e012673. DOI:10.1161/JAHA.119.012673
24. Sowton AP, Griffin JL, Murray AJ. Metabolic profiling of the diabetic heart: toward a richer picture. Front Physiol. 2019;10:639. DOI:10.3389/fphys.2019.00639
25. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108-14. DOI:10.2337/dc16-0330
26. Challa AA, Lewandowski ED. Short-chain carbon sources: exploiting pleiotropic effects for heart failure therapy. JACC Basic Transl Sci. 2022;7(7):730-42. DOI:10.1016/j.jacbts.2021.12.010
27. Chen-Izu Y, Shaw RM, Pitt GS, et al. Na+ channel function, regulation, structure, trafficking and sequestration. J Physiol. 2015;593(6):1347-60. DOI:10.1113/jphysiol.2014.281428
28. Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 inhibitors and their mode of action in heart failure – has the mystery been unravelled? Curr Heart Fail Rep. 2021;18(5):315-28. DOI:10.1007/s11897-021-00529-8
29. Packer M, Anker SD, Butler J, et al. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2(9):1025-9. DOI:10.1001/jamacardio.2017.2275
30. Verma S, Garg A, Yan AT, et al. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial? Diabetes Care. 2016;39(12):e212-3. DOI:10.2337/dc16-1312
31. Matsutani D, Sakamoto M, Kayama Y, et al. Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):73. DOI:10.1186/s12933-018-0717-9
32. Shim CY, Seo J, Cho I, et al. Randomized, controlled trial to evaluate the effect of dapagliflozin on left ventricular diastolic function in patients with type 2 diabetes mellitus: the IDDIA trial. Circulation. 2021;143(5):510-2. DOI:10.1161/CIRCULATIONAHA.120.051992
33. Cohen ND, Gutman SJ, Briganti EM, Taylor AJ. Effects of empagliflozin treatment on cardiac function and structure in patients with type 2 diabetes: a cardiac magnetic resonance study. Intern Med J. 2019;49(8):1006-10. DOI:10.1111/imj.14260
34. Pabel S, Wagner S, Bollenberg H, et al. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail. 2018;20(12):1690-700. DOI:10.1002/ejhf.1328
35. Garvey WT, Van Gaal L, Leiter LA, et al. Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes. Metabolism.
2018;85:32-7. DOI:10.1016/j.metabol.2018.02.002
36. Fu WJ, Huo JL, Mao ZH, et al. Emerging role of antidiabetic drugs in cardiorenal protection. Front Pharmacol. 2024;15:1349069. DOI:10.3389/fphar.2024.1349069
37. Durante W, Behnammanesh G, Peyton KJ. Effects of sodium-glucose co-transporter 2 inhibitors on vascular cell function and arterial remodeling. Int J Mol Sci. 2021;22(16):8786. DOI:10.3390/ijms22168786
38. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298-310. DOI:10.1016/j.freeradbiomed.2017.01.035
39. Kang S, Verma S, Teng G, et al. Direct effects of empagliflozin on extracellular matrix remodeling in human cardiac fibroblasts: novel translational clues to EMPA-REG Outcome. Can J Cardiol. 2017;33:S169.
40. Verma S, Mazer CD, Yan AT, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: The EMPA-HEART CardioLink – 6 randomized clinical trial. Circulation. 2019;140(21):1693-702. DOI:10.1161/CIRCULATIONAHA.119.042375
41. Brown AJM, Gandy S, McCrimmon R, et al. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial. Eur Heart J. 2020;41(36):3421-32. DOI:10.1093/eurheartj/ehaa419
42. Braunwald E. Diabetes, heart failure, and renal dysfunction: the vicious circles. Prog Cardiovasc Dis. 2019;62:298-302.
43. Salvatore T, Galiero R, Caturano A, et al. An Overview of the cardiorenal protective mechanisms of SGLT2 inhibitors. Int J Mol Sci. 2022;23(7):3651.
44. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28. DOI:10.1056/NEJMoa1504720
45. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-57.
46. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-57.
47. Mayer GJ, Wanner C, Weir MR, et al. Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics. Kidney Int. 2019;96(2):489-504. DOI:10.1016/j.kint.2019.02.033
48. Bae JH, Park EG, Kim S, et al. Effects of sodium-glucose cotransporter 2 inhibitors on renal outcomes in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Sci Rep. 2019;9(1):13009. DOI:10.1038/s41598-019-49525-y
49. Cassis P, Locatelli M, Cerullo D, et al. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight. 2018;3(15):e98720. DOI:10.1172/jci.insight.98720
50. Salvatore T, Galiero R, Caturano A, et al. An overview of the cardiorenal protective mechanisms of SGLT2 inhibitors. Int J Mol Sci. 2022;23(7):3651. DOI:10.3390/ijms23073651
51. Lee YH, Kim SH, Kang JM, et al. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am J Physiol Renal Physiol. 2019;317(4):F767-80. DOI:10.1152/ajprenal.00565.2018
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47. Mayer GJ, Wanner C, Weir MR, et al. Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics. Kidney Int. 2019;96(2):489-504. DOI:10.1016/j.kint.2019.02.033
48. Bae JH, Park EG, Kim S, et al. Effects of sodium-glucose cotransporter 2 inhibitors on renal outcomes in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Sci Rep. 2019;9(1):13009. DOI:10.1038/s41598-019-49525-y
49. Cassis P, Locatelli M, Cerullo D, et al. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight. 2018;3(15):e98720. DOI:10.1172/jci.insight.98720
50. Salvatore T, Galiero R, Caturano A, et al. An overview of the cardiorenal protective mechanisms of SGLT2 inhibitors. Int J Mol Sci. 2022;23(7):3651. DOI:10.3390/ijms23073651
51. Lee YH, Kim SH, Kang JM, et al. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am J Physiol Renal Physiol. 2019;317(4):F767-80. DOI:10.1152/ajprenal.00565.2018
Авторы
М.В. Леонова*
Межрегиональная общественная организация Ассоциации клинических фармакологов (Московское отделение), Москва, Россия
*anti23@mail.ru
Межрегиональная общественная организация Ассоциации клинических фармакологов (Московское отделение), Москва, Россия
*anti23@mail.ru
________________________________________________
Marina V. Leonova*
Interregional Public Organization Association of Clinical Pharmacologists (Moscow Branch), Moscow, Russia
*anti23@mail.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.