Cardioprotective mechanisms of sodium-glucose cotransporter 2 inhibitors

The findings of large-scale cardiovascular outcome trials have been demonstrated that sodium-glucose cotransporter 2 ­inhibitors (iSGLT-2) have shown beneficial cardiovascular effects. In this review proposed mechanisms underlying iSGLT-2-associated cardiovascular benefits have been discussed: haemodynamic and intracellular effects, including metabolic effects and electrolyte changes; and also, the effect on markers of cardiovascular disease (CVD). The hemodynamic effects of SGLT-2 are characterized by reduction of cardiac preload and afterload as a result of osmotic diuresis, a decrease in blood pressure and arterial stiffness. The metabolic effects of this medicine are accompanied by an increase the production of ketone bodies, followed by improving ATP production and myocardial energetics. Also, iSGLT-2 modulate ion transporters (NHE1 and NHE3). A reduction of cytoplasmic sodium and calcium levels and increasing mitochondrial calcium levels in the cardiomyocytes enhances the synthesis of ATP and increases cell viability. Effect of iSGLT-2 on CVD markers showed a decrease in the levels of the N-terminal pro-B-type natriuretic peptide and highly sensitive troponin I in elderly patients with type 2 diabetes mellitus (T2DM). Thus, this class of agents has a multifactorial effect on the functioning of cardiovascular system. Further studies will help to explain the all possible cardioprotective effects of iSGLT-2 in individuals with and without T2DM.

1. Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314(1):52-60. doi: https://doi.org/10.1001/jama.2015.7008

2. Sarwar N, Gao P, Kondapally Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-22. doi: https://doi.org/10.1016/S0140-6736(10)60484-9

3. Rørth R, Jhund PS, Mogensen UM, et al. Risk of incident heart failure in patients with diabetes and asymptomatic left ventricular systolic dysfunction. Diabetes Care. 2018;41:1285-1291. doi: https://doi.org/10.2337/dc17-2583

4. McMurray JJ, Gerstein HC, Holman RR, et al. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2:843-851. doi: https://doi.org/10.1016/S2213-8587(14)70031-2

5. Seferović PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20:853-872. doi: https://doi.org/10.1002/ejhf.1170

6. Shestakova MV, Vikulova OK, Zheleznyakova AV, et al. Diabetes epidemiology in Russia: what has changed over the decade? Terapevticheskii arkhiv. 2019;91(10):4-13. (In Russ.). doi: https://doi.org/10.26442/00403660.2019.10.000364

7. Verma S, McMurray JJV. The Serendipitous Story of SGLT2 Inhibitors in Heart Failure. Circulation. 2019;139(22):2537-2541. doi: https://doi.org/10.1161/circulationaha.119.040514.

8. Gerich J. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabetic Medicine. 2010;27(2):136-142. doi: https://doi.org/10.1111/j.1464-5491.2009.02894.x

9. Dedov II, Shestakova MV, Mayorov AYu, et al. Standards of specialized diabetes care. Ed. by I.I. Dedov, M.V. Shestakova, A.Yu. Mayorov. 9th ed. Diabetes Mellitus. 2019;22(S1-1):1−144. (In Russ.). doi: https://doi.org/10.14341/DM221S1

10. Buse JB, Wexler DJ, Tsapas A, 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;43:487-493. doi: https://doi.org/10.2337/dci19-0066

11. 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: https://doi.org/ 10.1056/NEJMoa1504720

12. Verma S. Potential Mechanisms of Sodium-Glucose Co-Transporter 2 Inhibitor-Related Cardiovascular Benefits. Am J Cardiol. 2019;124 Suppl 1:S36-S44. doi: https://doi.org/10.1016/j.amjcard.2019.10.028.

13. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in Type 2 diabetes. N Engl J Med. 2017;377(7):644-57. doi: https://doi.org/10.1056/NEJMoa1611925

14. Radholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus. Circulation. 2018;138:458-68. doi: https://doi.org/10.1161/CIRCULATIONAHA.118.034222

15. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi: https://doi.org/10.1056/NEJMoa1812389

16. Shestakova MV. DECLARE-TIMI 58 trial in the context of EMPA-REG OUTCOME and CANVAS. Diabetes mellitus. 2019;22(6):592-601 (In Russ.). doi: https://doi.org/10.14341/DM10289

17. Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and prior myocardial infarction: a sub-analysis from DECLARE TIMI-58 trial. Circulation. 2019;139:2516–27. doi: https://doi.org/10.1161/CIRCULATIONAHA.119.039996

18. ADA 2020 Presentation Slides. The VERTIS CV Trial. Available from: https://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail?id=307A7E103BC04A588A3370709253FC35

19. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi: https://doi.org/10.1056/NEJMoa1911303

20. Petrie MC, Verma S, Docherty KF, et al. Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes. JAMA. 2020 Mar. doi: https://doi.org/10.1001/jama.2020.1906

21. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11-26. doi: https://doi.org/10.1038/nrneph.2016.170.

22. Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137:323-34. doi: https://doi.org/10.1161/CIRCULATIONAHA.117.032038

23. Fitchett D, McKnight J, Lee J, et al. Empagliflozin (EMPA) reduces heart failure irrespective of control of blood pressure (BP), low density lipoprotein cholesterol (LDL-C), and HbA1c. Diabetes. 2017;66:A312-A313. Abstract.

24. Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137:119-129. doi: https://doi.org/10.1161/CIRCULATIONAHA.117.028268

25. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108-2117. doi: https://doi.org/10.1007/s00125-018-4670-7

26. Salukhov VV, Demidova TY. Empagliflozin as a new management strategy on outcomes in patients with type 2 diabetes mellitus. Diabetes mellitus. 2016;19(6):494-510 (In Russ.). doi: https://doi.org/10.14341/DM8216

27. Karg MV, Bosch A, Kannenkeril D, et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol. 2018;17:5. doi: https://doi.org/10.1186/s12933-017-0654-z

28. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41:356-63. doi: https://doi.org/10.2337/dc17-1096

29. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20:479-87. doi: https://doi.org/10.1111/dom.13126.

30. Mazidi M, Rezaie P, Gao HK, et al. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6:e004007. doi: https://doi.org/10.1161/JAHA.116.004007

31. Striepe K, Jumar A, Ott C, et al. Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus. Circulation. 2017;136:1167-9. doi: https://doi.org/10.1161/CIRCULATIONAHA.117.029529

32. 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;16:26. doi: 10.1186/s12933-017-0510-1

33. Kappel BA, Lehrke M, Schutt K, et al. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation. 2017;136:969–72. doi: https://doi.org/10.1161/CIRCULATIONAHA.117.029166

34. Gormsen LC, Svart M, Thomsen HH, et al. Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study. J Am Heart Assoc. 2017 6:e005066. doi: https://doi.org/10.1161/JAHA.116.005066

35. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73:1931-44. doi: https://doi.org/10.1016/j.jacc.2019.01.056

36. Karmazyn M, Gan XT, Humphreys RA, et al. The Myocardial Na+-H+ Exchange. Circulation Research. 1999;85(9):777-786. doi: https://doi.org/10.1161/01.RES.85.9.777

37. Baartscheer A, Schumacher CA, Wust RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60:568-73. doi: https://doi.org/10.1007/s00125-016-4134-x

38. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia. 2018;61(3):722-726. doi: https://doi.org/10.1007/s00125-017-4509-7

39. Uthman L, Baartscheer A, Schumacher CA, et al. Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients. Front Physiol. 2018;9:1575. doi: https://doi.org/10.3389/fphys.2018.01575

40. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12:78-89. doi: https://doi.org/10.1177/1479164114561992

41. Ponikowski P, Voors AА, Anker DS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Russ J Cardiol. 2017;(1):7-81 (In Russ.). doi: https://doi.org/10.15829/1560-4071-2017-1-7-81

42. Ru-Yi Xu, Xiao-Fa Zhu, Ye Yang, et al. High-sensitive cardiac troponin T. J Geriatr Cardiol. 2013;10(1):102-109. doi: https://doi.org/10.3969/j.issn.1671-5411.2013.01.015

43. Kremneva LV, Suplotov SN, Shalaev SV. Estimation of highly sensitive troponin tests in the diagnosis of acute coronary syndrome. RFK. 2016;12(2):204-209. (In Russ.). doi: https://doi.org/10.20996/1819-6446-2016-12-2-204-209

44. Pascual-Figal DA, Januzzi JL. The biology of ST2: The international ST2 consensus panel. Am J Cardiol. 2015;115(7 Suppl):3B-7B. doi: https://doi.org/10.1016/j.amjcard.2015

45. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokyne that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokynes. Immunity. 2005;23(5):479–490. doi: https://doi.org/10.1016/j.immuni.2005.09.015

46. Chukaeva II, Akhmatova FD, Khoreva MV, et al. New Markers of Chronic Heart Failure: Biochemical Aspects of Inflammation. Lechebnoe delo. 2016;(1):4-7 (In Russ.).

47. Fortuna-Costa A, Gomes AM, Kozlowski EO, et al. Extracellular galectin-3 in tumor progression and metastasis. Front Oncol. 2014;4:138. doi: https://doi.org/10.3389/fonc.2014.00138

48. Liu FT, Hsu DK, Zuberi RI, et al. Expression and function of galectin-3, a beta-galactoside-binding lectin, in human monocytes and macrophages. Am. J. Pathol. 1995;147:1016-1028.

49. Suarez G, Meyerrose G. Heart failure and galectin 3. Annals of Translational Medicine. 2014;2(9):86. doi: https://doi.org/10.3978/j.issn.2305-5839.2014.09.10

50. Sharma UC, Pokharel S, van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004;110(19):3121-3128. doi: https://doi.org/10.1161/01.CIR.0000147181.65298.4D

51. Filipe MD, Wouter C, Rogier AM. Galectin-3 and heart failure: Prognosis, prediction & clinical utility. Clinica Chimica Acta. 2015;443:48-56. doi: 10.1016/j.cca.2014.10.009

52. Yancy CW, Jessup M, Bozkurt B, et al. American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(13):e147-e239. doi: https://doi.org/10.1016/j.jacc.2013.05.020

53. Januzzi JL, Butler J, Jarolim P, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. Am Coll Cardiol. 2017;70(6):704-712. doi: https://doi.org/10.1016/j.jacc.2017.06.016