Inhibitors of the sodium-glucose transporter type 2 and new possibilities for managing vascular age in patients with type 2 diabetes mellitus

The article discusses the pathophysiological mechanisms of the development of vascular aging as a combination of the influence on the  body of  genetic, environmental, regulatory, metabolic and other factors causing biochemical, enzymatic and cellular changes in the arterial vascular bed. The concept of “early vascular aging” and “healthy vascular aging” is defined depending on the ratio of the biological and chronological age of the vessels. The role of diabetes mellitus in increasing vascular stiffness, early vascular aging, as well as the  progression of  atherosclerotic cardiovascular diseases and their complications is considered in detail. Approaches to multifactorial management of vascular age in patients with type 2 diabetes (lifestyle modification with strategy of aggressive treatment of modifiers of atherosclerosis, rejection of bad habits, adherence to dietary recommendations and the use of modern organo- and vasoprotective antidiabetic drugs) are revealed. The mechanism of realization of vasoprotective effects of inhibitors of sodium-glucose transporter-2 (iNGLT-2) is described in detail. The results of completed large random ized trials EMPA-REG Outcome and EMPA-REG BP of the most studied representative of the IGLT-2 group, empagliflozin, are presented. It has been shown that due to their glucose and natriuretic effects, the ability to reduce body weight and blood pressure, improve myocardial metabolism and bioenergetics, decrease the activity of the sympathetic nervous system, as well as positive effects on vascular stiffness, NGLT-2 inhibitors are the drugs of choice in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. This makes it possible to widely use this group of drugs for managing the vascular age of patients and represents a new opportunity in the prevention of vascular aging in T2DM. 

1. American Diabetes Association. Standards of Medical Care in Diabetes – 2015. Abridged for Primary Care Providers. Clin Diabetes. 2015;33(2):97– 111. https://doi.org/10.2337/diaclin.33.2.97.

2. Hamczyk M.R., Nevado R.M., Barettino A., Fuster V., Andrés V. Biological versus Chronological Aging: JACC Focus Seminar. J Am Coll Cardiol. 2020;75(8):919–930. https://doi.org/10.1016/j.jacc.2019.

3. Nilsson P.M., Olsen M.H., Laurent S. (eds.). Early vascular aging (EVA). New Directions in Cardiovascular Protection. Elsevier; 2015. 376 p. https://doi.org/10.1016/C2013-0-19168-4.

4. Ungvari Z., Tarantini S., Donato A.J., Galvan V., Csiszar A. Mechanisms of Vascular Aging. Circ Res. 2018;123(7):849–867. https://doi.org/10.1161/CIRCRESAHA.118.311378.

5. Kryukov E.V., Makeeva T.G., Potekhin N.P., Fursov A.N. Prevention of Vascular Wall Remodeling in Individuals with Prehypertension. Voenno-meditsinskiy zhurnal = The Military Medical Journal. 2020;341(5):82–85. (In Russ) Available at: https://sc.mil.ru/files/morf/military/archive/N_05%281%29.pdf.

6. Patoulias D., Papadopoulos C., Stavropoulos K., Zografou I., Doumas M., Karagiannis A. Prognostic Value of Arterial Stiffness Measurements in Cardiovascular Disease, Diabetes, and Its Complications: The Potential Role of Sodium-Glucose Co-Transporter-2 Inhibitors. J Clin Hypertens (Greenwich). 2020;22(4):562–571. https://doi.org/10.1111/jch.13831.

7. Nowak K., Rossman M., Chonchol M., Seals DR. Strategies for Achieving Healthy Vascular Aging. Hypertension. 2018;71(3):389–402. https://doi.org/10.1161/HYPERTENSIONAHA.117.10439.

8. Kryukov E.V., Potekhin N.P., Fursov A.N., Chaplyuk A.L., Sarkisov K.A., Makeeva T.G., Zakharova E.G. Values of the “Intima-Media” Complex of Carotid Arteries as a Reflection of the Evolution of High Normal Blood Pressure. Voenno-meditsinskiy zhurnal = The Military Medical Journal. 2018;339(2):11–20 (In Russ.) Available at: https://voenmed.ric.mil.ru/upload/site229/pS54kv4BSX.pdf.

9. Laurent S., Cockcroft J., Van Bortel L., Boutouyrie P., Giannattasio C., Hayoz D. et al. Expert Consensus Document on Arterial Stiffness: Methodological Issues and Clinical Applications. Eur Heart J. 2006;27(21):2588–605. https://doi.org/10.1093/eurheartj/ehl254.

10. Shirai K., Utino J., Otsuka K., Takata M. A Novel Blood PressureIndependent Arterial Wall Stiffness Parameter; Cardio-Ankle Vascular Index (CAVI). J Atheroscler Thromb. 2006;13(2):101–107. https://doi.org/10.5551/jat.13.101.

11. Williams B., Mancia G., Spiering W., Agabiti Rosei E., Azizi M., Burnier M. et al. 2018 ESC/ESH Guidelines for the Management of Arterial Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36(10):1953–2041. https://doi.org/10.1097/HJH.0000000000001940.

12. Kimoto E., Shoji T., Shinohara K., Inaba M., Okuno Y., Miki T. et al. Preferential stiffening of central over peripheral arteries in type 2 diabetes. Diabetes. 2003;52(2):448–452. https://doi.org/10.2337/diabetes.52.2.448.

13. Henry R.M., Kostense P.J., Spijkerman A.M., Dekker J.M., Nijpels G., Heine R.J. et al. Arterial Stiffness Increases with Deteriorating Glucose Tolerance Status: the Hoorn study. Circulation. 2003;107(16):2089–2095. https://doi.org/10.1161/01.CIR.0000065222.34933.FC.

14. Taniwaki H., Kawagishi T., Emoto M., Shoji T., Kanda H., Maekawa K. et al. Correlation between the Intima-Media Thickness of the Carotid Artery and Aortic Pulse-Wave Velocity in Patients with Type 2 Diabetes. Vessel Wall Properties in Type 2 Diabetes. Diabetes Care. 1999;22(11):1851–1857. https://doi.org/10.2337/diacare.22.11.1851.

15. Van Sloten T.T., Henry R.M.A., Dekker J.M., Nijpels G., Unger T., Schram M.T. et al. Endothelial Dysfunction Plays a Key Role in Increasing Cardiovascular Risk in Type 2 Diabetes the Hoorn Study. Hypertension. 2014;64(6):1299– 1305. https://doi.org/10.1161/HYPERTENSIONAHA.114.04221.

16. Rahman S., Ismail A.A., Ismail S.B., Naing N.N., Rahman A.R. Early Manifestation of Macrovasculopathy in Newly Diagnosed Never Treated Type II Diabetic Patients with No Traditional CVD Risk Factors. Diabetes Res Clin Pract. 2008;80(2):253–258. https://doi.org/10.1016/j.diabres.2007.12.010.

17. Chang S., Kim J., Sohn T., Son H., Lee J. Effects of Glucose Control on Arterial Stiffness in Patients with Type 2 Diabetes Mellitus and Hypertension: An Observational Study. J Int Med Res. 2018;46(1):284–292. https://doi.org/10.1177/0300060517722697.

18. Agnoletti D., Mansour A.S., Zhang Y., Protogerou A.D., Ouerdane S., Blacher J., Safar M.E. Clinical Interaction between Diabetes Duration and Aortic Stiffness in Type 2 Diabetes Mellitus. J Hum Hypertens. 2017;31(3):189–194. https://doi.org/10.1038/jhh.2016.58.

19. Elias M.F., Crichton G.E., Dearborn P.J., Robbins M.A., Abhayaratna W.P. Aortic Stiffness and Cardiovascular Risk in Type 2 Diabetes. J Hypertens. 2013;31(8):1584–1592. https://doi.org/10.1159/000479560.

20. Loehr L.R., Meyer M.L., Poon A.K., Selvin E., Palta P., Tanaka H. et al. Prediabetes and Diabetes Are Associated with Arterial Stiffness in Older Adults: the ARIC Study. Am J Hypertens. 2016;29(9):1038–1045. https://doi.org/10.1093/ajh/hpw036.

21. Teoh W.L., Price J.F., Williamson R.M., Payne R.A., Van Look L.A., Reynolds R.M. et al. Metabolic Parameters Associated with Arterial Stiffness in Older Adults with Type 2 Diabetes: the Edinburgh Type 2 Diabetes Study. J Hypertens. 2013;31(5):1010–1017. https://doi.org/10.1097/HJH.0b013e32835f7ecf.

22. Nilsson P., Boutouyrie P., Laurent S. Vascular Aging a Tale of EVA and ADAM in Cardiovascular Risk Assessment and Prevention. Hypertension. 2009;54(1):3–10. https://doi.org/10.1161/HYPERTENSIONAHA.109.129114.

23. Kraus W.E., Bhapkar M., Huffman K.M., Pieper C.F., Krupa Das S., Redman L.M. et al. 2 Years of Calorie Restriction and Cardiometabolic Risk (CALERIE): Exploratory Outcomes of a Multicentre, Phase 2, Randomised Controlled Trial. Lancet Diabetes Endocrinol. 2019;7(9):673–683. https://doi.org/10.1016/S2213-8587(19)30151-2.

24. Aburto N.J, Ziolkovska A., Hooper L., Elliott P., Cappuccio F.P, Meerpohl J.J. Effect of Lower Sodium Intake on Health: Systematic Review and MetaAnalyses. BMJ. 2013;346:f1326. https://doi.org/10.1136/bmj.f1326.

25. Del G.R., Ceresa C., Gabutti S., Troiani C., Gabutti L. Arterial Stiffness and Central Hemodynamics Are Associated with Low Diurnal Urinary Sodium Excretion. Diabetes Metab Syndr Obes. 2020;13:3289–3299. https://doi.org/10.2147/DMSO.S266246.

26. Grillo A., Salvi L., Coruzzi P., Salvi P., Parati G. Sodium Intake and Hypertension. Nutrients. 2019;11(9):1970. https://doi.org/10.3390/nu11091970.

27. Hasegawa N., Fujie S., Horii N., Miyamoto-Mikami E., Tsuji K., Uchida M. et al. Effects of Different Exercise Modes on Arterial Stiffness and Nitric Oxide Synthesis. Med Sci Sports Exerc. 2018;50(6):1177–1185. https://doi.org/10.1249/MSS.0000000000001567.

28. Miyachi M. Effects of Resistance Training on Arterial Stiffness: A MetaAnalysis. Br J Sports Med. 2013;47(6):393–396. https://doi.org/10.1136/bjsports-2012-090488.

29. Fleg J.L., Aronow W.S., Frishman W.H. Cardiovascular Drug Therapy in the Elderly: Benefits and Challenges. Nat Rev Cardiol. 2011;8(1):13–28. https://doi.org/10.1038/nrcardio.2010.162.

30. Wright J.T., Williamson J.D., Whelton P.K. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. New Engl J Med. 2015;373(22):2103–2116. https://doi.org/10.1056/NEJMoa1511939.

31. Cosentino F., Grant P.J., Aboyans V., Bailey C.J., Ceriello A., Delgado V. et al. 2019 ESC Guidelines on Diabetes, Pre-Diabetes, and Cardiovascular Diseases Developed in Collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. https://doi.org/10.1093/eurheartj/ehz486.

32. Driessen J.H.M., de Vries F., van Onzenoort H.A.W., Schram M.T., van der Kallen C., Reesink K.D. et al. Metformin Use in Type 2 Diabetic Patients Is Not Associated with Lower Arterial Stiffness: the Maastricht Study. J Hypertens. 2019;37(2):365–371. https://doi.org/10.1097/HJH.0000000000001892.

33. Harashima K., Hayashi J., Miwa T., Tsunoda T. Long-Term Pioglitazone Therapy Improves Arterial Stiffness in Patients with Type 2 Diabetes Mellitus. Metabolism. 2009;58(6):739–745. https://doi.org/10.1016/j.metabol.2008.09.015.

34. Koren S., Shemesh-Bar L., Tirosh A., Peleg RK., Berman S., Hamad RA. et al. The Effect of Sitagliptin versus Glibenclamide on Arterial Stiffness, Blood Pressure, Lipids, and Inflammation in Type 2 Diabetes Mellitus Patients. Diabetes Technol Ther. 2012;14(7):561–567. https://doi.org/10.1089/dia.2011.0296.

35. Cosenso-Martin L.N., Giollo-Júnior L.T., Fernandes L.A.B., Cesarino C.B., Nakazone M.A., Machado M.N. et al. Effect of Vildagliptin versus Glibenclamide on Endothelial Function and Arterial Stiffness in Patients with Type 2 Diabetes and Hypertension: A Randomized Controlled Trial. Acta Diabetol. 2018;55(12): 1237–1245. https://doi.org/10.1007/s00592-018-1204-1.

36. Batzias K., Antonopoulos A.S., Oikonomou E., Siasos G., Bletsa E., Stampouloglou P.K. et al. Effects of Newer Antidiabetic Drugs on Endothelial Function and Arterial Stiffness: A Systematic Review and Meta-Analysis. J Diabetes Res. 2018;1232583. https://doi.org/10.1155/2018/1232583.

37. Tuttolomondo A., Cirrincione A., Casuccio A., Del Cuore A., Daidone M., Di Chiara T. et al. Efficacy of Dulaglutide on Vascular Health Indexes in Subjects with Type 2 Diabetes: A Randomized Trial. Cardiovasc Diabetol. 2021;20(1):1. https://doi.org/10.1186/s12933-020-01183-5.

38. Alicic R., Neumiller J., Johnson E., Dieter B., Tuttle K. Sodium-Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease. Diabetes. 2019;68(2):248–257. https://doi.org/10.2337/dbi18-0007.

39. Salukhov V.V., Khalimov Yu.S., Shustov S.B., Popov S.I. SGLT2 Inhibitors and Kidneys: Mechanisms and Main Effects in Diabetes Mellitus Patients. Sakharnyy diabet = Diabetes Mellitus. 2020;23(5):475–491. (In Russ.) https://doi.org/10.14341/DM12123.

40. Fitchett D., Zinman B., Wanner C., Lachin J.M., Hantel S., Salsali A. et al. Heart Failure Outcomes with Empagliflozin in Patients with Type 2 Diabetes at High Cardiovascular Risk: Results of the EMPA-REG OUTCOME® Trial. Eur Heart J. 2016;37(19):1526–1534. https://doi.org/10.1093/eurheartj/ehv728.

41. Sharma A., Verma S. Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus. Can J Diabetes. 2020;44(1):93–102. https://doi.org/10.1016/j.jcjd.2019.09.003.

42. Bosch A., Ott C., Jung S., Striepe K., Karg M., Kannenkeril D. et al. How Does Empagliflozin Improve Arterial Stiffness in Patients with Type 2 Diabetes Mellitus? Sub Analysis of a Clinical Trial. Cardiovasc Diabetol. 2019;18(1):44. https://doi.org/10.1186/s12933-019-0839-8.

43. Iannantuoni F., Marañon A., Diaz-Morales N., Falcon R., Bañuls C., AbadJimenez Z. et al. The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes. J Clin Med. 2019;8(11):1814. https://doi.org/10.3390/jcm8111814.

44. Chilton R., Tikkanen I., Cannon C., Crowe S., Woerle H., Broedl U. 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):1180–1193. https://doi.org/10.1111/dom.12572.

45. Striepe K., Jumar A., Ott C., Karg M., Schneider M., Kannenkeril D. 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(12):1167– 1169. https://doi.org/ 10.1161/CIRCULATIONAHA.117.029529.

46. Nedogoda S.V., Barykina I.N., Salasyuk A.S., Sanina T.N., Smirnova V.O., Popova E.A. The Effect of Various Classes of Glucose-Lowering Medications on the Blood Vessel Elasticity in Patients with Type 2 Diabetes. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology. 2020;25(4):3766. (In Russ.) https://doi.org/10.15829/1560-4071-2020-3766.

47. Sugiyama S., Jinnouchi H., Kurinami N., Hieshima K., Yoshida A., Jinnouchi K. et al. The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus. Intern Med. 2018;57(15):2147–2156. https://DOI.org/10.2169/internalmedicine.0701-17.

48. Shigiyama F., Kumashiro N., Miyagi M., Ikehara K., Kanda E., Uchino H. et al. Effectiveness of Dapagliflozin on Vascular Endothelial Function and Glycemic Control in Patients with Early-Stage Type 2 Diabetes Mellitus: DEFENCE Study. Cardiovasc Diabetol. 2017;16(1):84. https://doi.org/10.1186/s12933-017-0564-0.

49. Katakami N., Mita T., Yoshii H., Shiraiwa T., Yasuda T., Okada Y. et al. Tofogliflozin Does Not Delay Progression of Carotid Atherosclerosis in Patients with Type 2 Diabetes: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study. Cardiovasc Diabetol. 2020;19(1):110. https://doi.org/10.1186/s12933-020-01079-4.