The role of sodium – glucose cotransporter-2 inhibitors in the treatment of different phenotypes of chronic heart failure




sodium-glucose cotransporter-2 inhibitors, congestive heart failure, inhibitors


The number of patients with chronic heart failure syndrome is steadily increasing worldwide and Ukraine is not an exception. About 50 % of patients with heart failure have preserved ejection fraction of left ventricle. Recently, there has been significant progress in the diagnosis of this phenotype of heart failure, many diagnostic scales and practice-oriented algorithms have been developed, but the issue of treatment of chronic heart failure remains open.

Aim of the study. To summarize and analyze the results of large-scale randomized trials and to discuss the possible pathophysiological mechanisms underlying the “pleiotropiс” effects of sodium-glucose cotransporter-2 inhibitors.

Sodium-glucose cotransporter-2 inhibitors are the first class of antidiabetic drugs that have demonstrated improved cardiovascular prognosis in patients with chronic heart failure with preserved ejection fraction regardless of the presence of diabetes mellitus.

Conclusions. The necessity of prescribing sodium-glucose cotransporter-2 inhibitors in a cohort of patients with heart failure, regardless of left ventricular ejection fraction, has the highest level of evidence. The pathophysiological mechanisms underlying these effects are not fully understood. Further trials will allow us to identify new mechanisms of action and establish potential relationships between them.

Author Biographies

M. Yu. Kolesnyk, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

MD, PhD DSc, Professor of the Department of Therapy and Cardiology

Ya. Yu. Maistrovych, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

MD, PhD student of the Department of Therapy and Cardiology


Sun Y, Wang N, Li X, Zhang Y, Yang J, Tse G, et al. Predictive value of H2FPEF score in patients with heart failure with preserved ejection fraction. ESC Heart Failure. 2021;8(2):1244-52. doi:

Kolesnyk MY, Maistrovych YY. [Current diagnostic algorithms for chronic heart failure with preserved left ventricular ejection fraction]. Zaporozhye medical journal. 2023;25(1):72-80. Ukrainian. doi:

Rosano GM, Moura B, Metra M, Böhm M, Bauersachs J, Ben Gal T, et al. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the heart failure association of the European Society of Cardiology. Eur J Heart Fail. 2021;23(6):872-81. doi:

Kjeldsen SE, von Lueder TG, Smiseth OA, Wachtell K, Mistry N, Westheim AS, et al. Medical therapies for heart failure with preserved ejection fraction. Hypertension. 2020;75(1):23-32. doi:

Kuno T, Ueyama H, Fujisaki T, Briasouli A, Takagi H, Briasoulis A. Meta-analysis evaluating the effects of renin-angiotensin-aldosterone system blockade on outcomes of heart failure with preserved ejection fraction. Am J Cardiol. 2020;125(8):1187-93. doi:

Solomon SD, McMurray JJ, Anand IS, Ge J, Lam CS, Maggioni AP, et al. Angiotensin–NEPRILYSIN inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-20. doi:

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-726. doi:

Fonseca-Correa JI, Correa-Rotter R. Sodium-glucose cotransporter 2 inhibitors mechanisms of action: A Review. Front Med (Lausanne). 2021;8:777861. doi:

Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N. SGLT2 inhibitors: A review of their antidiabetic and cardioprotective effects. Int J Environ Res Public Health. 2019;16(16):2965. doi:

Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences. Diab Vasc Dis Res. 2015;12(2):78-89. doi:

Rosas-Guzman J, Rosas-Saucedo J, Romero-Garcia A. SGLT2 inhibitors in diabetes mellitus treatment. Rev Recent Clin Trials. 2017;12(1):8-18. doi:

Liki Control [Internet]. JARDIANCE® UA/14980/01/01 [updated 2023 Dec 3; cited 2024 Jan 2]. Available from:

Liki Control [Internet]. FORXIGA® UA/13302/01/01 [updated 2024 Jan 3; cited 2024 Jan 2]. Available from:

Cinti F, Moffa S, Impronta F, Cefalo CM, Sun VA, Sorice GP, et al. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017;11:2905-19. doi:

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28. doi:

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-57. doi:

Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(19):1880-2. doi:

McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. New N Engl J Med. 2019;381(21):1995-2008. doi:

Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with Empagliflozin in heart failure. New N Engl J Med. 2020;383(15):1413-24. doi:

Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. New N Engl J Med. 2021;385(16):1451-61. doi:

Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. New N Engl J Med. 2022;387(12):1089-98. doi:

Lam CSP, Chandramouli C, Ahooja V, Verma S. SGLT-2 Inhibitors in Heart Failure: Current Management, Unmet Needs, and Therapeutic Prospects. J Am Heart Assoc. 2019;8(20):e013389. doi:

Hallow KM, Helmlinger G, Greasley PJ, McMurray JJ, Boulton DW. Why do sglt2 inhibitors reduce heart failure hospitalization? a differential volume regulation hypothesis. Diabetes Obes Metab. 2017;20(3):479-87. doi:

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:

Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure. JAMA Cardiol. 2017;2(9):1025. doi:

Patoulias D, Fragakis N, Rizzo M. The therapeutic role of SGLT-2 inhibitors in acute heart failure: From pathophysiologic mechanisms to clinical evidence with pooled analysis of relevant studies across safety and efficacy endpoints of interest. Life. 2022;12(12):2062. doi:

Brust-Sisti L, Rudawsky N, Gonzalez J, Brunetti L. The role of sodium-glucose cotransporter-2 inhibition in heart failure with preserved ejection fraction. Pharmacy. 2022;10(6):166. doi:

Verma S, McMurray JJ. SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review. Diabetologia. 2018;61(10):2108-17. doi:

Sitina M, Lukes M, Sramek V. Empagliflozin-associated postoperative mixed metabolic acidosis. case report and review of pathogenesis. BMC Endocr Disord. 2023;23(1). doi:

Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors. JACC Basic Transl Sci. 2020;5(6):632-44. doi:

Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: The pleiotropic effects of SGLT2 inhibition. Diabetologia. 2016;60(2):215-25. doi:

Natali A, Nesti L, Tricò D, Ferrannini E. Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: A narrative review of clinical evidence. Cardiovasc Diabetol. 2021;20(1):196. doi:

Ceriello A, Genovese S, Mannucci E, Gronda E. Glucagon and heart in type 2 diabetes: New perspectives. Cardiovasc Diabetol. 2016;15(1):123. doi:

Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Barsotti E, Clerico A, et al. Renal handling of ketones in response to sodium–glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care. 2017;40(6):771-6. doi:

Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, et al. Empagliflozin in heart failure. Circulation. 2020;142(11):1028-39. doi:

Dick SA, Epelman S. Chronic heart failure and inflammation. Circ Res. 2016;119(1):159-76. doi:

Mehta JL, Pothineni NV. Inflammation in heart failure. Hypertension. 2016;68(1):27-9. doi:

Iannantuoni F, M. de Marañon A, Diaz-Morales N, Falcon R, Bañuls C, Abad-Jimenez Z, et al. The SGLT2 inhibitor Empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes. Journal of Clinical Medicine. 2019;8(11):1814. doi:

Heerspink HJ, Perco P, Mulder S, Leierer J, Hansen MK, Heinzel A, et al. Canagliflozin reduces inflammation and fibrosis biomarkers: A potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019;62(7):1154-66. doi:

Leng W, Wu M, Pan H, Lei X, Chen L, Wu Q, et al. The SGLT2 inhibitor Dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann Transl Med. 2019;7(18):429. doi:

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:

Kang S, Verma S, Hassanabad AF, Teng G, Belke DD, Dundas JA, et al. Direct effects of Empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: Novel translational clues to explain Empa-Reg Outcome results. Can J Cardiol. 2020;36(4):543-53. doi:

Grubić Rotkvić P, Cigrovski Berković M, Bulj N, Rotkvić L. Minireview: Are SGLT2 inhibitors heart savers in diabetes? Heart Fail Rev. 2019;25(6):899-905. doi:

Lee Y, Kim SR, Han DH, Yu HT, Han YD, Kim JH, et al. Senescent T cells predict the development of hyperglycemia in humans. Diabetes. 2018;68(1):156-62. doi:

Ye Y, Jia X, Bajaj M, Birnbaum Y. Dapagliflozin attenuates na+/h+ exchanger-1 in cardiofibroblasts via AMPK activation. Cardiovasc Drugs Ther. 2018;32(6):553-8. doi:

Byrne NJ, Matsumura N, Maayah ZH, Ferdaoussi M, Takahara S, Darwesh AM, et al. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ Heart Fail. 2020;13(1):e006277. doi:

Kravchun PH, Ryndina NH. Syndrom kardiorenalnoi anemii [Cardiorenal anemia syndrome]. Kharkiv, Ukraine: FOP Mezina V.V.; 2018.

Kanbay M, Tapoi L, Ureche C, Tanriover C, Cevik E, Demiray A, et al. Effect of sodium–glucose cotransporter 2 inhibitors on hemoglobin and hematocrit levels in type 2 diabetes: A systematic review and meta-analysis. Int Urol Nephrol. 2021;54(4):827-41. doi:

Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M, Makdissi A, et al. Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metab. 2020;105(4):dgaa057. doi:

Soga F, Tanaka H, Tatsumi K, Mochizuki Y, Sano H, Toki H, et al. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol. 2018;17(1). doi: 10.1186/s12933-018-0775-z

Shi FH, Li H, Shen L, Xu L, Ge H, Gu ZC, et al. Beneficial effect of sodium-glucose co-transporter 2 inhibitors on left ventricular function. J Clin Endocrinol Metab. 2021;107(4):1191-203. doi:

Theofilis P, Antonopoulos AS, Katsimichas T, Oikonomou E, Siasos G, Aggeli C, et al. The impact of SGLT2 inhibition on imaging markers of cardiac function: A systematic review and meta-analysis. Pharmacol Res. 2022;180:106243. doi:

Lim VG, Bell RM, Arjun S, Kolatsi-Joannou M, Long DA, Yellon DM. SGLT2 inhibitor, Canagliflozin, attenuates myocardial infarction in the diabetic and Nondiabetic heart. JACC Basic Transl Sci. 2019;4(1):15-26. doi:

Mustroph J, Wagemann O, Lücht CM, Trum M, Hammer KP, Sag CM, et al. Empagliflozin reduces ca/calmodulin-dependent kinase ii activity in isolated ventricular cardiomyocytes. ESC Heart Fail. 2018;5(4):642-8. doi:

Dalama B, Mesa J. New oral hypoglycemic agents and cardiovascular risk. crossing the metabolic border. Rev Esp Cardiol (Engl Ed). 2016;69(11):1088-97. doi:

Epstein B, Rosenwasser R, Sutton D, Choksi R, Sultan. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab Syndr Obes. 2013;453. doi:

Bailey CJ. Uric acid and the cardio-renal effects of SGLT2 inhibitors. Diabetes Obes Metab. 2019;21(6):1291-8. doi:

Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-46. doi:

Cherney D, Lund SS, Perkins BA, Groop P-H, Cooper ME, Kaspers S, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59(9):1860-70. doi:



How to Cite

Kolesnyk, M. Y., & Maistrovych, Y. Y. (2024). The role of sodium – glucose cotransporter-2 inhibitors in the treatment of different phenotypes of chronic heart failure. Modern Medical Technology, 16(1), 60–67.



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