A personalized approach to the treatment of patients with chronic heart failure with preserved ejection fraction and non-alcoholic fatty liver disease using dapagliflozin

Relevance. Recently, the attention of researchers has been focused on finding the pleiotropic effects of gliflozins, which include potential therapeutic efficacy against non-alcoholic fatty liver disease (NAFLD). NAFLD is considered not only as an independent risk factor for the development and progression of liver dysfunction, but also cardiovascular diseases. Objective. To evaluate the effect of dapagliflozin after 12 weeks of use on clinical and biochemical parameters, body composition and the degree of liver fibrosis in patients with chronic heart failure with preserved ejection fraction (HFpEF) in combination with NAFLD. Material and methods. A prospective, randomized, open-label study in parallel groups involving 60 patients with HFpEF in combination with NAFLD. The main group received dapagliflozin 10 mg once a day in addition to standard therapy for 12 weeks. The main evaluation parameters were biochemical parameters, non-invasive indices of liver fibrosis assessment, clinical manifestations of chronic heart failure (CHF) and body composition according to bioimpedance measurements. Results. In the main group, a statistically significant decrease in ALT from 48.5 [12.0; 66.0] to 29.5 [11.0; 46.0] U/L, p=0.031, AST - from 47.0 [21.0; 69.5] to 25.5 [10.0; 44.5] U/L, p=0.011), total bilirubin from 16.6 [7.6; 18.1] to 11.3 [3.6; 14.1] mmol/L, p=0.047 and TG - from 1.2 [0.8; 1.8] to 0.9 [0.8; 1.2] mmol/l, p=0.022; decrease in the FIB-4 index from 1.44 [0.94; 3.01] to 1.18 [0.64; 3.11], p=0.022; BARD scale - from 1 [0; 2] to 0 [0; 2], p=0.028; NFS scale - from -1.435 [-1.634; 0.665] to -1.616 [-1.852; 0.365], p=0.040; decrease in body mass index (BMI) from 29.6 [25.5; 33.1] to 27.1 [22.2; 31.0] kg/m², p=0.047; waist circumference (WC) - from 99.5 [91.5; 104.5] to 96.5 [89.5; 100.5] cm, p=0.044 and percentage of body fat according to bioimpedancemetry - from 22.3 [19.5; 25.6] to 20.3 [17.4; 23.9]%, p=0.022. Dynamics of functional class CHF from II to I was revealed in the main group, p<0.05. Conclusion. Taking dapagliflozin for 12 weeks in patients with CHFpEF and NAFLD was accompanied by a decrease in liver transaminases, plasma TG, hepatoprotective antifibrotic effect (FIB-4 index, NFS and BARD scales), a decrease in BMI, WC and percentage of body fat, as well as regression of clinical symptoms of CHF.

chronic heart failure with preserved ejection fraction, non-alcoholic fatty liver disease, dapagliflozin, FIB-4 index, NFS scale, BARD scale, body mass index, body fat percentage

1. Chronic heart failure. Clinical guidelines 2020. Rossiyskiy kardiologicheskiy zhurnal. 2020;25(11):4083. (In Russ.) doi:10.15829/1560-4071-2020-4083.@@ Хроническая сердечная недостаточность. Клинические рекомендации 2020. Российский кардиологический журнал. 2020;25(11):4083. doi:10.15829/1560-4071-2020-4083.

2. Peikert A, Martinez FA, Vaduganathan M, et al. Efficacy and Safety of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Age: The DELIVER Trial. Circ Heart Fail. 2022 Oct;15(10): e010080. doi: 10.1161/CIRCHEARTFAILURE.122.010080.

3. Yang CD, Pan WQ, Feng S, et al. Insulin Resistance Is Associated With Heart Failure With Recovered Ejection Fraction in Patients Without Diabetes. J Am Heart Assoc. 2022 Oct 4;11(19): e026184. doi: 10.1161/JAHA.122.026184.

4. Sanyal AJ, Van Natta ML, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, Loomba R, Chalasani N, Kowdley K, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N Engl J Med. 2021 Oct 21;385(17):1559-1569. doi: 10.1056/NEJMoa2029349.

5. Hassen G, Singh A, Belete G, et al. Nonalcoholic Fatty Liver Disease: An Emerging Modern-Day Risk Factor for Cardiovascular Disease. Cureus. 2022 May 30;14(5): e25495. doi: 10.7759/cureus.25495.

6. Dongiovanni P, Paolini E, Corsini A, et al. Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches. Eur J Clin Invest. 2021 Jul;51(7): e13519. doi: 10.1111/eci.13519.

7. Tsygankova O.V., Nikolaev K. Yu., Fedorova E.L. et al. Risk factors for cardiovascular diseases. A look at a woman. Ateroskleroz. 2014;10(1):44-55. (In Russ.)@@ Цыганкова О.В., Николаев К.Ю., Федорова Е.Л. и соавт. Факторы риска сердечно-сосудистых заболеваний. Взгляд на женщину. Атеросклероз. 2014. Т. 10. № 1. С. 44-55.

8. Tsygankova O.V., Nikolaev K. Yu., Fedorova E.L., Bondareva Z.G. Exchange of sex hormones in the male body through the prism of cardiovascular risk. Ateroskleroz i dislipidemii. 2014;1 (14):17-24. (In Russ.)@@ Цыганкова О.В., Николаев К.Ю., Федорова Е.Л., Бондарева З.Г. Обмен половых гормонов в организме мужчины через призму кардиоваскулярного риска. Атеросклероз и дислипидемии. 2014. № 1 (14). С. 17-24.

9. Targher G, Byrne CD, Lonardo A, et al. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016, 65:589-600. doi: 10.1016/j.jhep.2016.05.013.

10. Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015, 61:1547-54. doi: 10.1002/hep.27368.

11. Golabi P, Paik JM, Eberly K, et al. Causes of death in patients with Non-alcoholic Fatty Liver Disease (NAFLD), alcoholic liver disease and chronic viral hepatitis B and C. Ann Hepatol. 2022, 27:100556. doi: 10.1016/j.aohep.2021.100556.

12. Lin Y, Gong X, Li X, et al. Distinct cause of death profiles of hospitalized non-alcoholic fatty liver disease: a 10 years’ cross-sectional multicenter study in China. Front Med. 2020, 7:584396. doi: 10.3389/fmed.2020.584396.

13. Kasper P, Martin A, Lang S, et al. NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol. 2021 Jul;110(7):921-937. doi: 10.1007/s00392-020-01709-7.

14. Tsygankova O.V., Timoshchenko O.V., Tuzovskaya O.V., et al. Potential new application points of SGLT2 inhibitors in patients with heart failure in combination with diabetes mellitus, non-alcoholic fatty liver disease and anemia (literature review). Sibirskij nauchnyj medicinskij zhurnal = Siberian Scientific Medical Journal. 2022;42(6):4-14. (In Russ.) doi: 10.18699/SSMJ20220601.@@ Цыганкова О.В., Тимощенко О.В., Тузовская О.В. и соавт. Потенциальные новые точки приложения ингибиторов SGLT2 у пациентов с сердечной недостаточностью в сочетании с сахарным диабетом, неалкогольной жировой болезнью печени и анемией (обзор литературы). Сибирский научный медицинский журнал. 2022;42(6):4-14. doi: 10.18699/SSMJ20220601.

15. Scheen A.J. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: A common comorbidity associated with severe complications. Diabetes Metab. 2019;45(3):213-223. doi: 10.1016/j. diabet.2019.01.008.

16. Chrysavgis L, Papatheodoridi AM, Chatzigeorgiou A, Cholongitas E. The impact of sodium glucose co-transporter 2 inhibitors on non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2021 Apr;36(4):893-909. doi: 10.1111/jgh.15202.

17. Sun L, Deng C, Gu Y, et al. Effects of dapagliflozin in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol. 2022 Apr;46(4):101876. doi: 10.1016/j.clinre.2022.101876.

18. Shi M, Zhang H, Wang W, et al. Effect of dapagliflozin on liver and pancreatic fat in patients with type 2 diabetes and non-alcoholic fatty liver disease. J Diabetes Complications. 2023 Oct;37(10):108610. doi: 10.1016/j.jdiacomp.2023.108610.

19. Prikhodko V.A., Okovity S.V., Kulikov A.N. Gliflozins in non-alcoholic fatty liver disease: Perspectives of use outside diabetes, cardiac and nephroprotection. Therapy. 2023; 9(7): 130-141. (In Russ.) doi: 10.18565/therapy.2023.7.130-141.@@ Приходько В.А., Оковитый С.В., Куликов А.Н. Глифлозины при неалкогольной жировой болезни печени: перспективы применения за границами диабета, кардио- и нефропротекции. Терапия. 2023; 9(7): 130-141. doi: 10.18565/therapy.2023.7.130-141.

20. Clinical guidelines. Non-alcoholic fatty liver disease in adults. 2022. (In Russ.) Available at: https://cr.minzdrav.gov.ru/schema/748_1.@@ Клинические рекомендации. Неалкогольная жировая болезнь печени у взрослых. 2022. Интернет ресурс: https://cr.minzdrav.gov.ru/schema/748_1.

21. All-Russian public organization “Russian Scientific Medical Society of Therapists”, Scientific Society of Gastroenterologists of Russia. Clinical guidelines. Alcoholic liver disease (ALD) in adults. 2021. (In Russ.) Available at: https://cr.minzdrav.gov.ru/schema/711_1.@@ Общероссийская общественная организация «Российское научное медицинское общество терапевтов», Научное общество гастроэнтерологов России. Клинические рекомендации. Алкогольная болезнь печени (АБП) у взрослых. 2021. Электронный ресурс: https://cr.minzdrav.gov.ru/schema/711_1.

22. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178.

23. Harrison SA, Oliver D, Arnold HL. Development and validation of a simple NALFD clinical scoring system for identifying patient without advanced diseases. Gut. 2008;57:1441-1447. doi: 10.1136/gut.2007.146019.

24. Adams LA, George J, Bugianesi E, et al.Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2011 Oct;26(10):1536-43. doi: 10.1111/j.1440-1746.2011.06774.x.

25. Chalasani N, Younossi Z, et al. The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142: 1592-1609. doi: 10.1002/hep.25762.

26. Kotsoeva O.T., Tyrenko V.V., Koltsov A.V., Bestaev D.V., Kachnov V.A. Assessment of the dynamics of quality of life in patients with chronic heart failure on the background of therapy. Kardiologiya: novosti, mneniya, obuchenie = Cardiology: News, Opinions, Training. 2022; 10 (3): 26-35. (in Russian) doi: 10.33029/2309-1908-2022-10-3-26-35.@@ Коцоева О.Т., Тыренко В.В., Кольцов А.В. и соавт. Оценка динамики качества жизни у пациентов, страдающих хронической сердечной недостаточностью, на фоне терапии // Кардиология: новости, мнения, обучение. 2022. Т. 10, № 3. С. 26-35. doi: 10.33029/2309-1908-2022-10-3-26-35.

27. Libis R.A., Kots YA.I., Ageyev F.T., Mareyev V.YU. Quality of life as a criterion for successful therapy of patients with chronic heart failure. RMZH. 1999;2:8. (In Russ.)@@ Либис Р.А., Коц Я.И., Агеев Ф.Т., Мареев В.Ю. Качество жизни как критерий успешной терапии больных с хронической сердечной недостаточностью. РМЖ. 1999;2:8.

28. Orynbasarоva B.A., Shalgumbayeva G.M., Dautov D.H. et al. Assessment of the quality life of patients with chronic heart failure with normal ejection fraction. Nauka i Zdravookhranenie = Science & Healthcare. 2020;22(2):93-99. (In Russ.) doi 10.34689/SH.2020.22.2.011.@@ Орынбасарова Б.А., Шалгумбаева Г.М., Даутов Д.Х и соавт. Оценка качества жизни пациентов с хронической сердечной недостаточностью с сохраненным сердечным выбросом. Наука и Здравоохранение. 2020. 2(Т.22). С. 93-99. doi 10.34689/SH.2020.22.2.011.

29. Mak JHC, Lui DT, Fong CH, et al. Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes. Clin Endocrinol (Oxf). 2024 Mar;100(3):230-237. doi: 10.1111/cen.15010.

30. Shimizu M, Suzuki K, Kato K, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab. 2019 Feb;21(2):285-292. doi: 10.1111/dom.13520.

31. Phrueksotsai S, Pinyopornpanish K, Euathrongchit J, et al. The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2021 Oct;36(10):2952-2959. doi: 10.1111/jgh.15580.

32. Hjelkrem M, Stauch C, Shaw J, Harrison SA. Validation of the non-alcoholic fatty liver disease activity score. Aliment Pharmacol Ther. 2011 Jul;34(2):214-8. doi: 10.1111/j.1365-2036.2011.04695.x.

33. Zhu J, He M, Zhang Y, et al. Validation of simple indexes for nonalcoholic fatty liver disease in western China: a retrospective cross-sectional study. Endocr J. 2018 Mar 28;65(3):373-381. doi: 10.1507/endocrj.EJ17-0466.

34. Cox B, Trasolini R, Galts C. et al.Comparing the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score with transient elastography scores of people with non-alcoholic fatty liver disease. Can Liver J. 2021 Aug 9;4(3):275-282. doi: 10.3138/canlivj-2021-0004.

35. Cho K.Y., Nakamura A., Omori K. et al. Favorable effect of sodium-glucose cotransporter 2 inhibitor, dapagliflozin, on non-alcoholic fatty liver disease compared with pioglitazone. J Diabetes Investig. 2021; 12(7): 1272-77.

36. Rudnev S.G., Soboleva N.P., Sterlikov S.A. et al. Bioimpedance study of body composition of the population of Russia. Moscow: RIO TSNIIOIZ, 2014. 492 P. (In Russ.).@@ Руднев С.Г., Соболева Н.П., Стерликов С.А. и др. Биоимпедансное исследование состава тела населения России. Москва: РИО ЦНИИОИЗ, 2014. 492 с.

37. Pavlova Z.SH., P’yanykh O.P., Golodnikov I.I. Bioimpedance analysis: clinical examples and interpretation of changes in human body composition under the influence of various factors. Endokrinologiya: novosti, mneniya, obucheniye. 2020;9(4):74-81. (In Russ.) doi: 10.33029/2304-9529-2020-9-4-74-81.@@ Павлова З.Ш., Пьяных О.П., Голодников И.И. Биоимпедансный анализ: клинические примеры и интерпретация изменений состава тела человека при воздействии различных факторов. Эндокринология: новости, мнения, обучение. 2020;9(4):74-81. doi: 10.33029/2304-9529-2020-9-4-74-81.

38. Kabil SL, Mahmoud NM. Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation. Eur J Pharmacol. 2018 Jun 5;828:135-145. doi: 10.1016/j.ejphar.2018.03.043.

39. Garrido-Sánchez L, Vendrell J, Fernández-García D, et al. De novo lipogenesis in adipose tissue is associated with course of morbid obesity after bariatric surgery. PLoS One. 2012;7(2): e31280. doi: 10.1371/journal.pone.0031280.

40. Tahara A, Kurosaki E, Yokono M, et al. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013 Sep 5;715(1-3):246-55. doi: 10.1016/j.ejphar.2013.05.014.

41. Said Ahmed WM, Soliman A, Ahmed Amer AE, et al. Effect of dapagliflozin against NAFLD and dyslipidemia in type 2 diabetic albino rats: possible underlying mechanisms. Eur Rev Med Pharmacol Sci. 2023 Sep;27(17):8101-8109. doi: 10.26355/eurrev_202309_33570.