Metabolic effects of ramipril and indapamide in hypertensive patients with non-alcoholic fatty liver disease

Objective. To assess the effects of combined antihypertensive therapy with ramipril and indapamide on insulin resistance, carbohydrate, lipid and purine metabolism, as well as the structure and function of the liver in hypertensive patients with non-alcoholic fatty liver disease (NAFLD).

Design and methods. In a pre-post study, we included 30 patients with hypertension (HTN) 1–2 degrees in combination with NAFLD (Fatty Liver Index (FLI) > 60) aged 45 to 65 years. Patients discontinued antihypertensive therapy 5–7 days before the initial examination. After that one of the fixed combinations of ramipril (2,5/5 mg/day) and indapamide (0,625/1,25 mg) were prescribed along with the lifestyle and weight reduction recommendations (the Mediterranean type of diet, a decrease in calorie intake by 500–1000 kcal from baseline, and physical aerobic exercise at least 150 minutes per week). All patients underwent clinical examination, measurement of office blood pressure (BP), ambulatory BP monitoring (ABPM), anthropometric parameters, assessment of the visceral obesity index (VAI), anthropometric parameters, VAI, the degree of adipose tissue dysfunction (ATD), the percentage of visceral and subcutaneous fat by the bioelectrical impedance method. We also assessed lipid, carbohydrate, purine metabolism and the structural and functional state of the liver before and after the treatment.

Results. After 24-week therapy with a fixed combination of ramipril and indapamide (average dosage of 4,04 ± 1,24 and 1,01 ± 0,31 mg, respectively) HTN patients with NAFLD achieved target BP. There was a decrease in both office systolic BP (SBP) (p < 0,001) and office diastolic BP (DBP) (p = 0,007) in 100 % of patients, as well as in ABPM indices. We observed a decrease in waist and hip circumferences (p ≤ 0,001 and p ≤ 0,001, respectively), the proportion of subcutaneous (p = 0,0134) and visceral (p = 0,002) fat. The number of patients with normal ATD increased (p = 0,030), while the proportion of patients with dysfunction decreased (p = 0,039). There was also a significant increase in high-density lipoprotein cholesterol (p = 0,027) and a decrease in insulin resistance (p = 0,002) and metabolic index (p = 0,030). We also found an improvement in carbohydrate metabolism with no change in purine metabolism. There was a favorable effect on the liver structure and function, and the number of patients with high alaninaminotransferase > 40 U/L decreased (5 (16,7 %) vs 0, p = 0,026).

Conclusions. Twenty-fourweek treatment with a fixed combination of ramipril and indapamide, together with recommendations for lifestyle changes and weight loss, led to a significant decrease in BP levels, the severity of insulin resistance, and visceral obesity. In addition, the treatment had a beneficial effect on the parameters of carbohydrate and lipid metabolism, as well as liver structure and function (decreased severity of steatosis and fibrosis).

1. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–285. doi:10.1111/j.1365-2036.2011.04724.x

2. Younossi ZM. Non-alcoholic fatty liver disease — a global public health perspective. J Hepatol. 2019;70(3):531–544. doi:10.1016/j.jhep.2018.10.033

3. Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15(1):45. doi:10.1186/s12916-017-0806-8

4. Maurice J, Manousou P. Non-alcoholic fatty liver disease. Clin Med (Lond). 2018;18(3):245–250. doi:10.7861/clinmedicine.18-3-245

5. Lazebnik LB, Golovanova EV, Turkina SV, Raikhelson KL, Okovityy SV, Drapkina OM et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Experimental and Clinical Gastroenterology. 2021;1(1):4–52. doi:10.31146/1682-8658-ecg-185-1-4-52. In Russian.

6. Drapkina OM, Yafarova AA. Non-alcoholic fatty liver disease and cardiovascular risk: scientific problem state. Rational Pharmacotherapy in Cardiology. 2017;13(5):645–650. doi:10.20996/1819-6446-2017-13-5-645–650. In Russian.

7. Drapkina OM, Korneeva ON. Continuum of non-alcoholic fatty liver disease: from hepatic steatosis to cardiovascular risk. Rational Pharmacotherapy in Cardiology. 2016;12(4):424–429. doi:10.20996/1819-6446-2016-12-4-424-429. In Russian.

8. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D et al. 2020 international society of hypertension global hypertension practice guidelines. Hypertension. 2020;75(6):1334–1357. doi:10.1161/HYPERTENSIONAHA.120.15026

9. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923–1994. doi:10.1016/S0140-6736(18)32225-6

10. Sung KC, Wild SH, Byrne CD. Development of new fatty liver, or resolution of existing fatty liver, over five years of followup, and risk of incident hypertension. J Hepatol. 2014;60(5):1040–1045. doi:10.1016/j.jhep.2014.01.009

11. Feng RN, Du SS, Wang C, Li YC, Liu LY, Guo FC et al. Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol. 2014;20(47):17932–17940. doi:10.3748/wjg.v20.i47.17932

12. Oikonomou D, Georgiopoulos G, Katsi V, Kourek C, Tsioufis C, Alexopoulou A et al. Non-alcoholic fatty liver disease and hypertension. Eur J Gastroenterol Hepatol. 2018;30(9):979–985. doi:10.1097/meg.0000000000001191

13. Ono M, Ochi T, Munekage K, Ogasawara M, Hirose A, Nozaki Y et al. Angiotensinogen gene haplotype is associated with the prevalence of Japanese non-alcoholic steatohepatitis. Hepatol Res. 2011;41(12):1223–1229. doi:10.1111/j.1872-034X.2011.00883

14. Statsenko ME, Streltsova AM, Turovets MI. The influence of non-alcoholic fatty liver disease on indicators of arterial stiffness and risk of cardiovascular complications in patients with arterial hypertension. Russian Archive of Internal Medicine. 2020;10(4):296–304. doi:10.20514/2226-6704-2020-10-4-296-304. In Russian.

15. Sevostyanova EV, Nikolaev YuA, Mitrofanov IM, Polyakov VY. Risk factors for cardiovascular disease in patients with non-alcoholic fatty liver disease with polymorbidity. Cardiovascular Therapy and Prevention. 2019;18(5):74–79. doi:10.15829/1728-8800-2019-5-74-79. In Russian.

16. Drapkina OM, Korneeva ON. Continuum of non-alcoholic fatty liver disease: from hepatic steatosis to cardiovascular risk. Rational Pharmacotherapy in Cardiology. 2016;12(4):424–429. doi:10.20996/1819-6446-2016-12-4-424-429. In Russian.

17. Kobalava ZhD, Konradi AO, Nedogoda SV, Shlyakhto EV, Arutyunov GP, Baranova EI et al. Arterial hypertension in adults. Clinical guidelines 2020. Russian Journal of Cardiology. 2020;25(3):3786. doi:10.15829/1560-4071-2020-3-3786. In Russian

18. 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. doi:10.1097/HJH.0000000000001940

19. Dedov II, Mokrysheva NG, Mel’nichenko GA, Troshina EA, Mazurina NV, Ershova EV et al. Obesity. Clinical guidelines. Consilium Medicum. 2021;23(4):311–325. doi:10.26442/20751753.2021.4.200832. In Russian.

20. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(4):920–922. doi:10.2337/dc09-1825

21. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33–38. doi:10.1186/1471-230X-6-33

22. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, GC Farrell et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846–854. doi:10.1002/hep.21496

23. Roytberg GE, Dorosh JV, Sharhun OO, Ushakova TI, Trubino EA et al. New metabolic index use potentialities in evaluation of insulin resistance in clinical practice. Rational Pharmacotherapy in Cardiology. 2014;10(3):264–274. doi:10.20996/1819-6446-2014-10-3-264-274. In Russian.

24. Zhou MS, Schulman IH, Zeng Q. Link between the renin-angiotensin system and insulin resistance: implications for cardiovascular disease. Vasc Med. 2012;17(5):330–341. doi:10.1177/1358863x12450094

25. Mahmood IH, Abed MN, Merkhan MM. Effects of blocking of angiotensin system on the prevalence of metabolic syndrome in type 2 diabetic patients. Pak J Med Sci. 2013;29(1):140–143. doi:10.12669/pjms.291.2782

26. Kalupahana NS, Moustaid-Moussa N. The reninangiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2011;13(2):136–149. doi:10.1111/j.1467-789x.2011.00942.x

27. Frampton JE, Peters DH. Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure. Drugs. 1995;49(3):440–466. doi:10.2165/00003495-199549030-00008

28. Konradi AO, Nedogoda SV, Nedoshivin AO, Ratova LG, Libis RA, Arutyunov GP et al. Modern antihypertensive therapy: the effectiveness of a unique Russian fixed-dose combination of ramipril and indapamide. Russian Journal of Cardiology. 2020;25(3):89–97. doi:10.15829/1560-4071-2020-3-3782. In Russian.

29. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355(9200):253–259. doi:10.1016/s0140-6736(99)12323–7

30. Kolos IP, Martynyuk TV, Safaryan AS, Nebieridze DV, Chazova IE. Effectiveness of ACE inhibitor ramipril and its combination with hydrochlorothiazide in patients with arterial hypertension and overweight: CHARISMA Study. Cardiovascular Therapy and Prevention. 2008;7(2):65–71. In Russian.

31. DREAM Trial Investigators. Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355(15):1551–1562. doi:10.1056/NEJMoa065061

32. Zidek W, Schrader J, Lüders S, Matthaei S, Hasslacher C, Hoyer J et al. Ramiprilbased versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes (ADaPT) study. Cardiovasc Diabetol. 2012;11:1. doi:10.1186/1475-2840-11-1

33. Statsenko ME, Derevyanchenko MV. Correction of endothelial dysfunction in hypertensive patients with Type 2 diabetes on the background of combined antihypertensive therapy. Ter Arkh. 2014;86(8):90–93. In Russian.

34. Ames RP. A comparison of blood lipid and blood pressure responses during the treatment of systemic hypertension with indapamide and with thiazides. Am J Cardiol. 1996;77(6):12b-16b. doi:10.1016/s0002-9149(97)89233-8

35. Leonetti G, Rappelli A, Salvetti A, Scapellato L. Tolerability and well-being with indapamid in the treatment of mildmoderate hypertension. An Italian multicenter study. Am J Med. 1988;84(1B):59–64.

36. Chazova IE, Mychka VB. Open, multicenter, randomized, scientific and practical program MINOTAUR: intermediate analysis of results. Cardiovascular Therapy and Prevention. 2006;5(2):81–88. In Russian.

37. Sassard J, Bataillard A, McIntyre H. An overview of the pharmacology and clinical efficacy of indapamide sustained release. Fundam Clin Pharmacol. 2005;19(6):637–645. doi:10.1111/j.1472-8206.2005.00377.x

38. Kseneva SI, Baradulina EV, Kulakova NV, Semiglazova TA, Udut VV. Low-dose combination of perindopril arginine with indapamide in correction of metabolic syndrome. Ter Arkh. 2011;83(10):40–45. In Russian.

39. Alferov PK, Tretyakov AYu. Associated liver pathology in the context of long-term drug correction of arterial hypertension. Clinical Gerontology. 2007;12:63–66. In Russian.

40. Tanyanskiy DA, Firova EM, Shatilina LV, Denisenko AD. Role of adipokines and nonesterified fatty acids in the development of insulin resistance. Probl Endocrinol (Mosk). 2009;55(3):13–16. doi:10.14341/probl200955313-16. In Russian.

41. Gruzdeva OV, Akbasheva OE, Borodkina DA. Relationship of obesity parameters and adiponectins with the risk of 2nd type diabetes development in a year after myocardial infarction. Russ J Cardiol. 2015;4(120):59–67. doi:10.15829/1560-4071-2015-04-59-67. In Russian.