Beneficial Effect of Ezetimibe on Cholesterol Metabolism Ameliorates Hepatic Steatosis
European Journal of Clinical and Biomedical Sciences
Volume 4, Issue 2, April 2018, Pages: 29-38
Received: May 5, 2018;
Accepted: May 31, 2018;
Published: Jun. 14, 2018
Views 1073 Downloads 75
Yichao Zheng, Department of Gastroenterology, Zhangzhou Municipal Hospital of Fujian Medical University, Zhangzhou, China
Yifen Wu, Department of Internal Medicine, Zhangzhou Municipal Hospital of Fujian Medical University, Zhangzhou, China
Guian Zheng, Department of Internal Medicine, Zhangzhou Municipal Hospital of Fujian Medical University, Zhangzhou, China
Yadong Lai, Department of Gastroenterology, Zhangzhou Municipal Hospital of Fujian Medical University, Zhangzhou, China
Jiaji Jiang, Center for Liver Disease, Fujian Medical University, Fuzhou, China
Background and aim: Cholesterol absorption inhibitor ezetimibe is being used to treat nonalcoholic fatty liver disease (NAFLD) and related metabolic comorbidities. However, its specific efficacy remains unclear. Hence, a meta-analysis was undertaken to clarify the effects of ezetimibe on NAFLD and related metabolic comorbidities. Methods: Electronic databases were searched for clinical trials that investigated the effects of ezetimibe on NAFLD and related metabolic comorbidities. The primary outcome of interest was the effect of ezetimibe on liver enzymes and histology. The secondary outcome of interest was the effect of ezetimibe on lipid metabolism and hepatic insulin resistance. Results: The end-of-treatment (vs. baseline) hepatic steatosis grade and NAFLD activity score (NAS) were significantly improved (steatosis grade: weighted mean difference [WMD]: −0.62, 95% CI: −0.96 to −0.27, P = 0.0005; NAS: WMD: −1.00, 95%CI: −1.46 to −0.55, P < 0.0001) without significant improvement in hepatic lobular inflammation, ballooning, or fibrosis. In Asian participants, the end-of-treatment alanine aminotransferase was significantly decreased (WMD: −12.11 IU/L, 95%CI: −23.81 to −0.41 IU/L, P = 0.04). Treatment with ezetimibe significantly reduced total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (TC: WMD: −37.96 mg/dL, 95%CI: −59.52 to −16.40 mg/dL, P = 0.0006; LDL-C: WMD: −35.55 mg/dL, 95%CI: −57.02 to −14.07 mg/dL, P = 0.001) without a significant effect on triglycerides, high-density lipoprotein cholesterol, glycosylated haemoglobin or the homeostasis model of assessment for insulin resistance index. Conclusions: Results of the meta-analysis confirm beneficial effects of ezetimibe on hepatic steatosis and cholesterol metabolism in patients with NAFLD.
Beneficial Effect of Ezetimibe on Cholesterol Metabolism Ameliorates Hepatic Steatosis, European Journal of Clinical and Biomedical Sciences.
Vol. 4, No. 2,
2018, pp. 29-38.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64(1): 73-84.
Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43: 617-49.
McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62: 1148-55.
Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, Hunt S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015; 62: 1723-30.
Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62(1 Suppl): S47-S64.
Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 2: 901-10.
Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114: 842-5.
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; pii: S0168-8278(15)00734-5.
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67: 328-357.
Ganesh S, Rustgi VK. Current pharmacologic therapy for nonalcoholic fatty liver disease. Clin Liver Dis 2016; 20: 351-64.
Takeshita Y, Takamura T, Honda M, Kita Y, Zen Y, Kato K, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 2014; 57: 878-90.
Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, Yasui K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011; 46: 101-7.
Oza N, Takahashi H, Eguchi Y, Kitajima Y, Kuwashiro T, Ishibashi E, et al. Efficacy of ezetimibe for reducing serum low-density lipoprotein cholesterol levels resistant to lifestyle intervention in patients with non-alcoholic fatty liver disease. Hepatol Res 2014; 44: 812-7.
Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, Hosono K, et al. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: an open-label, pilot study. Hepatol Res 2010; 40: 566-73.
Abel T, Fehér J, Dinya E, Eldin MG, Kovács A. Safety and efficacy of combined ezetimibe/simvastatin treatment and simvastatin monotherapy in patients with non-alcoholic fatty liver disease. Med Sci Monit 2009; 15: MS6-11.
Enjoji M, Machida K, Kohjima M, et al. NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease. Lipids Health Dis 2010; 9: 29.
Shiwa T, Kawanami Y, Yokoyama T, Moritani A, Hashimoto M, Gotoh T. The efficacy of ezetimibe on nonalcoholic fatty liver disease (NAFLD). Nihon Shokakibyo Gakkai Zasshi 2011; 108: 1383-92.
Husain NE, Hassan AT, Elmadhoun WM, Ahmed MH. Evaluating the safety of Liptruzet (ezetimibe and atorvastatin): what are the potential benefits beyond low-density lipoprotein cholesterol-lowering effect? Expert Opin Drug Saf 2015; 14: 1445-55.
Averna M. The effect of ezetimibe on NAFLD. Atheroscler Suppl 2015; 17: 27-34.
Park H, Hasegawa G, Shima T, et al. The fatty acid composition of plasma cholesteryl esters and estimated desaturase activities in patients with nonalcoholic fatty liver disease and the effect of long-term ezetimibe therapy on these levels. Clin Chim Acta 2010; 411: 1735-40.
Loomba R, Sirlin CB, Ang B, et al.; San Diego Integrated NAFLD Research Consortium (SINC). Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61: 1239-50.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097.
GA Wells, B Shea, D O'Connell, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Department of Epidemiology and Community Medicine, University of Ottawa, Canada. Available: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed April 1, 2016.
Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94: 2467-74.
Kleiner DE, Brunt EM, Van Natta M, et al.; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-21.
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135.
Khukhlina OS, Mandryk Ole, Drozd Vlu, Haĭdychuk VS, Kosar Llu. The use of complex tools ezetimibe, hepadyfu fosinopril and correction of blood pressure and endothelial dysfunction in patients with nonalcoholic steatohepatitis and essential hypertension stage II [in Urkrainian]. Wiad Lek 2014; 67: 269-72.
Simon TG, Corey KE, Chung RT, Giugliano R. Cardiovascular Risk Reduction in Patients with Nonalcoholic Fatty Liver Disease: The Potential Role of Ezetimibe. Dig Dis Sci 2016; 61: 3425-3435.
Musso G. Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD? Diabetologia 2014; 57: 850-5.
Wong VW, Chan WK, Chitturi S, et al. Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 1: Definition, risk factors and assessment. J Gastroenterol Hepatol. 2018 Jan; 33(1):70-85.
Van Rooyen DM, Gan LT, Yeh MM, et al. Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. J Hepatol 2013; 59: 144-52.
Matono T, Koda M, Tokunaga S, et al. Therapeutic effects of ezetimibe for non-alcoholic steatohepatitis in fatty liver shionogi-ob/ob mice. Hepatol Res 2011; 41: 1240-8.
Fraunberger P, Gröne E, Gröne HJ, Drexel H, Walli AK. Ezetimibe reduces cholesterol content and NF-kappaB activation in liver but not in intestinal tissue in guinea pigs. J Inflamm (Lond) 2017; 14:3.
Lee DH, Han DH, Nam KT, et al. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radic Biol Med 2016; 99: 520-532.
X Wang, Y Meng, J Zhang. Ezetimibe alleviates non-alcoholic fatty liver disease through the miR-16 inhibiting mTOR/p70S6K1 pathway. Rsc Advances 2017; 7: 37967-37974.
Jia L, Betters JL, Yu L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol 2011; 73: 239-59.
Yamanashi Y, Takada T, Kurauchi R, Tanaka Y, Komine T, Suzuki H. Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K. J Atheroscler Thromb 2017; 24: 347-359.
Wang Y, Tang W, Yang P, Shin H, Li Q. Hepatic NPC1L1 promotes hyperlipidemia in LDL receptor deficient mice. Biochem Biophys Res Commun 2018; 499: 626-633.
Yang F, Chen G, Ma M, Qiu N, Zhu L, Li J. Fatty acids modulate the expression levels of key proteins for cholesterol absorption in Caco-2 monolayer. Lipids Health Dis 2018; 17: 32.
Zambrano T, Saavedra N, Lanas F, Caamaño J, Salazar LA. Efficacy of ezetimibe is not related to NPC1L1 gene polymorphisms in a pilot study of Chilean hypercholesterolemic subjects. Mol Diagn Ther 2015; 19: 45-52.