Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study)

Yongin Cho, Hyungjin Rhee, Young-Eun Kim, Minyoung Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Jin-Young Choi, Yong-Ho Lee, Yongin Cho, Hyungjin Rhee, Young-Eun Kim, Minyoung Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Jin-Young Choi, Yong-Ho Lee

Abstract

Background: The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD).

Methods: A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change.

Results: Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104).

Conclusions: Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population.

Trial registration: The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 ).

Keywords: Hepatic fibrosis; Hepatic steatosis; Niemann-Pick C1-like 1 inhibitor; Statins.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
CONSORT flow diagram. Abbreviations: CONSORT, Consolidated Standard of Reporting Trial
Fig. 2
Fig. 2
Liver fat (%) by MRI-PDFF at baseline and end of treatment by regimen
Fig. 3
Fig. 3
Odds ratio of steatosis improvement by subgroups. Response (≥30% relative reduction or ≥5% absolute decline by MRI-PDFF from baseline to end of treatment) by age (≥ or 2), type 2 diabetes, sarcopenia (skeletal muscle mass index % <2 standard deviations below gender-specific mean for the Korean population: men, 29.0; women, 22.9), HOMA-IR (≥3.7, study median), baseline MRI-PDFF (≥14.3%, study median), and baseline MRE (≥2.1, study median)

References

    1. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–397.e310. doi: 10.1053/j.gastro.2015.04.043.
    1. Wagenknecht LE, Zaccaro D, Espeland MA, Karter AJ, O'Leary DH, Haffner SM. Diabetes and progression of carotid atherosclerosis: the insulin resistance atherosclerosis study. Arterioscler Thromb Vasc Biol. 2003;23(6):1035–1041. doi: 10.1161/01.ATV.0000072273.67342.6D.
    1. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;41(1):111–188. doi: 10.1093/eurheartj/ehz455.
    1. Ramkumar S, Raghunath A, Raghunath S. Statin therapy: review of safety and potential side effects. Acta Cardiol Sin. 2016;32(6):631.
    1. Ioannou GN. The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol Metab. 2016;27(2):84–95. doi: 10.1016/j.tem.2015.11.008.
    1. Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007;47(1):135–141. doi: 10.1016/j.jhep.2007.02.013.
    1. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43(10):990–994. doi: 10.1097/MCG.0b013e31819c392e.
    1. Takase H, Dohi Y, Okado T, Hashimoto T, Goto Y, Kimura G. Effects of ezetimibe on visceral fat in the metabolic syndrome: a randomised controlled study. Eur J Clin Investig. 2012;42(12):1287–1294. doi: 10.1111/eci.12000.
    1. Deushi M, Nomura M, Kawakami A, Haraguchi M, Ito M, Okazaki M, Ishii H, Yoshida M. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett. 2007;581(29):5664–5670. doi: 10.1016/j.febslet.2007.11.023.
    1. Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010;12(Suppl 2):83–92. doi: 10.1111/j.1463-1326.2010.01275.x.
    1. Kim SH, Kim G, Han DH, Lee M, Kim I, Kim B, Kim KH, Song Y-M, Yoo JE, Wang HJ. Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Autophagy. 2017;13(10):1767–1781. doi: 10.1080/15548627.2017.1356977.
    1. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, Soaft L, Hooker J, Kono Y, Bhatt A. 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(4):1239–1250. doi: 10.1002/hep.27647.
    1. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397. doi: 10.1056/NEJMoa1410489.
    1. Korean guidelines for the management of dyslipidemia 4th ed. In.: Committee of clinical practice guideline of the Korean Society of Lipid and Atherosclerosis (KSoLA); 2018.
    1. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, Richards L, Salotti J, Bhatt A, Hooker J. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2016;65(2):369–376. doi: 10.1016/j.jhep.2016.04.021.
    1. Kim KM, Lim S, Choi SH, Kim JH, Shin CS, Park KS, Jang HC. Cardiometabolic implication of sarcopenia: The Korea National Health and Nutrition Examination Study (KNHANES) 2008–2010. IJC Metab Endocr. 2014;4:63–69. doi: 10.1016/j.ijcme.2014.06.001.
    1. Loomba R. MRI-PDFF treatment response criteria in nonalcoholic steatohepatitis. Hepatology. 2020;73:881–883. doi: 10.1002/hep.31624.
    1. Labonté ED, Camarota LM, Rojas JC, Jandacek RJ, Gilham DE, Davies JP, Ioannou YA, Tso P, Hui DY, Howles PN. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1−/− mice. Am J Physiol Gastrointestinal Liver Physiol. 2008;295(4):G776–G783. doi: 10.1152/ajpgi.90275.2008.
    1. Muraoka T, Aoki K, Iwasaki T, Shinoda K, Nakamura A, Aburatani H, Mori S, Tokuyama K, Kubota N, Kadowaki T. Ezetimibe decreases SREBP-1c expression in liver and reverses hepatic insulin resistance in mice fed a high-fat diet. Metabolism. 2011;60(5):617–628. doi: 10.1016/j.metabol.2010.06.008.
    1. Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, Yasui K, Itoh Y, Yoshikawa T, Fukui M, Hasegawa G. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol. 2011;46(1):101–107. doi: 10.1007/s00535-010-0291-8.
    1. Miettinen TA, Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment. Eur J Clin Investig. 2003;33(11):976–982. doi: 10.1046/j.1365-2362.2003.01229.x.
    1. Davies JP, Scott C, Oishi K, Liapis A, Ioannou YA. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. J Biol Chem. 2005;280(13):12710–12720. doi: 10.1074/jbc.M409110200.
    1. Subramanian S, Goodspeed L, Wang S, Kim J, Zeng L, Ioannou GN, Haigh WG, Yeh MM, Kowdley KV, O'Brien KD. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. J Lipid Res. 2011;52(9):1626–1635. doi: 10.1194/jlr.M016246.
    1. Toyoda Y, Takada T, Umezawa M, Tomura F, Yamanashi Y, Takeda K, Suzuki H. Identification of hepatic NPC1L1 as an NAFLD risk factor evidenced by ezetimibe-mediated steatosis prevention and recovery. FASEB BioAdv. 2019;1(5):283–295. doi: 10.1096/fba.2018-00044.
    1. Cho Y, Kim R-H, Park H, Wang HJ, Lee H, Kang ES. Effect of ezetimibe on glucose metabolism and inflammatory markers in adipose tissue. Biomedicines. 2020;8(11):512. doi: 10.3390/biomedicines8110512.
    1. Hong N, Lee Y-H, Tsujita K, Gonzalez JA, Kramer CM, Kovarnik T, Kouvelos GN, Suzuki H, Han K, Lee CJ. Comparison of the effects of ezetimibe-statin combination therapy on major adverse cardiovascular events in patients with and without diabetes: a meta-analysis. Endocrinol Metab. 2018;33(2):219–227. doi: 10.3803/EnM.2018.33.2.219.
    1. Lee Y-H, Hong N, Lee CJ, Park SH, Lee B-W, Cha B-S, Kang ES. Differential association of ezetimibe-simvastatin combination with major adverse cardiovascular events in patients with or without diabetes: a retrospective propensity score-matched cohort study. Sci Rep. 2018;8(1):1–7.
    1. Lee B-W, Lee Y-H, Park C-Y, Rhee E-J, Lee W-Y, Kim N-H, Choi KM, Park K-G, Choi Y-K, Cha B-S. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: a position statement of the Fatty Liver Research Group of the Korean Diabetes Association. Diabetes Metab J. 2020;44(3):382–401. doi: 10.4093/dmj.2020.0010.
    1. Catry E, Pachikian BD, Salazar N, Neyrinck AM, Cani PD, Delzenne NM. Ezetimibe and simvastatin modulate gut microbiota and expression of genes related to cholesterol metabolism. Life Sci. 2015;132:77–84. doi: 10.1016/j.lfs.2015.04.004.
    1. Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol. 2017;67(5):1084–1103. doi: 10.1016/j.jhep.2017.05.007.
    1. Vuppalanchi R, Noureddin M, Alkhouri N, Sanyal AJ. Therapeutic pipeline in nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2021;18(6):373–392. doi: 10.1038/s41575-020-00408-y.
    1. Toyoda Y, Takada T, Yamanashi Y, Suzuki H. Pathophysiological importance of bile cholesterol reabsorption: hepatic NPC1L1-exacerbated steatosis and decreasing VLDL-TG secretion in mice fed a high-fat diet. Lipids Health Dis. 2019;18(1):1–10. doi: 10.1186/s12944-019-1179-0.
    1. Albano E, Mottaran E, Occhino G, Reale E, Vidali M. Role of oxidative stress in the progression of non-alcoholic steatosis. Aliment Pharmacol Ther. 2005;22:71–73. doi: 10.1111/j.1365-2036.2005.02601.x.
    1. Han DH, Nam KT, Park JS, Kim SH, Lee M, Kim G, Min BS, Cha B-S, Lee YS, Sung SH. 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. doi: 10.1016/j.freeradbiomed.2016.09.009.
    1. Guebre-Xabier M, Yang S, Lin HZ, Schwenk R, Krzych U, Diehl AM. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology. 2000;31(3):633–640. doi: 10.1002/hep.510310313.
    1. Ciardullo S, Perseghin G. Statin use is associated with lower prevalence of advanced liver fibrosis in patients with type 2 diabetes. Metabolism. 2021;121:154752. doi: 10.1016/j.metabol.2021.154752.
    1. El-Din SHS, El-Lakkany NM, El-Naggar AA, Hammam OA, Abd El-Latif HA, Ain-Shoka AA, Ebeid FA. Effects of rosuvastatin and/or β-carotene on non-alcoholic fatty liver in rats. Res Pharm Sci. 2015;10(4):275.
    1. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, Maggioni M, Kakela P, Wiklund O, Mozzi E. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63(3):705–712. doi: 10.1016/j.jhep.2015.05.006.
    1. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150(3):626–637.e627. doi: 10.1053/j.gastro.2015.11.048.

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