title: The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial.
abstract: OBJECTIVE
  The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial.
  
  
  METHODS
  We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA(1c)) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic-euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group.
  
  
  RESULTS
  Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA1c and was associated with a significant increase in hepatic long-chain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the L-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids.
  
  
  CONCLUSIONS
  Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies.
  
  
  BACKGROUND
  University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000005250.
  
  
  BACKGROUND
  The study was funded by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and research grants from MSD.
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Yumie
authors.initials: Y
authors.lastname: Takeshita
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kita
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kato
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Misu
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Yamada
authors.forename: Hajime
authors.initials: H
authors.lastname: Sunagozaka
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Arai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001384:Azetidines / Q000627:therapeutic use*; D001706:Biopsy; D002331:Carnitine / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D000069438:Ezetimibe; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D000637:Transaminases / Q000097:blood; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D002331:Carnitine; D002784:Cholesterol; D000069438:Ezetimibe; D005227:Fatty Acids; D005947:Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D000637:Transaminases