The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

Abstract

Aims/hypothesis 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 HbA 1c and was associated with a significant increase in hepatic longchain 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/interpretation Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA 1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies.

Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD?

“…HbA 1c and a worsening in whole-body, muscle and adipose tissue insulin sensitivity (the latter with borderline significance), while plasma pro-/anti-inflammatory markers and cytokines, including C-reactive protein, TNF-α, leptin, plasminogen activator inhibitor (PAI)-1 and adiponectin were unaffected by treatment (Table 2 of the article [6]). 3.…”

“…3. Ezetimibe treatment was associated with hepatic downregulation of genes involved in skeletal muscle development, cell adhesion and long chain NEFA β-oxidation (including the rate-limiting enzyme, carnitine palmitoyltransferase 1A) and with upregulation of genes involved in cholesterol biosynthesis (including sterol regulatory binding factor [SREBF]-2) and immune response/ phagocytosis (Table 3 of the article [6]). 4.…”

“…4. These changes were accompanied by a significant increase in the hepatic fraction of several saturated fatty acids, including margaric (C17:0) and stearic (C18:0) acids (Table 6 of the article [6]). …”

“…The randomised trial by Takeshita and colleagues [6] provides a unique, thorough insight into the impact of selective cholesterol absorption inhibition on liver disease, and glucose and lipid metabolism in NAFLD. The main findings of this study are as follows:…”

“…In 32 biopsy-diagnosed NAFLD patients, treatment for 6 months with the Niemann-Pick C1-like 1 (NPC1L1) inhibitor ezetimibe ameliorated histological features of fibrosis and hepatocyte ballooning, while there was no significant difference in steatosis, inflammation or NAFLD activity score (NAS) compared with controls (see electronic supplementary material [ESM] Table 2 of the Takeshita et al article [6]). …”