Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents

Abstract

Context Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or non-alcoholic steatohepatitis (NASH). No treatment has been established. Objective To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. Design, Setting, and Patients Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8–17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. Main Outcome Measures The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. Results Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P=.26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P=.83). The mean change in ALT level from baseline to 96 weeks was −35.2 U/L (95% CI, −56.9 to −13.5) with placebo vs −48.3 U/L (95% CI, −66.8 to −29.8) with vitamin E (P=.07) and −41.7 U/L (95% CI, −62.9 to −20.5) with metformin (P=.40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, −0.2 to 0.3) vs −0.5 with vitamin E (95% CI, −0.8 to −0.3; P=.006) and −0.3 with metformin (95% CI, −0.6 to −0.0; P=.04); and in NAFLD activity score, −0.7 with placebo (95% CI, −1.3 to −0.2) vs −1.8 with vitamin E (95% CI, −2.4 to −1.2; P=.02) and −1.1 with metformin (95% CI, −1.7 to −0.5; P=.25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P=.006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P=.23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. Conclusion Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. Trial Registration clinicaltrials.gov Identifier: NCT00063635

Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes

“…Although metformin is suggested as a first‐line pharmacologic treatment for prediabetes and T2D, several randomized controlled trials (RCTs) reported no effects of metformin on histologic improvement of NAFLD in either children or adults 14, 15. However, metformin may help with weight loss and may lower the risk of HCC in patients with diabetes 16.…”

The management of childhood liver diseases in adulthood

“…The primary outcomes was a sustained reduction in alanine transferase whilst secondary outcomes were improvement in histological features and resolution of nonalcoholic steatohepatitis (NASH). Although the primary outcome was not achieved, vitamin E was associated with resolution of NASH and an improvement in hepatocyte ballooning suggesting the need for future studies [129].…”

“…The study also reported an improvement in liver enzymes, insulin resistance and serum lipid levels [128]. The TONIC study, a double-blind placebo controlled trial compared vitamin E or metformin for 96 weeks [129]. The primary outcomes was a sustained reduction in alanine transferase whilst secondary outcomes were improvement in histological features and resolution of nonalcoholic steatohepatitis (NASH).…”

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

“…Considering that insulin resistance is the hallmark of NAFLD, drugs acting on glucose metabolism have long been considered for NAFLD treatment [35,58,[72][73][74][75][76][77][78][79][80]. Insulin sensitizers have been tested in several clinical trials of different duration.…”

“…This therapeutic effect has been demonstrated with metformin, which is the basis of diabetes treatment and significantly reduces the progression of pre-diabetes to diabetes in several large intervention trials. However, initial evidence for an effect of metformin on NAFLD histology was not confirmed [72,76,77,80], and the effects of metformin on liver disease progression have been questioned [81]. Many more data are available with the peroxisome-proliferator activator receptor- (PPAR-) agonists (glitazones) as insulin sensitizers.…”