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Clinical Trial
. 2010 May 6;362(18):1675-85.
doi: 10.1056/NEJMoa0907929. Epub 2010 Apr 28.

Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

Arun J Sanyal  1 , Naga Chalasani, Kris V Kowdley, Arthur McCullough, Anna Mae Diehl, Nathan M Bass, Brent A Neuschwander-Tetri, Joel E Lavine, James Tonascia, Aynur Unalp, Mark Van Natta, Jeanne Clark, Elizabeth M Brunt, David E Kleiner, Jay H Hoofnagle, Patricia R Robuck; NASH CRN
Collaborators, Affiliations
Clinical Trial

Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

Arun J Sanyal et al. N Engl J Med. .

Abstract

Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease.

Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance.

Results: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups.

Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)

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Figures

Figure 1
Figure 1. Screening, Randomization, and Follow-up of Study Subjects
Figure 2
Figure 2. Changes from Baseline in Aminotransferase Levels, Insulin Resistance, and Weight, According to Study Group
Mean values are shown for changes from baseline (the value at follow-up minus the baseline value) in alanine aminotransferase levels, aspartate aminotransferase levels, insulin resistance, and weight among the 83 subjects in the placebo group, 84 subjects in the vitamin E group, and 80 subjects in the pioglitazone group. All available data were included in the calculation of means; data were missing for less than 10% of subjects. Insulin resistance was calculated according to the homeostasis model assessment, with the use of the following formula: (milligrams of glucose per deciliter × microunits of insulin per milliliter) ÷ 405.
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