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Vitamin E (and pioglitazone) Tops for NASH Therapy
 
 
  MedPage Today
Published: April 28, 2010
 
Nonalcoholic steatohepatitis (NASH) was improved significantly with vitamin E supplements, but pioglitazone (Actos), although beneficial, did not meet the significance criteria compared with placebo in a randomized trial, researchers said.
 
Improvement in a composite of four histologic features of NASH was seen in 43% of patients taking 800 IU/day of vitamin E versus 19% taking placebo (P=0.001) in the 96-week trial, Arun Sanyal, MD, of Virginia Commonwealth University in Richmond, and colleagues reported online in the New England Journal of Medicine.
 
Action Points
 
* Explain to interested patients that nonalcoholic steatohepatitis is a liver disease sometimes seen in overweight, obese, and/or diabetic or prediabetic patients.
 
* Explain that there is no currently accepted standard treatment known to be effective.
 
* Explain that the study had too few patients to adequately assess the safety of pioglitazone or vitamin E for this purpose.
 
Treatment with 30 mg/day of pioglitazone led to improvement in 34% of patients. Although the Bonferroni-corrected P value with respect to the placebo group was 0.04, Sanyal and colleagues had set a value of 0.025 as the threshold for statistical significance because two comparisons were planned in the study.
 
The researchers did note, however, that pioglitazone was associated with "highly significant" reductions in steatosis, inflammation, hepatocellular ballooning, insulin resistance, and liver transaminase levels.
 
The drug also appeared to be more effective than vitamin E in another measure of efficacy, the percentage of patients with resolution of definite NASH: 47% of patients taking pioglitazone met this standard versus 36% of the vitamin E group and 21% of those on placebo (P=0.001, pioglitazone versus placebo; P=0.05, vitamin E versus placebo).
 
But mean body weight and body fat percentage in the pioglitazone group increased significantly with respect to the two other treatment groups. These effects are commonly seen in patients taking pioglitazone for diabetes.
 
Sanyal and colleagues deliberately did not compare pioglitazone directly with vitamin E in the study. "No conclusions can be drawn about their relative efficacy," they wrote.
 
What can be said, they added, is that "vitamin E was superior to placebo and ... pioglitazone may also have efficacy."
 
"The decision about which specific therapy to use for the treatment of nonalcoholic steatohepatitis should include a consideration of both the efficacy and the toxic effects of the therapy as compared with those of other available therapies," they wrote.
 
The study assigned 247 patients to each of the three treatment groups. Liver biopsies were taken at baseline and after 96 weeks of treatment. Laboratory tests were conducted periodically during the treatment period and 24 weeks after it ended.
 
Steatohepatitis was assessed with measurements of steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis in the biopsy samples.
 
Sanyal and colleagues defined improvement as all of the following: no progression of fibrosis; at least a one-point improvement in hepatocellular ballooning score; and either a decrease in the non-alcoholic fatty liver disease (NAFLD) activity score to a score of 3 or less, or a decrease in the activity score of at least two points accompanied by a decrease of one point or more in either the lobular inflammation or steatosis score.
 
The NAFLD score was itself based on steatosis, ballooning, and inflammation in the biopsy samples. The mean score at baseline was 4.9 (SD 1.4).
 
Lab tests included blood levels of lipids and liver enzymes, insulin resistance, and fasting serum glucose. Quality of life was also assessed with the Short Form-36 physical and mental components.
 
Neither treatment had any impact on quality of life compared with placebo.
 
But most measures of physical disease improved significantly with both vitamin E and pioglitazone.
 
NAFLD activity scores declined a mean of 0.5 points with placebo versus 1.9 points with both treatments (P<0.001), with significant improvements in each of its three components.
 
There was no significant difference between treatment groups in the effects on fibrosis. Most patients in all groups showed no change, with 31%, 41% and 44% of the placebo, vitamin E, and pioglitazone groups, respectively, showing some improvement (P>0.10).
 
The lab tests also indicated beneficial effects of treatment, with 30% to 40% reductions in alanine aminotransferase and 15% to 25% declines in aspartate aminotransferase levels in both active-treatment groups versus much smaller changes in the placebo group.
 
Insulin resistance showed a nearly one-point improvement in HOMA-IR scores with pioglitazone, whereas vitamin E and placebo had essentially no effect.
 
When patients were retested at week 120, however, the liver enzymes and insulin resistance measures had returned to baseline levels.
 
"Given the certainty of relapse after discontinuation of the drug, it is likely that whichever drug is prescribed for nonalcoholic steatohepatitis, it will need to be taken indefinitely," Sanyal and colleagues wrote.
 
Other than weight and fat gain in the pioglitazone patients, there were no differences between groups in adverse events, and no reports of serious liver toxicity requiring treatment cessation in the study.
 
Sanyal and colleagues noted that the study had too few patients to adequately assess safety endpoints, and its design precluded a direct comparison of the efficacy of pioglitazone versus vitamin E.
 
 
 
 
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