A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis

Abstract

In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .).

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

“…28 Not all studies have reported on changes in the recently described nonalcoholic fatty liver disease activity score (NAS). In a 6-month study, 22 the score improved in 46% of pioglitazone-treated patients by 2 points versus 14% in the placebo group (P ¼ 0.02), although this could be due to steatosis reduction, which is part of the score. A 1-year study with rosiglitazone failed to show significant changes in the NAS score, 21 whereas a 2-year study with pioglitazone improved the NAS score significantly more often than placebo.…”

“…26 Fibrosis. No studies convincingly demonstrated improvement in fibrosis: despite an end-of-treatment reduction 22,27,30 there was no statistical difference with the comparator arm, or only a marginal level suggestive of type 1 error. 27 When measured by micromorphometry, a more sensitive and quantitative technique, there was still no significant improvement, even after prolonged treatment with rosiglitazone.…”

“…Ballooning improved in 32%-54% of patients, which was significantly more than placebo in two RCTs. 22,27 In the PIVENS trial the change in ballooning score was significantly higher with pioglitazone. 26 Intralobular inflammation improved in most 22,26,27,30 but not all 21 studies.…”

“…Glitazones robustly reduced aminotransferase levels by 30%-58%. 21,22 Interestingly, the reduction in the comparator arm was highly variable, 10%-34% for placebo 21,22 and 67% for vitamin E. 23 Normal end-of-treatment ALT was reported in 38%-100% of patients. Direct comparisons between studies can be misleading, as the magnitude of change might simply reflect variable baseline values, whereas the proportion of normal ALT depends on the reference range, which varies between laboratories.…”

“…However, individual response was variable with only 47%-65% of patients experiencing reduction in steatosis. 21,22,26,28 Importantly, the magnitude of reduction is usually not reported. With rosiglitazone it was 20%, ranging from 30%-60% in responders.…”