Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis

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

“…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.…”

“…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. 25 In a subset of patients from the same trial, molecular markers of active fibrogenesis (type 1 a1 collagen, transforming growth factor beta [TGF-b], and asmooth-muscle actin) were unchanged by treatment.…”

“…All but one 27 trials showed a reduction in steatosis higher than placebo. In that trial a quarter of patients had minimal steatosis (5%-25%), 27 making differences between groups harder to detect. However, individual response was variable with only 47%-65% of patients experiencing reduction in steatosis.…”

“…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.…”

“…22 Only one study showed no reduction in HOMA, only less deterioration in serum glucose or HbA1c levels. 27 A crucial question is whether the improvement in IS correlates with the biochemical and/or histological response. Two studies showed that aminotransferase reduction has a weak but significant correlation with improvement in hepatic IS 22 and a stronger correlation with improvement in surrogate markers of systemic IR.…”