3 Focusing on NAFLD, both TZDs have now been studied in prospective, placebo-controlled trials ranging from 6-24 months duration. The results have been varied (Table 1). The TZDs most reliably improve steatosis, just as they do with insulin resistance. However, there are variable responses to other histopathologic lesions commonly seen in NASH to include lobular inflammation, ballooning degeneration, and fibrosis. Intuitively, we would all like to see fibrosis regression. However, no study has conclusively shown TZD therapy to improve fibrosis. Alternatively, no study has shown significant progression of fibrosis either, albeit the follow-up periods are relatively

short. Improvement in ballooning degeneration check details with the TZDs has been varied. Rosiglitazone improved ballooning in a small uncontrolled study,12 but in a larger controlled trial, no improvement in ballooning was found.13 Similarly, two relatively small, ABT-199 molecular weight placebo-controlled trials with pioglitazone of 6-12 months duration using 30 mg daily in one trial and 45 mg daily in another, found different results.5, 14 The lower dose pioglitazone study did not show significant improvement within the pioglitazone group,14 but the higher dose study found improved ballooning within and between the two groups.5 Improvement in inflammation among the randomized controlled trials was only shown with pioglitazone.5, 15 This finding

may be of particular importance because a recent study found that inflammation was an independent predictor of fibrosis progression.16 Interestingly, a larger placebo-controlled trial with pioglitazone in which patients were treated for 24 months using the 30 mg dose showed improvement in steatosis and inflammation but not in ballooning (P = 0.08).15 Prior to the publication by Ratziu et al.17, no studies of greater than

12 months duration existed 上海皓元医药股份有限公司 for rosiglitazone. In the current issue of HEPATOLOGY, Ratziu et al report on 40 patients who underwent liver biopsies a minimum of 2 years after starting rosiglitazone therapy for NASH.17 The patients were part of a previous trial in which rosiglitazone was compared prospectively to placebo for the treatment of NASH. All patients originally received study drug for 1 year. In the current trial, 22 of the original placebo patients were then put on roglitazone and 18 of the original patients on rosiglitazone were continued on the drug. All patients were then followed for 2 years and repeat biopsies were obtained. Overall, insulin sensitivity, as defined by the Homeostasis Model Assessment (HOMA) score, improved by 30% and serum alanine aminotransferase improved by 24% over the study period. Among the original placebo patients, steatosis decreased by a median of 15% (P < 0.001) over the 2-year follow-up period, but no improvement in necroinflammation or fibrosis was seen.