Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial§


  • Members of the LIDO Study Group are listed in the acknowledgments.

  • ClinicalTrial.gov identifier number: NCT00492700.

  • §

    Conflict of interest: This was an investigator initiated trial and GlaxoSmithKline Pharmaceuticals had no direct or indirect involvement in the design of the trial, data collection or preparation, or submission of the article. GSK provided rosiglitazone for this trial and partly funded the trial. None of the authors has a personal conflict of interest with the manufacturers of any of the marketed glitazones. V.R. is a consultant to Astellas, Axcan, Gilead, Genentech, Intercept, and Sanofi-Aventis. T.P. is a consultant for and owns 15% of Biopredictive, a company that markets FibroTest and SteatoTest. These conflicts of interest have been disclosed to study participants.


Short-term trials of glitazones in nonalcoholic steatohepatitis (NASH) yielded controversial histological results. Longer treatment might result in additional improvement. After a 1-year randomized trial, 53 patients underwent a control liver biopsy and were enrolled in an open-label extension trial of rosiglitazone (RSG), 8 mg/day for 2 additional years. In all, 44 completed the extension phase including 40 with a third liver biopsy. Of these, 22 received placebo (PLB) in the randomized phase (PLB-RSG), and 18 RSG (RSG-RSG). During the 2-year extension phase serum insulin decreased by 26%, homeostasis model assessment (HOMA) by 30%, and alanine aminotransferase (ALT) by 24%. However, there was no significant change in the mean NASH activity score (NAS) (3.8 ± 2.11 versus 3.68 ± 1.8), ballooning score, fibrosis stage (1.76 ± 1.18 versus 1.85 ± 1.19), or area of fibrosis by micromorphometry (4.43% ± 0.68 to 5.54% ± 0.68). In the PLB-RSG group steatosis significantly decreased after 2 years of RSG (median decrease of 15%); in the RSG-RSG group, after an initial decline in the first year of 20%, 2 additional years of RSG did not result in further improvement. Likewise, there was no improvement in the NAS score, ballooning, intralobular inflammation, fibrosis stage, or area of fibrosis with 2 additional years of RSG in the RSG-RSG group. Conclusion: Rosiglitazone has a substantial antisteatogenic effect in the first year of treatment without additional benefit with longer therapy despite a maintained effect on insulin sensitivity and transaminase levels. This suggests that improving insulin sensitivity might not be sufficient in NASH and that additional targets of therapy for liver injury should be explored. (HEPATOLOGY 2009.)