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


CONCLUSIONS
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.
Ratziu
Vlad
V
Hôpital Pitié-Salpêtrière, Service d'Hépatogastroentérologie, Université Pierre et Marie Curie Paris VI, Assistance Publique-Hôpitaux de Paris, France.
Charlotte
Fréderic
F
Bernhardt
Carole
C
Giral
Philippe
P
Halbron
Marine
M
Lenaour
Gilles
G
Hartmann-Heurtier
Agnès
A
Bruckert
Eric
E
Poynard
Thierry
T
D004311:Double-Blind Method; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D013997:Time Factors
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone