Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.
OBJECTIVE
Nonalcoholic steatohepatitis (NASH) is a liver disease that complicates insulin-resistant states. This trial tested the efficacy and safety of rosiglitazone, an insulin-sensitizing agent, in patients with NASH.


METHODS
Sixty-three patients with histologically proven NASH were randomly assigned to receive rosiglitazone (4 mg/day for the first month and 8 mg/day thereafter; n = 32) or placebo (n = 31) for 1 year. Liver biopsy was performed at the end of treatment. End points were improvement in the histologic score of steatosis, normalization of serum transaminase levels, and improvement in necroinflammation and fibrosis.


RESULTS
More patients treated with rosiglitazone than receiving placebo had improved steatosis (47% vs 16%; P = .014) and normalized transaminase levels (38% vs 7%; P = .005), although only half of patients responded. There was no improvement in other histologic lesions, including fibrosis, and a composite score of activity, the nonalcoholic fatty liver disease activity score. Improvement of steatosis correlated with reduction of transaminase levels (r = 0.36; P < .005), improvement in insulin sensitivity (r = 0.34; P = .008), and increase in adiponectin levels (r = -0.54; P < .01) but not with weight variations. Independent predictors of response were rosiglitazone treatment, the absence of diabetes, and massive steatosis. Weight gain was the main adverse effect (mean gain of 1.5 kg in the rosiglitazone group vs -1 kg in the placebo group; P < .01), and painful swollen legs was the main reason for dose reduction/discontinuation. Serum hemoglobin level was slightly but significantly reduced. There was no hepatic toxicity.


CONCLUSIONS
In patients with NASH, rosiglitazone improves steatosis and transaminase levels despite weight gain, an effect related to an improvement in insulin sensitivity. However, there is no improvement in other parameters of liver injury.
Ratziu
Vlad
V
Université Pierre et Marie Curie Paris VI, Assistance Publique-Hôpitaux de Paris, Service d'Hépatogastroentérologie, Paris, France. vratziu@teaser.fr
Giral
Philippe
P
Jacqueminet
Sophie
S
Charlotte
Fréderic
F
Hartemann-Heurtier
Agnès
A
Serfaty
Lawrence
L
Podevin
Philippe
P
Lacorte
Jean-Marc
JM
Bernhardt
Carole
C
Bruckert
Eric
E
Grimaldi
André
A
Poynard
Thierry
T
D052242:Adiponectin / Q000097:blood; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006505:Hepatitis / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010919:Placebos; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects; D005723:gamma-Glutamyltransferase / Q000097:blood
C499918:ADIPOQ protein, human; D052242:Adiponectin; D007004:Hypoglycemic Agents; D010919:Placebos; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase