By Liz Highleyman

Rosiglitazone (Avandia)

Experts increasingly recognize a connection between the metabolic syndrome and fatty liver disease (steatosis). However, the underlying mechanisms are not well understood, especially in individuals with hepatitis C virus (HCV) and/or HIV, which also have complex links to metabolic complications.

Insulin resistance -- a condition in which the body does not respond properly to insulin -- has been associated with steatosis, fibrosis, and poor response to interferon-based therapy for hepatitis C.

In the present study, published in the July 2008 issue of Gastroenterology, a French research team assessed the efficacy and safety of the insulin-sensitizing medication rosiglitazone (Avandia) in individuals with non-alcoholic steatohepatitis (NASH).

The Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial randomly assigned 63 patients with histologically proven NASH to receive rosiglitazone (4 mg/day for the first month, then 8 mg/day thereafter) or else placebo for 1 year.

Liver biopsies were performed at the end of treatment. Study endpoints were improvement in histological steatosis score, normalization of serum transaminase (ALT and AST) levels, and improvement in necroinflammation and fibrosis.

Results

• More patients treated with rosiglitazone than placebo experienced improvement in steatosis (47% vs 16%; P = 0.014).

• More participants in the rosiglitazone arm experienced normalization of transaminase levels (38% vs 7%; P = 0.005).

• However, only about half of the patients receiving rosiglitazone responded.

• There was no improvement in other histological measures including fibrosis or non-alcoholic fatty liver disease activity score.

• Improvement of steatosis was correlated with:

• Reduced transaminase levels (R 0.36; P < 0.005);

• Improved insulin sensitivity (R 0.34; P = .008);

• Increased levels of adiponectin, a hormone produced by fat cells (R -0.54; P < 0.01).

• Steatosis improvement was not associated with weight changes.
Independent predictors of response were use of rosiglitazone, absence of diabetes, and massive steatosis.

• The main adverse event associated with rosiglitazone was weight gain (mean gain of 1.5 kg in the rosiglitazone group vs mean loss of 1 kg in the placebo group; P < 0.01).

• The main reason for rosiglitazone dose reduction or discontinuation was painful leg swelling.

• Serum hemoglobin was slightly but significantly reduced in the rosiglitazone arm.

• No liver toxicity was observed.

"In patients with NASH, rosiglitazone improves steatosis and transaminase levels despite weight gain, an effect related to an improvement in insulin sensitivity," the study authors concluded. "However, there is no improvement in other parameters of liver injury."

Though this study did not focus on patients with HCV and/or HIV, it sheds further light on a type of liver disease -- steatosis -- that is common in both groups.

8/29/08

Reference
V Ratziu, P Giral, S Jacqueminet, and others. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135(1):100-110. July 2008.