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Pioglitazone for Treating Patients with Nonalcoholic Steatohepatitis

Pioglitazone improved metabolic parameters and histology in NASH patients with diabetes in this small study.

Nonalcoholic steatohepatitis (NASH) is an increasingly common cause of chronic liver disease worldwide. Currently, no specific pharmacologic therapy has been shown to treat NASH effectively. Because insulin resistance is a central feature of NASH, pioglitazone (a thiazolidinedione), which improves insulin resistance, was tested in an industry-sponsored, randomized, placebo-controlled U.S. trial. Fifty-five patients with biopsy-proven NASH and with either abnormal glucose tolerance tests or diabetes mellitus were enrolled to evaluate the efficacy of pioglitazone for treating NASH.

Patients received either daily pioglitazone (30 mg initially, titrated to 45 mg) or placebo for 6 months. Baseline characteristics were similar between the groups. All participants underwent dietary counseling and were placed on individualized hypocaloric diets (500 kcal less daily than the calculated caloric intake required to maintain body weight). Before and after treatment, liver histology (via biopsy), hepatic fat content (via magnetic resonance spectroscopy), and glucose turnover during oral glucose tolerance tests were evaluated. Forty-eight patients completed the study, with 95% adherence to study medication.

Compared with placebo recipients, who exhibited no significant changes in metabolic responses, patients who received pioglitazone showed improved insulin sensitivity (33% reduction in mean fasting plasma insulin concentration [P<0.001] and 20% reduction in free fatty-acid level [P=0.04]), reduction in hepatic fat content (54%; P<0.001), and less severe steatohepatitis (i.e., steatosis, ballooning necrosis, and centrilobular inflammation). However, no significant differences in hepatic fibrosis were detected between the two groups. The pioglitazone group experienced modest mean increases in weight (2.5±0.5 kg) and body fat (1.5±0.5%).

Comment: The results of this randomized trial demonstrate that pioglitazone improves metabolic parameters and histology in NASH patients with type 2 diabetes mellitus or abnormal glucose tolerance tests. However, hepatic fibrosis did not improve significantly, probably because of the small number of participants and the short duration of the study. Clinicians should consider using a thiazolidinedione as part of a treatment regimen in type 2 diabetic patients who have NASH, but larger studies are required to verify these results and to determine if pioglitazone is effective in nondiabetic NASH patients.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology November 29, 2006

Citation(s):

Belfort R et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006 Nov 30; 355:2297-307.

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