Pioglitazone: The beginning of a new era for NASH?

A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. Background/Aims No pharmacologic therapy has conclusively proved to be effective for the treatment of non-alcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. Methods We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed non-alcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500kcal/d in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([ 14 C]glucose given with the oral glucose load and [ 3 H]glucose given by intravenous infusion). Results Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance ( P P =0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P P P =0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis ( P =0.003), ballooning necrosis ( P =0.02), and inflammation ( P =0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P =0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group ( P =0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed. Conclusions In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with non-alcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. [Abstract reproduced by permission of N Engl J Med 2006;355:2297–2307]