Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease for which there is limited therapy available. Insulin sensitizing, anti-inflammatory, and antifibrotic properties of thiazolidinediones support their use in treating NASH. We have evaluated pioglitazone in the treatment of nondiabetic patients with NASH. Methods: We randomized 74 nondiabetic patients (45 men; median age, 54 y) with histologically proven NASH to 12 months of standard diet, exercise, and either placebo or pioglitazone (30 mg/day). Sixty-one patients (30 placebo, 31 pioglitazone) had liver biopsies both at the beginning and the end of the study. Results: Compared with placebo, pioglitazone therapy was associated with an increase in weight (mean change, −0.55 vs +2.77 kg; P = .04) and a reduction in glucose (+0.4 vs −0.1 mmol/L; P = .02), HbA1c (+0.16% vs −0.18%; P = .006), insulin C peptide level (+42 vs −78 pmol/L; P = .02), alanine aminotransferase level (−10.9 vs −36.2 u/L; P = .009), γ-glutamyltransferase level (−9.4 vs −41.2 u/L; P = .002), and ferritin (−11.3 vs −90.5 μg/L; P = .01). Histologic features including hepatocellular injury (P = .005), Mallory–Denk bodies (P = .004), and fibrosis (P = .05) were reduced in patients treated with pioglitazone compared with those in the placebo group. Conclusions: Pioglitazone therapy over a 12-month period in nondiabetic subjects with NASH resulted in improvements in metabolic and histologic parameters, most notably liver injury and fibrosis. Larger extended trials are justified to assess the long-term efficacy of pioglitazone in this patient group.