Gastroenterology

Gastroenterology

Volume 135, Issue 4, October 2008, Pages 1176-1184
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis

https://doi.org/10.1053/j.gastro.2008.06.047Get rights and content

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.

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Materials and Methods

We recruited patients for the randomized, double-blind, placebo-controlled trial between November 25, 2002, and March 31, 2006, from the Queen's Medical Centre in Nottingham and from Derby City General Hospital (see Supplementary diagram online at www.gastrojournal.org). The study was approved by the Nottingham Joint Ethics Committee. (National Research Register Document: N0192119052; ISRCTN: 10319160.) Takeda Pharmaceuticals UK provided the pioglitazone and placebo tablets for this

Results

Baseline characteristics were similar for the 2 groups except for lower alkaline phosphatase and fasting insulin levels in the pioglitazone-treated group (Table 2, Table 3, Table 4). Although the mean γ-glutamyltransferase (GGT) level appears higher in the pioglitazone group, the 2 study groups were not significantly different in this respect.

Discussion

This was a randomized controlled trial evaluating a pharmacologic treatment for NASH in exclusively nondiabetic subjects. We have shown that treatment with pioglitazone 30 mg over a 12-month period reduced the degree of steatosis, hepatocellular injury, lobular inflammation, Mallory–Denk bodies, and fibrosis. Although hepatic steatosis improved in the placebo group, hepatocellular injury (representing ballooning degeneration, apoptosis, and drop-out hepatocytes) worsened during the study

References (41)

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Takeda Pharmaceuticals UK provided the pioglitazone and placebo tablets for this investigator-initiated study. Jonathan Webber has received funding from Takeda, Novo, Sanofi-Aventis, and Pfizer to attend meetings. Investigator conflicts of interests were disclosed to study participants.

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