Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)
Condition: Nonalcoholic Steatohepatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      To determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis (NASH)
      in patients with glucose intolerance or type 2 diabetes mellitus (T2DM).
    

Detailed description: 
      v. 4/1/2003 Role of Pioglitazone in the Treatment of Nonalcoholic Steatohepatitis

      1. PURPOSE/SPECIFIC AIMS To determine the role of pioglitazone in the treatment of
      nonalcoholic steatohepatitis (NASH) in patients with glucose intolerance or type 2 diabetes
      mellitus (T2DM). NASH is a disease characterized by elevated plasma aminotransferases and
      histopathological changes in liver characterized by hepatocellular steatosis, chronic
      inflammation and fibrosis (1-3). Pioglitazone, a new thiazolidinedione (TZD), has proven to
      be safe and effective for the treatment of type 2 diabetes mellitus (T2DM) (4). NASH affects
      ~10-20% of obese and type 2 diabetic subjects (1-3, 5, 6). While the pathogenesis of NASH is
      poorly understood, there is consensus that insulin resistance and its associated
      abnormalities in lipid metabolism play a key role in the development of liver fat
      accumulation, and TNF-alpha is a major mediator in the progression of liver damage (7-9).
      Currently, there is no satisfactory therapy for NASH.

      Pioglitazone improves insulin sensitivity and glycemic control in patients with T2DM (4,
      10-12), but the mechanism of action of TZDs is unclear (13, 14). Pioglitazone activates genes
      involved in lipid synthesis, causing a reduction in plasma free fatty acid (FFA) and
      triglycerides (15). TZDs decrease excessive triglyceride accumulation in liver (16), muscle
      (17), and visceral fat (11, 16, 18), with a redistribution of fat to subcutaneous adipose
      stores (14). TZDs also antagonize the metabolic effects of TNF-alpha (19-22). Because
      pioglitazone ameliorates insulin resistance, reverses the metabolic abnormalities that
      contribute to hepatic fat infiltration (increased plasma glucose, FFA, and triglyceride
      concentrations), and antagonizes the effects of TNF-alpha, it follows that pioglitazone may
      prove useful for the treatment of patients with NASH.

      In order to evaluate this hypothesis, we plan to treat for 6 months a group of patients with
      impaired glucose tolerance (IGT) or T2DM with pioglitazone in a randomized, double-blinded,
      placebo-controlled trial. Three major endpoints will be measured before and after treatment
      (see Methods for a detailed description):

        1. Liver histologic response; assessed by liver biopsy. Steatosis and inflammatory changes
           will be quantified using a standardized staging system.

        2. Liver fat content: measured by liver magnetic resonance spectroscopy (MRS).

        3. Hepatic insulin sensitivity and glucose metabolism: Because fat infiltration of liver
           and muscle causes insulin resistance and impairs glucose tolerance, we will measure
           parameters of metabolic control including fasting plasma glucose, free fatty acids,
           fructosamine, HbA1c and fasting lipid profile. To assess the effect of pioglitazone on
           hepatic insulin sensitivity, fasting (basal) and postprandial hepatic glucose production
           will be studied using a double-tracer technique (infusion of 3-3H glucose combined with
           an oral glucose load radiolabeled with 1-14C glucose) (23). Glucose and lipid oxidation
           will be measured by indirect calorimetry (24). In addition, an index of hepatic and
           peripheral insulin sensitivity will be derived from the oral glucose tolerance test
           (OGTT) (25).
    

Intervention name(s): Pioglitazone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 30 mg/d for 8 weeks and titrated to 45 mg/d until completing 6 months of treatment.; Placebo is given to match pioglitazone.
Other intervention name(s): Actos (Takeda Pharmaceuticals).
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: NASH, IGT, T2DM