title: A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
abstract: BACKGROUND
  No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic 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 nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg 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 ([14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion).
  
  
  RESULTS
  Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, 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 nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .).
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Belfort
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Harrison
authors.forename: Kenneth
authors.initials: K
authors.lastname: Brown
authors.forename: Celia
authors.initials: C
authors.lastname: Darland
authors.forename: Joan
authors.initials: J
authors.lastname: Finch
authors.forename: Jean
authors.initials: J
authors.lastname: Hardies
authors.forename: Bogdan
authors.initials: B
authors.lastname: Balas
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: Fermin
authors.initials: F
authors.lastname: Tio
authors.forename: Joseph
authors.initials: J
authors.lastname: Pulcini
authors.forename: Rachele
authors.initials: R
authors.lastname: Berria
authors.forename: Jennie Z
authors.initials: JZ
authors.lastname: Ma
authors.forename: Sunil
authors.initials: S
authors.lastname: Dwivedi
authors.forename: Russell
authors.initials: R
authors.lastname: Havranek
authors.forename: Chris
authors.initials: C
authors.lastname: Fincke
authors.forename: Ralph
authors.initials: R
authors.lastname: DeFronzo
authors.forename: George A
authors.initials: GA
authors.lastname: Bannayan
authors.forename: Steven
authors.initials: S
authors.lastname: Schenker
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cusi
mesh_terms: D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D031204:Caloric Restriction; D003131:Combined Modality Therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000178:diet therapy / Q000188:drug therapy; D004311:Double-Blind Method; D005234:Fatty Liver / Q000150:complications / Q000178:diet therapy* / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D018149:Glucose Intolerance / Q000178:diet therapy / Q000188:drug therapy; D006505:Hepatitis / Q000178:diet therapy / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077205:Pioglitazone