A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
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] .).
Belfort
Renata
R
University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Harrison
Stephen A
SA
Brown
Kenneth
K
Darland
Celia
C
Finch
Joan
J
Hardies
Jean
J
Balas
Bogdan
B
Gastaldelli
Amalia
A
Tio
Fermin
F
Pulcini
Joseph
J
Berria
Rachele
R
Ma
Jennie Z
JZ
Dwivedi
Sunil
S
Havranek
Russell
R
Fincke
Chris
C
DeFronzo
Ralph
R
Bannayan
George A
GA
Schenker
Steven
S
Cusi
Kenneth
K
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*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077205:Pioglitazone