Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.
BACKGROUND
The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited.


OBJECTIVE
To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM.


METHODS
Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682).


METHODS
University hospital.


METHODS
Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics.


METHODS
All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment.


METHODS
The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters.


RESULTS
Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).


CONCLUSIONS
Single-center study.


CONCLUSIONS
Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH.


BACKGROUND
Burroughs Wellcome Fund and American Diabetes Association.
Kenneth
K
Cusi
Beverly
B
Orsak
Fernando
F
Bril
Romina
R
Lomonaco
Joan
J
Hecht
Carolina
C
Ortiz-Lopez
Fermin
F
Tio
Jean
J
Hardies
Celia
C
Darland
Nicolas
N
Musi
Amy
A
Webb
Paola
P
Portillo-Sanchez
D015415:Biomarkers / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004038:Diet, Reducing; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000077205:Pioglitazone; D011236:Prediabetic State / Q000150:complications / Q000188:drug therapy*; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*; D000637:Transaminases / Q000097:blood; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
D015415:Biomarkers; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014280:Triglycerides; D000637:Transaminases; D000077205:Pioglitazone