Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US

Drug Saf. 2009;32(9):787-800. doi: 10.2165/11316510-000000000-00000.


Background/aims: Non-alcoholic fatty liver disease (NAFLD), the major hepatic manifestation of type 2 diabetes mellitus, is the most common liver disease in the US. Thiazolidinediones, a commonly used drug class for the treatment of type 2 diabetes, have emerged as a potentially useful treatment for NAFLD. There are, however, lingering concerns about their potential toxicity as well as emerging concerns about how to monitor for and assess hepatotoxicity. We conducted a randomized, long-term, double-blind, hepatic safety study at 171 centres in the US in which 2097 patients with type 2 diabetes received either pioglitazone or glibenclamide (glyburide).

Methods: Patients were randomized to receive either pioglitazone (15-45 mg once daily) or glibenclamide (5-15 mg once daily) for 3 years. The primary objective was to evaluate drug-induced liver injury manifested by liver enzyme elevations, measured every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint was a confirmed ALT greater than three times the upper limit of normal (>3 x ULN) with a secondary endpoint of 8 x ULN.

Main results: The intent-to-treat population included 1051 pioglitazone-treated and 1046 glibenclamide-treated patients; of these, 411 pioglitazone patients and 413 glibenclamide patients completed the study. The incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617). Analyses of the secondary endpoints revealed no ALT >8 x ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 x ULN + total bilirubin 2 x ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 x ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p < or = 0.05) fewer cases of ALT >1.5 x ULN, aspartate aminotransferase >1.5 x ULN and gamma-glutamyl transpeptidase >1.5 x ULN were seen with pioglitazone compared with glibenclamide. No case of hepatic dysfunction or hepatic failure was reported in either treatment group; two cases of hepatic cirrhosis with glibenclamide were reported.

Conclusion: This study demonstrates an hepatic safety profile of pioglitazone similar to that of glibenclamide in long-term use in patients with poorly controlled type 2 diabetes. Trial registration number ( NCT00494312.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Blood Glucose / metabolism
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / epidemiology*
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Drug Approval
  • Endpoint Determination
  • Female
  • Glyburide / therapeutic use
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use*
  • Liver Function Tests
  • Male
  • Middle Aged
  • Pioglitazone
  • Thiazolidinediones / adverse effects*
  • Thiazolidinediones / therapeutic use*
  • United States
  • United States Food and Drug Administration
  • Young Adult


  • Blood Glucose
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Glyburide
  • Pioglitazone

Associated data