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

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 (clinicaltrials.gov): NCT00494312.