Authors: Tolman, Keith G.¹; Freston, James W.²; Kupfer, Stuart³; Perez, Alfonso³

Source: Drug Safety, Volume 32, Number 9, 1 September 2009 , pp. 787-800(14)

Publisher: Adis International

Abstract:

Backgroundaims 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 × ULN) with a secondary endpoint of 8 × 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 × ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 × ULN + total bilirubin 2 × ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 × ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p ≤ 0.05) fewer cases of ALT >1.5 × ULN, aspartate aminotransferase >1.5 × ULN and γ-glutamyl transpeptidase >1.5 × 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

Document Type: Research article

Affiliations: 1: 1 University of Utah, Salt Lake City, Utah, USA 2: 2 University of Connecticut Health Centre, Framingham, Connecticut, USA 3: 3 Takeda Global Research & Development Centre, Inc., Deerfield, Illinois, USA

Publication date: 2009-09-01

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• By this author: Tolman, Keith G. ;  Freston, James W. ;  Kupfer, Stuart ;  Perez, Alfonso

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