Troglitazone-induced liver failure: a case study.
BACKGROUND
Troglitazone was removed from the U.S. market because its use was associated with an increased risk of liver failure. We evaluated the clinical features of all cases reported to the Food and Drug Administration and estimated the duration and magnitude of the risk of liver failure associated with continued use of the drug.


METHODS
Data from cases of liver failure associated with troglitazone use were abstracted and analyzed. The extent of troglitazone use was determined from national marketing data, and the duration of use was estimated with data from a large, multistate, health care company. Survival analysis was performed to estimate monthly incidence rates and the cumulative risk of liver failure.


RESULTS
Ninety-four cases of liver failure (89 acute, 5 chronic) were reported. Of the acute cases, 58 (67%) were women and only 11 (13%) recovered without liver transplantation. Progression from normal hepatic functioning to irreversible liver injury occurred within 1 month in 19 patients who were indistinguishable clinically from the 70 patients who had an unknown time course to irreversibility, except for the post hoc observation that prior cholecystectomy was less common in those with rapid onset. The incidence of liver failure was elevated from the first through at least the 26th month of troglitazone use. Accounting for case underreporting, the number needed to harm from troglitazone use was between 600 to 1500 patients at 26 months.


CONCLUSIONS
The progression to irreversible liver injury probably occurred within a 1-month interval in most patients, casting doubt on the value of monthly monitoring of serum aminotransferase levels as a means of preventing troglitazone-induced acute liver failure. The cumulative risk of hepatic failure increased with continued use.
Graham
David J
DJ
Office of Drug Safety, Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, HFD-400, Room 15B-32, Rockville, MD 20857, USA. grahamd@cder.fda.gov
Green
Lanh
L
Senior
John R
JR
Nourjah
Parivash
P
D017677:Age Distribution; D000368:Aged; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D002839:Chromans / Q000008:administration & dosage / Q000009:adverse effects*; D002908:Chronic Disease; D016001:Confidence Intervals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004335:Drug and Narcotic Control; D005260:Female; D006801:Humans; D017093:Liver Failure / Q000139:chemically induced / Q000453:epidemiology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000453:epidemiology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011336:Probability; D012042:Registries; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D015996:Survival Rate; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014481:United States; D014486:United States Food and Drug Administration
D002839:Chromans; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone