Special article
Troglitazone-induced liver failure: a case study

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Abstract

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.

Conclusion

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.

Section snippets

Methods

All domestic cases of hospitalized or fatal liver injury associated with troglitazone that were voluntarily reported to the FDA were reviewed. Follow-up information was sought from reporting physicians to capture missing clinical details. Case data were abstracted describing patient demographic characteristics, dose and duration of troglitazone therapy, other treatments for diabetes, time of onset and progression of symptoms of hepatic failure, outcome, and pathology results, when available.

Results

Ninety-four cases of liver failure (89 acute, 5 chronic) in association with troglitazone use were reported. About two thirds of the patients with acute liver failure were women (Table 1). The onset of liver injury began from 3 days to after more than 2 years of troglitazone use. Viral hepatitis testing was reported in 57 patients (64%), with prior infection noted in 17 patients (hepatitis A: 6; hepatitis B: 8; hepatitis A and B: 2; hepatitis C: 1). Monitoring of hepatic enzymes, either at the

Discussion

Ninety-four cases of troglitazone-induced liver failure were reported to the FDA, of which 89 (95%) were acute. The ages of these patients were similar to those seen in patients with type 2 diabetes, but women were overrepresented (43), as has been observed with other hepatotoxins (44). Consistent with the literature 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 45, 46, 47, 48, 49, most patients in this series had hepatocellular damage, although cholestatic and mixed presentations were also observed.

Acknowledgements

We thank Carol R. Drinkard, PhD, and Deborah Shatin, PhD, of the Center for Health Care Policy and Evaluation, UnitedHealth Group, for providing the cohort data used in this study; Curt Furberg, MD, PhD, and Paul Stolley, MD, MPH, for constructive suggestions; and Robert T. O’Neill, PhD, for statistical review of the methods used in this study.

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  • Cited by (0)

    This study was supported in part by cooperative agreements FD-U-000149 and FD-U-0001643-01/02 with the U.S. Food and Drug Administration, Rockville, Maryland.

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