Troglitazone-Induced Hepatic Failure Leading to Liver Transplantation: A Case Report

Neuschwander‐Tetri, Brent A.; Isley, William L.; Oki, Julie C.; Ramrakhiani, Sanjay; Quiason, Stella G.; Phillips, Nancy J.; Brunt, Elizabeth M.

doi:10.7326/0003-4819-129-1-199807010-00009

Cited by 186 publications

(83 citation statements)

References 6 publications

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“…The discovery of the selective peroxisomal proliferator-activated receptor-␥ (PPAR-␥) agonist thiazolidinediones and the introduction of the first approved thiazolidinedione, troglitazone, were significant advances in the search for effective insulinsensitizing agents (6,8 -10). However, postmarketing reports of serious hepatic reactions to troglitazone, including fatal fulminant hepatitis (11)(12)(13)(14)(15)(16), raised concerns about the safety of troglitazone and other members of this class. In the U.K., troglitazone was voluntarily withdrawn from the market, and in the U.S., the Food and Drug Administration (FDA) requested removal of the drug after prescribing information had been revised several times to include stronger warnings and guidelines for extensive monitoring of hepatic function in patients taking troglitazone (6,17,18).…”

Section: Diabetes Care 25:815-821 2002mentioning

confidence: 99%

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

2002

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OBJECTIVE -Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-␥ (PPAR-␥) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class. RESEARCH DESIGN AND METHODS-This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised Ͼ6,000 patients aged 30 -80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6-to 12-week intervals thereafter. Patients with at least one on-therapy ALT value Ͼ3 times the upper limit of the reference range were identified, and their case records examined in detail.RESULTS -At baseline, 5.6% of the patients with type 2 diabetes (mean HbA 1c 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients (ϳ83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value Ͼ3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulintreated 0.40%. The respective rates of ALT values Ͼ3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64.CONCLUSIONS -No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 personyears. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-␥ agonist class effect. Poorly controlled patients with type 2 diabetes may ...

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Section: Diabetes Care 25:815-821 2002mentioning

confidence: 99%

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

2002

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“…Because troglitazone is banned from the US market due to idiosyncratic hepatotoxicity (36) and rosiglitazone treatment is associated with increased in vivo adipogenesis (33), and induction of in vitro lipogenic genes, we used rosiglitazone to test the hypothesis that blockade of FASN would enhance the rosiglitazone anti-tumor effect. As shown in Fig.…”

Section: Combined Rosiglitazone and Fasn Blockers Cerulenin Or Its Anmentioning

confidence: 99%

Thiazolidinediones/PPARÎ³ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

Haddad

2011

Int J Oncol

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Abstract. The prostate cancer (PCa) cell lines LNCaP, PC-3, and DU-145 express peroxisome proliferator-activated receptor Á (PPARÁ) but its role in PCa is unclear. Thiazolidinediones (TZDs), a family of PPARÁ activators and type 2 anti-diabetic drugs, exhibit anti-tumor apoptotic effects in human PCa cell lines. Likewise, pharmacological inhibitors of fatty acid synthase (FASN), a metabolic enzyme highly expressed in PCa, induce apoptosis in prostate and other cancer cells. Here, we show positive correlation between PPARÁ and FASN protein in PCa cell lines and synergism between TZDs and FASN blockers in PCa cell viability reduction and apoptosis induction. Combined TZDs/FASN has enhanced anti-tumor properties in both androgen-dependent LNCaP and androgen-independent PC-3 and DU-145 cells when compared with single drug exposure. Low concentrations (5-10 μM) of the TZD drug rosiglitazone failed to alter cell viability but, paradoxically, upregulated lipogenic genes [PPARÁ, FASN, sterol regulatory element binding protein-1c (SREBP-1c) and acetyl-Co A carboxylase-1 (ACC1)], which diminish the apoptotic effects of rosiglitazone. The mean IC 50 in all cell lines was 45±2 μM for rosiglitazone compared with significantly lower 5±1 μM for rosiglitazone plus the FASN blocker cerulenin, and 10.2±2 μM for rosiglitazone plus the cerulenin synthetic analog C75. The IC 50 for the combined rosiglitazone and FASN blockers contrasts with the relatively higher IC 50 for rosiglitazone (45±2 μM), the TZD drug troglitazone (13±2 μM), cerulenin (32±1 μM), or C75 (26±3 μM) when these drugs were used alone. In summary, this study shows proof-of-principle for combining FASN blockers and TZDs for PCa treatment. IntroductionProstate cancer (PCa) is second to lung cancer as a cause of cancer-related death in American men (1). Multiple preclinical studies show anti-cancer effects of thiazolidinediones (TZDs) PPARÁ agonist ligands (2-6). In contrast, clinical studies suggest that TZDs are largely ineffective as monotherapeutic agents in treating PCa (7). Because cancer cells modify several transduction pathways to achieve continuous progression and survival (8), it is important that multiple drug-strategies are used to achieve effective treatment. Such a strategy should allow for synergistic anti-proliferative effects and/or permit the use of low drug doses that might otherwise be less effective when used as monotherapy (7). For example, the antiproliferative effects of the tyrosine kinase inhibitor gefitinib in A549 lung cancer cells is enhanced with rosiglitazone as the result of rosiglitazone-induced augmentation of PTEN (phosphatase and tensin homolog) expression (9). PTEN inhibits the phosphatidylinositol 3-kinase (PI3-K)-Akt pathway, which is essential for progression of PCa cells. Likewise, the combination of rosiglitazone and the platinum cytotoxic drugs (carboplatin and cisplatin) synergistically inhibit the growth of A549 lung cancer cells compared with single-agent therapy (10). The latter effect appears to be due to down-regulatio...

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“…1 Although only 49 of these liver failure cases were considered to be possibly or probably related to TGZ, 9 the numbers may be higher because of incompleteness of reporting. 1 TGZ treatment was associated with a characteristic hepatocellular injury, 18,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] with rare instances of either a mixed hepatocellular/cholestatic injury or a predominant cholestatic reaction. [36][37][38] The liver injury associated with TGZ is idiosyncratic 39 ; it is unpredictable, neither timenor dose-dependent, 40 and cannot be reproduced in animals.…”

Section: In the Unitedmentioning

confidence: 99%