Troglitazone was the first thiazolidinedione approved for use in the United States and was licensed for use in type 2 diabetes in 1997, but withdrawn 3 years later because of the frequency of liver injury including acute liver failure associated with its use.
Troglitazone (troe gli' ta zone) is an insulin sensitizing agent thought to act by engagement of PPAR-γ receptors which induce multiple genes involved in glucose and fatty acid metabolism. In clinical trials, troglitazone was found to lower blood glucose and HbA1c levels and had additive effects with the sulfonylureas and metformin. Troglitazone was approved for use in the United States in 1997 to be used alone or in combination with other antidiabetic medications. However, reports of severe liver injury and death from acute liver failure began to arise soon after its general availability, and it was withdrawn from use in 2000. Troglitazone was sold under the brand name Rezulin and was available in 400 mg tablets. The recommended dosage was 400 to 800 mg once daily. Troglitazone was used as monotherapy as well as in combination with metformin, sulfonylureas or insulin.
Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients. These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations >10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice. Soon after the approval of troglitazone as therapy for type 2 diabetes in the United States, cases of severe acute liver injury began to be reported, and dramatic case reports as well as small case series documented that clinically significant injury was occurring in 1:1000 to 1:10,000 recipients. The latency to onset of injury was typically 1 to 6 months and the onset was marked by fatigue, weakness, dark urine and jaundice, and an acute hepatitis-like elevation in serum enzymes (hepatocellular pattern). Allergic phenomena (rash, fever, eosinophilia) were uncommon and serum autoantibodies were not usually present. Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis. At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000.
Mechanism of Injury
The mechanism of liver injury due to troglitazone is unknown. Signs and symptoms of allergic and immune reactivity are rare and a metabolic defect in its metabolism is suspected to be the cause. Troglitazone is a potent inducer of CYP 3A4 and has a distinctive alpha tocopherol (vitamin E-like) side chain which can be metabolized to a highly active quinolone-like metabolite, which may account for its occasional aberrant metabolism and hepatotoxicity.
Outcome and Management
The liver injury from troglitazone can be severe and even fatal. In several cases there was incomplete recovery at the time of the last follow up evaluation, suggesting that the injury can become chronic in some instances. Prednisone has been reported to have a beneficial effect, but only in anecdotal reports. While several patients with mild troglitazone liver injury were later treated with other thiazolidinediones without recurrence of injury, other patients have developed worsening liver injury; switching therapy to other thiazolidinediones is inadvisable and, if done, should be with careful monitoring of serum aminotransferase levels.
References to safety and hepatotoxicity of troglitazone are given together with references to the related agents in the Overview section on the Thiazolidinediones.
Drug Class: Antidiabetic Agents
Other Drugs in the Subclass, Thiazolidinediones: Pioglitazone, Rosiglitazone
Case 1. Acute hepatitis arising after 4 months of troglitazone therapy.
|Medication:||Troglitazone (20 mg/day for 18 weeks)|
|Severity:||3+ (jaundice and hospitalization)|
|Other medications:||Aspirin (81 mg daily), vitamin E (5000 U/day), pravastatin (20 mg/day), glipizide (5 mg/day)|
|Time After Starting||Time After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|18 weeks||0||1961||213||13.2||GGT 168 U/L; protime normal|
|20 weeks||2 weeks||358||168||36.9|
|6 months||6 weeks||218||146||13.9|
|10 months||6 months||Normal||Normal||Normal|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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