Thiazolidinedione hepatotoxicity: a class effect?

Type 2 diabetes mellitus, which affects approximately 7% of the population, is a disease of relative insulin insufficiency manifested by insulin resistance in skeletal muscle, liver and adipose tissue. This results in increased hepatic glucose production with compensatory hyperinsulinaemia. The secondary hyperinsulinaemia is associated with an increased incidence of hepatocellular carcinoma and non-alcoholic steatohepatitis (NASH). It is estimated that insulin resistance is present in 50-70% of patients with NASH and that the incidence of NASH in type 2 diabetes is 60-80%. The prevalence of cirrhosis in established type 2 diabetes is as high as 10% and the prevalence of hepatitis C is 3-11%. It was in this setting that the insulin sensitisers were developed. The thiazolidinediones represent a significant and unique pharmacological breakthrough for the management of type 2 diabetes mellitus. The first of the drugs, troglitazone, proved to be hepatotoxic and has been withdrawn from the market. Two cases of hepatotoxicity of rosiglitazone have been reported. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. However, it appears that the incidence of hepatotoxicity of rosiglitazone is much lower than that of troglitazone. It is not yet known if any hepatotoxicity occurs with pioglitazone.