Abstract
A thiazolidinedione derivative, troglitazone, which binds peroxysome proliferator-activated receptor γ (PPARγ) to improve insulin resistance, was introduced into the market in 1997 as the first agent to improve insulin resistance in type2 diabetes mellitus. However, this agent caused severe hepatic dysfunction and was withdrawn from the market in 2003. Causes for severe hepatic dysfunction by troglitazone have not yet been fully understood. Based on the clinical course, the lack of eruption, fever and eosinophia hepatic dysfunction is thought to be caused not by allergic reactions but by drug idiosyncracy. It has been reported that the combined null genotype of glutathione-S-transferase (GST) theta 1 and GST mu 1 are more prevalent among patients of hepatic dysfunction caused by troglitazone than among those who showed no hepatic abnormality. Pioglitazone, another thiazolidinedione derivative on the market, has been shown not to cause hepatic failure in a large-scale postmarketing surveillance study of more than 20,000 patients. Rosiglitazone, a thiazolidinedione derivative, has been reported to increase myocardial infarction compared with other hypoglycaemic agents or placebo by meta-analyses. Both rosiglitazone and pioglitazone increase the incidence of congestive heart failure presumably by increasing sodium and water retention.
