[The development of thiazolidinedione drugs as anti-diabetic agents]

Thiazolidinedione drugs which increase insulin sensitivity are attracting attention of diabetologists. The first drug, ciglitazone ameliorated hyperglycemia in animal models of obese type 2 diabetes such as KKAy mice, but the effect was too weak for clinical application. The first clinical drug troglitazone was approved and marketed in 1997, and the second drug pioglitazone in 1999. Troglitazone was designed to combine tocopherol, anti-peroxidant, and thiazolidinedione. Plasma glucose is lowered in type 2 diabetic patients by troglitazone or pioglitazone alone or in combination with sulfonylureas. The decrease in glycemia is accompanied with the decrease in plasma insulin, suggesting that the effect is mediated by the improvement of insulin sensitivity. Other new thiazolidinedione drugs such as rosiglitazone are in development. Rare but severe hepatic injury occasionally leading to death has been noticed after several months of clinical application of troglitazone. Monthly examination of liver enzymes reduced the number of severe hepatotoxicity. The ultimate evaluation of thiazolidinediones awaits more clinical experiences.