The thiazolidinediones are a relatively new family of agents for type 2 diabetes that act by increasing insulin sensitivity through a unique mechanism of engagement of the so-called peroxisome proliferator-activated receptor gamma, PPAR-γ. Attachment of ligand to the PPAR-γ receptor activates a series of genes that are involved in glucose and fatty acid metabolism, the overall effect being an increase in insulin effect. The thiazolidinediones reduce blood glucose levels in patients with type 2 diabetes and act additively with other antidiabetic medications. Troglitazone was the first thiazolidinedione that received approval for use in the United States (January 1997). However, within a year of its approval, reports of severe liver injury and deaths from acute liver failure began to appear. Cautionary statements and recommendations for monitoring of ALT levels were made, but after more than two dozen reports of hepatic failure and the introduction of two new thiazolidinediones in 1999, troglitazone was withdrawn from use in 2000. The newer thiazolidinediones, rosiglitazone and pioglitazone, have been associated with only rare instances of acute liver injury. Both rosiglitazone and pioglitazone are linked to increased weight gain, heart failure and fracture risk and they are considered second-line agents for type 2 diabetes and recommended only after failure of metformin and lifestyle modifications.
All references on hepatotoxicity of the thiazolidinediones are given together at the end of this Overview section (updated June 2018). Representative cases are given in the records of specific agents.
Drug Class: Antidiabetic Agents