Thiazolidinediones were developed in Japan and have been available in the United States since March 1997. Today, more than 600,000 people in the United States are being treated with troglitazone. Until recently, troglitazone was the only available member of this group.
Troglitazone
Brand Name Drug: Rezulin, Resulin or Romozin
Troglitazone has been shown to improve peripheral insulin sensitivity (ie, increase peripheral glucose disposal) by an as yet undetermined mechanism. We do know that the drug binds to an intranuclear receptor (PPARgamma), and this complex has been found to function as a transcriptional activator. How PPARgamma activation by troglitazone results in improved insulin sensitivity is not clear.
Troglitazone comes in 200-mg and 400-mg tablets, and patients are started at 200 mg in the morning with food to aid in rapid absorption. Thereafter, the dose can be increased to 400 mg/day and eventually to the maximum of 600 mg/day. The tablets should be given once in the morning, as there is no advantage to dividing the dose.
Troglitazone was initially proven effective in type 2 diabetic patients who already were being treated with insulin. In 1998, troglitazone was approved by the FDA for use as monotherapy in the treatment of type 2 diabetes. Studies in patients already receiving insulin therapy have shown a significant improvement in HgbA1C and a reduction in insulin requirements. A 1.5% reduction in HgbA1C has been reported when troglitazone is added to conventional insulin therapy. Monotherapy has been less effective, with an average decrease in HgbA1C of .9%. Whether used as single or combination therapy, there is a lag time of several weeks for troglitazone to have a glucose-lowering effect and a delay of several months for maximum glucose lowering effect. The drug is not effective in those patients with relative insulinopenia. It is important to use clinical judgment in determining which patients with type 2 diabetes have significant insulin resistance with hyperinsulinemia and therefore are better candidates for troglitazone therapy. Significant reduction in HgbA1C recently has been shown when troglitazone is used in combination therapy with glyburide or metformin.
Adverse effects range from mild peripheral edema and weight gain to recendy reported cases of florid hepatic failure. Weight gain can be seen in many patients, likely secondary to increased insulin sensitivity and improved glycemic control. The cases of hepatotoxicity are more concerning and recendy were detailed in Annals of Internal Medicine. In the initial clinical studies, troglitazone was associated with mild increases in liver function tests (1.9% compared with .6% for placebo) and reversible jaundice. However, there have been at least five cases of troglitazone-induced hepatotoxicity and death in the United States since the drug’s release in 1997.
Despite these events, the incidence of liver disease is rare, and troglitazone remains a useful weapon against type 2 diabetes, particularly in those with significant insulin resistance. The FDA now recommends that patients undergo monitoring of their liver function tests (LFTs) on a monthly basis for the first eight months of use. Over the next four months, LFTs can be monitored every other month and then periodically thereafter. Troglitazone should be stopped with any evidence of significant hepatic impairment or a threefold rise in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.
Recendy, two additional thiazolidinediones have become available. It is hoped that rosiglitazone and pioglitazone will have many of the same insulin-sensitizing effects as troglitazone without the risk of hepatic injury.