Thiazolidinedione

The thiazolidinediones, also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.

Mechanism of action
Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARγ (gamma). The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.

Genes upregulated by PPARγ can be found in the main article on peroxisome proliferator-activated receptors.

By activating PPARγ:
 * Insulin resistance is decreased
 * Adipocyte differentiation is modified
 * VEGF-induced angiogenesis is inhibited
 * Leptin levels decrease (leading to an increased appetite)
 * Levels of certain interleukins (e.g. IL-6) fall
 * Adiponectin levels rise

TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.

Members of the class
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
 * Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to an increased risk of cardiovascular events.
 * Pioglitazone (Actos), France and Germany have suspended the sale of the diabetes drug Actos after a study suggested the drug, also known as pioglitazone, could raise the risk of bladder cancer.
 * Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.

Experimental agents include MCC-555, an antidiabetic agent, rivoglitazone, and the early non-marketed thiazolidinedione ciglitazone.

Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a rhodanine.

Uses
The only approved use of the thiazolidinediones is in diabetes mellitus type 2.

It is being investigated experimentally in polycystic ovary syndrome (PCOS), non-alcoholic steatohepatitis (NASH), psoriasis, autism, ovarian hyperstimulation syndrome (by VEGF inhibition in granulosa cells) and other conditions.

Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of the protection against initial stages of the breast carcinoma development.

Side effects and contraindications
The withdrawal of troglitazone has led to concerns of the other thiazolidinediones also increasing the incidence of hepatitis and potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, rosiglitazone and pioglitazone have been free of this problem.

The main side effect of all thiazolidinediones is water retention, leading to edema, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (NYHA grade III or IV heart failure).

Though recent studies have shown there may be an increased risk of coronary heart disease and heart attacks with rosiglitazone, pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progression.

Preliminary data from a 10-year epidemiological study from Takeda Pharmaceutical Company indicated a possible link between pioglitazone (Actos) and bladder cancer. The findings prompted the FDA to order safety reviews for the drug in September 2010.