Thiazolidinedione
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The medication class of thiazolidinedione (also called glitazones) was introduced in the late 1990s as an adjunctive therapy for diabetes mellitus (type 2) and related diseases.

Mode 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 normal 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^[1]
• Leptin levels decrease (leading to an increased appetite)
• Levels of certain interleukins (e.g. IL-6) fall
• Adiponectin levels rise

Members of the class

The chemical structure of thiazolidinedione

Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:

• Rosiglitazone (Avandia)
• Pioglitazone (Actos)
• Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.

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

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),^[2] psoriasis,^[3] autism,^[4] and other conditions.^[5]

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^[6] pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progression^[7][8][9].

Footnotes