The thiazolidinediones ( /θaɪ.əˌzoʊlɨdiːnˈdaɪ.oʊn/), 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.
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Thiazolidinediones or TZDs act by activating 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:
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.[3]
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
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.
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),[5] psoriasis,[6] autism,[7] ovarian hyperstimulation syndrome (by VEGF inhibition in granulosa cells)[8] and other conditions.[9]
Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of protection against the initial stages of breast carcinoma development.
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,[10] pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progression.[11][12][13] These studies led to a period of Food and Drug Administration advisories (in February 2007) that, along with scientific publications and media exposure, were associated with a substantial decrease in rosiglitazone use. Despite a class-level FDA advisory, pioglitazone use was not similarly affected. [14]
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.[15]
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