Mechanism of action
Thiazolidinediones or TZDs act by activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptors, with greatest specificity for PPARγ (gamma). The endogenous ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor binds to DNA in complex with the retinoid X receptor (RXR), another nuclear receptor, increasing transcription of a number of specific genes and decreasing transcription of others.
The activated PPAR/RXR heterodimer binds to peroxisome proliferator hormone response elements upstream of target genes in complex with a number of coactivators such as nuclear receptor coactivator 1 and CREB binding protein, this causes upregulation of genes (for a full list see 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
- Antiproliferative action
- 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.
Binding of PPARγ to coactivators appears to reduce the levels of coactivators available for binding to pro-inflammatory transcription factors such as NF-κB, this causes a decrease in transcription of a number of pro inflammatory genes, including various interleukins and tumour necrosis factors.
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- Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions.
- Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.
- Lobeglitazone (Duvie), approved for use in Korea
- Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.
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), psoriasis, autism, ovarian hyperstimulation syndrome (by VEGF inhibition in granulosa cells), lichen planopilaris, 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 protection against the initial stages of 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 older studies suggested 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. These studies led to a period of Food and Drug Administration advisories (2007 - 2013) that, aided by extensive media coverage, led to a substantial decrease in rosiglitazone use. In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease.  The new recommendations were largely based on the reasoning that prior meta-analyses leading to the original restrictions were not designed to assess cardiac outcomes and, thus, not uniformly collected or adjudicated. In contrast, one of the largest trials (RECORD trial) that was specifically designed to assess cardiac outcomes found no increased risk of myocardial infarction with rosiglitazone use, even after independent re-evaluation for FDA review.
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.
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