Тиазолидиндиондар: 2 типті қант диабетін емдеу және зерттелудегі қолданыстары

Class of chemical compounds

The thiazolidinediones /θ//aɪ//.//ə/,/z//oʊ//l//ᵻ//d//iː//n/'/d//aɪ//.//oʊ//n/, abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five membered C3NS ring. The term usually refers to a family of drugs used in the treatment of diabetes mellitus type 2 that were introduced in the late 1990s.

Thiazolidinediones or TZDs act by activating PPARs (peroxisome proliferator activated receptors), a group of nuclear receptors, specific for PPARγ (PPAR gamma, PPARG). They are thus the PPARG agonists subset of PPAR agonists. 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 main effect of expression and repression of specific genes is an increase in the storage of fatty acids in adipocytes, thereby decreasing the amount of fatty acids present in circulation. As a result, cells become more dependent on the oxidation of carbohydrates, more specifically glucose, in order to yield energy for other cellular processes.

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.

The only approved use of the thiazolidinediones is in diabetes mellitus type 2. According to a 2014 Cochrane systematic review of four randomized controlled trials, PPARγ agonists may be effective in preventing further strokes in those who have already had a stroke or a transient ischemic attack (TIA) and may stabilize atherosclerotic plaques in the carotid arteries.

Experimental investigations on TZDs have been carried out since 2005 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. Evidence was emerging in 2008 that vitamin E with thiazolidinediones is effective in the treatment of non alcoholic steatohepatitis due to their combined antioxidant and insulin sensitizing effects, producing histological improvements in steatosis severity. Thiazolindinediones induce adipogenesis in subcutaneous fat deposits by activating PPARγ receptors. This effect has been used in transgender patients to shift body fat distribution towards a more gynoid pattern.

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. A 2013 meta analysis concluded that use of pioglitazone is associated with a slightly higher risk of bladder cancer compared to the general population. The authors of the same analysis recommended that other blood sugar lowering agents be considered in people with other risk factors for bladder cancer such as cigarette smoking, family history, or exposure to certain forms of chemotherapy. A 2020 Cochrane systematic review did not find enough evidence of reduction of all cause mortality, serious adverse events, cardiovascular mortality, non fatal myocardial infarction, non fatal stroke or end stage renal disease when comparing metformin monotherapy to Thiazolidinedione for treatment of type 2 diabetes. Thiazolidinediones reduce bone mineral density and increase the risk of fractures in women, possibly as a result of biasing the differentiation of bone marrow stromal cells away from osteoblast differentiation and toward adipocyte formation.