Thiazolidinedione

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The thiazolidinediones /a.zoldinda.on/, 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.
Contents
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1 Mechanism of action

o o

1.1 PPAR transactivation 1.2 PPAR transrepression

2 Members of the class 3 Uses 4 Side effects and contraindications 5 Footnotes

Mechanism of action[edit]
Thiazolidinediones or TZDs act by activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptors, with greatest specificity for PPAR (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.

PPAR transactivation[edit]

Thiazolidinedione ligand dependent transactivation is responsible for the majority of anti-diabetic effects.

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 PPAR):

Insulin resistance is decreased

Adipocyte differentiation is modified[1] VEGF-induced angiogenesis is inhibited[2] Leptin levels decrease (leading to an increased appetite) Levels of certain interleukins (e.g. IL-6) fall Antiproliferative action[citation needed] 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.[3]

PPAR transrepression[edit]

Thiazolidinedione ligand dependent transrepression mediates the majority of anti-inflammatory effects.

Binding of PPAR to coactivators appears to reduce the levels of coactivators available for binding to pro inflammatory transcription factors such as NF-B, this causes a decrease in transcription of a number of pro inflammatory genes, including various interleukins and tumour necrosis factors.

Members of the class[edit]

The chemical structure of thiazolidinedione

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. [4]

Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of druginduced hepatitis.

Experimental agents include netoglitazone, 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[edit]
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] lichen planopilaris, 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.

Side effects and contraindications[edit]

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]

Footnotes[edit]
1. Jump up^ Waki H, Yamauchi T, Kadowaki T (February 2010). "[Regulation of differentiation and hypertrophy of adipocytes and adipokine network by PPARgamma]". Nippon Rinsho (in Japanese) 68 (2): 2106. PMID 20158086. 2. Jump up^ Panigrahy D, Singer S, Shen LQ, et al. (2002). "PPAR ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis". J. Clin. Invest. 110 (7): 923 32.doi:10.1172/JCI15634. PMC 151148. PMID 12370270. 3. 4. 5. Jump up^ NHS: Avandia diabetes drug suspended, Friday 24 September 2010 Jump up^ http://www.huliq.com/3257/diabetes-drug-actos-sales-suspended-france-and-germany Jump up^ Belfort R, Harrison SA, Brown K, et al. (November 2006). "A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis". N. Engl. J. Med. 355 (22): 2297 307.doi:10.1056/NEJMoa060326. PMID 17135584. Clinical trial info 6. Jump up^ Krentz AJ, Friedmann PS (March 2006). "Type 2 diabetes, psoriasis and thiazolidinediones". Int. J. Clin. Pract. 60 (3): 3623. doi:10.1111/j.1368-5031.2005.00765.x.PMID 16494655. 7. Jump up^ Boris et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children, Journal of Neuroinflammation 2007,4:3 [1] 8. Jump up^ Shah DK, Menon KM, Cabrera LM, Vahratian A, Kavoussi SK, Lebovic DI (April 2010). "Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro". Fertil. Steril. 93 (6): 2042 7. doi:10.1016/j.fertnstert.2009.02.059. PMC 2847675. PMID 19342033. 9. Jump up^ Clinical Trials for Rosiglitazone - from ClinicalTrials.gov, a service of the U.S. National Institutes of Health 10. Jump up^ "Avandia to Carry Stronger Heart Failure Warning - Forbes.com". Archived from the original on 2007-10-21. Retrieved 2007-08-15. 11. Jump up^ Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A (July 2004). "The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce

cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients". Diabetes Care 27 (7): 164753. doi:10.2337/diacare.27.7.1647.PMID 15220241. 12. Jump up^ Mannucci E, Monami M, Lamanna C, Gensini GF, Marchionni N (May 2008). "Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials".Diabetes Obes Metab 0 (12): 122138. doi:10.1111/j.1463-1326.2008.00892.x. PMID 18505403. 13. Jump up^ Nissen SE, Nicholls SJ, Wolski K, et al. (April 2008). "Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial". JAMA 299 (13): 156173. doi:10.1001/jama.299.13.1561. PMID 18378631. 14. Jump up^ Cohen, Andrew; Atonu Rabbani, Nilay Shah and G. Caleb Alexander (April 2010). "Changes in Glitazone Use Among Office-Based Physicians in the U.S., 20032009". Diabetes Care 33 (4): 823 825. doi:10.2337/dc09-1834. PMC 2845035. PMID 20103549. Retrieved 11/10/2011. 15. Jump up^ Peck, Peggy (September 17, 2010). "FDA Says It Will Review Pioglitazone Safety". MedPage Today. Retrieved 18 September 2010.

Oral anti-diabetic drugs and Insulin analogs (A10)

Metformin#

Buformin Biguanides
Insulin Sensitizers

Phenformin Pioglitazone

TZDs/"glitazones" (PPAR)

Rivoglitazone

Rosiglitazone

Troglitazone

Aleglitazar Dual PPAR agonists

Muraglitazar

Saroglitazar

Tesaglitazar

1st generation: Acetohexamide

Carbutamide

Chlorpropamide

Metahexamide

Tolbutamide Tolazamide

2nd generation: Glibenclamide (Glyb

Glibornuride Sulfonylureas
Secretagogues K+ ATP

Meglitinides/"glinides"

Glipizide

Gliquidone

Glisoxepide

Glyclopyramide

Glimepiride

Gliclazide Nateglinide


Exenatide

Repaglinide

Mitiglinide

Liraglutide

Taspoglutide GLP-1 agonists

DPP-4 inhibitors

Albiglutide

Lixisenatide Alogliptin

Anagliptin

Gemigliptin

Linagliptin

Saxagliptin

Sitagliptin

Teneligliptin

Vildagliptin

1 Fasiglifam GPR40 Free fatty acid receptor

Analogs/other insulins fast-acting (Insulin lispro

Insulin aspart

Insulin glulisine)

short-acting (Regular insulin)

long-acting (Insulin glargine

Insulin detemir

NPH insulin) ultra-long-acting (Insulin degludec)

inhalable Exubera

Acarbose

Miglitol Alpha-glucosidase inhibitors

Voglibose

Pramlintide Amylin analog

Other Canagliflozin

Dapagliflozin

SGLT2 inhibitors

Empagliflozin

Other

Remogliflozin

Sergliflozin

Tofogliflozin Benfluorex

Tolrestat