Thiazolidinedione

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The thiazolidinediones /θ.əˌzlɨdnˈd.n/, 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.

Mechanism of action[edit]

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.

PPARγ 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 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]

PPARγ transrepression[edit]

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

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[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 meta analyses suggesting an increased risk of cardiovascular events. It was banned in the UK and India in 2010.[4]In New Zealand, rosiglitazone was withdrawn from the market in April 2011.[5]Upon re-evaluation of the not blinded Record study in 2013, the FDA lifted the restrictions.
  • Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested it could raise the risk of bladder cancer.[6]
  • Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced 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.

Side effects and contraindications[edit]

The most frequently reported adverse events in placebo controlled trials were edema, hypoglycemia, and weight gain.[7]

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. The newer thiazolidinediones, rosiglitazone and pioglitazone had a low risk, the same as metformin.

Heart failure and edema[edit]

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).

Both thiazolidinediones increase the risk of heart failure (high strength of evidence) and edema (high strength of evidence).[7]

Heart infarction[edit]

Several meta analyses and systematic reviews suggested an increased risk of coronary heart disease and heart attacks with rosiglitazone in trials and in real life; also an increased risk of heart infarction and mortality in cohort studies against pioglitazone.[8][9][10][11] [12][13]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 2000 a study to address the concerns regarding cardiovascular safety was requested by the EMA. GSK agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed non-inferiority with regard to cardiovascular events and cardiovascular death when the treatment with rosiglitazone was compared with metformin or a sulfonylurea. For myocardial infarction, there was a non-statistically significant increase in risk. In their assessment, the European regulators acknowledged weaknesses of the study, such as an unexpectedly low rate of cardiovascular events and the open-label design, which may lead to reporting bias. They found that the results were inconclusive.[14]In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks. It stated that the availability of recent studies (including the Record trial) has added to the knowledge about rosiglitazone and overall, the accumulated data support an increased cardiovascular risk of rosiglitazone.[15][16] In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease. [17] 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, but not blinded 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.[18] Under the FDA’s instruction, Avandia’s maker, GlaxoSmithKline, had funded the Duke Clinical Research Institute to re-analyze the raw data from the study.[19]

Pioglitazone treatment, in contrast, was not shown to be associated with an increased mortality ; some studies suggest a reduced risk of all-cause and cardiovascular mortality with pioglitazone (low strength of evidence).[7][20]

Fractures[edit]

A meta-analysis of 10 RCTs, involving 13,715 patients and including both rosiglitazone- and pioglitazone-treated patients, showed an overall 45% increased risk of fracture with thiazolidone use compared with placebo or active comparator. It doubled the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes (moderate streght of evidence) [21][7]

Bladder cancer[edit]

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.[22]

On June 9, 2011 the French Agency for the Safety of Health Products decided to withdraw pioglitazone in regards to high risk of bladder cancer.[23] This suspension was based on the results of an epidemiological study conducted by the French National Health Insurance. According to the results of the epidemiological study, the French agency found that patients, who were taking Actos for a long time to aid in type 2 diabetes mellitus, significantly increased risk of bladder cancer compared with patients who were taking other diabetes medications.[24] On June 10, 2011 Germany's Federal Institute for Drugs and Medical Devices also advised doctors not to prescribe the medication until further investigation of the cancer risk had been conducted.[25]

On June 15, 2011 the U.S. FDA announced that pioglitazone use for more than one year may be associated with an increased risk of bladder cancer, and that the information about this risk will be added to the Warnings and Precautions section of the label for pioglitazone-containing medicines. The patient Medication Guide for these medicines will also be revised to include information on the risk of bladder cancer.[26] On 21 July 2011 the European Medicines Agency recommended new contra-indications and warnings for pioglitazone to reduce the small increased risk of bladder cancer; but also concluded the balance remained positive in a limited population of type 2 diabetics. [27]

A 2012 meta analysis found a numerically higher risk of bladder cancer in one trial and a 22% higher risk in three cohort studies.[28] It was criticised because in fact in the Proactive trial from 2005 there was a 2,8% significantly higher risk of bladder cancer, and a numerically higher risk of bladder tumours.[29]Another meta analysis found a modest but clinically significant increased risk of bladder cancer with pioglitazone that appeared related to cumulative dose and duration of exposure. [30]

In 2013 the health ministry of India has suspended the sale of Pioglitazone and all its combinations, after the drug was banned in France, Canada, Australia, New Zealand and Japan.[31]

Weight gain[edit]

Both thiazolidinthiones cause a similar degree of weight gain to that caused by sulfonylureas (moderate strength of evidence).[7]

Eye disorders[edit]

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone.[32]A retrospective cohort study showed an association between the use of thiazolineiones (TZDs) and the incidence of diabetic macular edema (DME). Both use was associated with a 2,3 higher risk at 1 year and at 10 year follow-up, rising to 3 if associated with insulin.[7]

Footnotes[edit]

  1. ^ 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): 210–6. PMID 20158086. 
  2. ^ Panigrahy D, Singer S, Shen LQ, et al. (2002). "PPARγ 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. ^ NHS: Avandia diabetes drug suspended, Friday 24 September 2010
  4. ^ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Retrieved 2013-09-17. 
  5. ^ "Diabetes drug withdrawn". Stuff.co.nz. NZPA. 17 February 2011. Retrieved 5 November 2011. 
  6. ^ http://www.huliq.com/3257/diabetes-drug-actos-sales-suspended-france-and-germany
  7. ^ a b c d e f Jonas, Dan. "Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations Final Original Report Drug Class Reviews". Oregon Health & Science University;. Retrieved 1 April 2014. 
  8. ^ Richter, B; Bandeira-Echtler, E; Bergerhoff, K; Clar, C; Ebrahim, SH (Jul 18, 2007). "Rosiglitazone for type 2 diabetes mellitus.". The Cochrane database of systematic reviews (3): CD006063. doi:10.1002/14651858.CD006063.pub2. PMID 17636824. 
  9. ^ "Avandia to Carry Stronger Heart Failure Warning - Forbes.com". Archived from the original on 2007-10-21. Retrieved 2007-08-15. 
  10. ^ Nissen, SE; Wolski, K (2010 Jul 26). "Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.". Archives of internal medicine 170 (14): 1191–1201. doi:10.1001/archinternmed.2010.207. PMID 20656674. 
  11. ^ Loke, Yoon Kong; Chun Shing Kwok, Sonal Singh. "Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies". BMJ. 2011;342:d1309. doi:10.1136/bmj.d1309. 
  12. ^ Hughes, Sue (27 March 2011). "More damning data on rosiglitazone". theheart.org. Retrieved 6 April 2011. 
  13. ^ Chen, X; Yang, L; Zhai, SD (December 2012). "Risk of cardiovascular disease and all-cause mortality among diabetic patients prescribed rosiglitazone or pioglitazone: a meta-analysis of retrospective cohort studies.". Chinese medical journal 125 (23): 4301–6. PMID 23217404. 
  14. ^ Blind E, Dunder K, de Graeff PA, Abadie E (2011). "Rosiglitazone: a European regulatory perspective". Diabetologia 54 (2): 213–8. doi:10.1007/s00125-010-1992-5. PMID 21153629. 
  15. ^ "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim". European Medicines Agency. 
  16. ^ "Call to 'suspend' diabetes drug". BBC News. 
  17. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm
  18. ^ http://www.ncbi.nlm.nih.gov/pubmed/?term=23895806
  19. ^ Herper, Matthew (6/6/2013). "Avandia Vote Ends An Era Of Drug Safety Scandals". Forbes. Retrieved 31 March 2014. 
  20. ^ 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): 1221–38. doi:10.1111/j.1463-1326.2008.00892.x. PMID 18505403. 
  21. ^ Loke YK, Singh S, Furberg CD (2009). "Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis". CMAJ 180 (1): 32–9. doi:10.1503/cmaj.080486. PMC 2612065. PMID 19073651. 
  22. ^ Peck, Peggy (September 17, 2010). "FDA Says It Will Review Pioglitazone Safety". MedPage Today. Retrieved 18 September 2010. 
  23. ^ "INFO LE FIGARO - L'antidiabétique Actos retiré du marché". 
  24. ^ "France and Germany Suspended Use of Actos for Bladder Cancer Risk". 
  25. ^ Topham, James (June 10, 2011). "UPDATE 2-Germany joins France in suspending top Takeda drug". Reuters. 
  26. ^ "FDA Drug Safety Communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer". 
  27. ^ "European Medicines Agency recommends new contra-indications and warnings for pioglitazone to reduce small increased risk of bladder cancer". EMA. Retrieved 31 March 2014. 
  28. ^ Colmers IN, Bowker SL, Majumdar SR, Johnson JA (2012). "Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis". CMAJ 184 (12): E675–83. doi:10.1503/cmaj.112102. PMC 3447078. PMID 22761478. 
  29. ^ Singh S (July 17, 2012). "A Significantly increased risk of bladder cancer with Pioglitazone in the PROactive trial". CMAJ. 
  30. ^ Turner, RM; Kwok, CS; Chen-Turner, C; Maduakor, CA; Singh, S; Loke, YK (2013 Dec 10). "Thiazolidinediones and associated risk of Bladder Cancer: a Systematic Review and Meta-analysis.". British journal of clinical pharmacology. PMID 24325197. 
  31. ^ "Health ministry bans two drugs Analgin and Pioglitazone; industry protests". The economic times. 
  32. ^ "Pioglitazone SUMMARY OF PRODUCT CHARACTERISTICS". EMA. Retrieved 29 March 2014.