Chemistry:Pioglitazone

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Short description: Chemical compound
Pioglitazone
Pioglitazone.svg
Pioglitazone ball-and-stick model.png
Clinical data
Trade namesActos, others
AHFS/Drugs.comMonograph
MedlinePlusa699016
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
Drug classThiazolidinedione
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [1]
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding>99%
Metabolismliver (CYP2C8)
Elimination half-life3–7 hours
Excretionin bile
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H20N2O3S
Molar mass356.44 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point183 to 184 °C (361 to 363 °F)
  (verify)

Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes.[2] It may be used with metformin, a sulfonylurea, or insulin.[2][3] Use is recommended together with exercise and diet.[3] It is not recommended in type 1 diabetes.[3] It is taken by mouth.[3]

Common side effects include headaches, muscle pains, inflammation of the throat, and swelling.[3] Serious side effects may include bladder cancer, low blood sugar, heart failure, and osteoporosis.[3][2] Use is not recommended in pregnancy or breastfeeding.[2] It is in the thiazolidinedione (TZD) class and works by improving sensitivity of tissues to insulin.[2]

Pioglitazone was patented in 1985, and came into medical use in 1999.[4] It is available as a generic medication.[2] In 2020, it was the 168th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[5][6] It was withdrawn in France and Germany in 2011.[7][8][9]

Medical uses

Pioglitazone is used to lower blood glucose levels in type 2 diabetes either alone or in combination with a sulfonylurea, metformin, or insulin.[1] The effects of pioglitazone have been compared in a Cochrane systematic review to that of other blood sugar lowering-medicine, including metformin, acarbose, and repaglinide, as well as with appropriate diet and exercise, not showing any benefit in reducing the chance of developing type 2 diabetes in people at risk.[10] It did, however, show reduction of risk of developing type 2 diabetes when compared to a placebo or to no treatment.[10] These results should be interpreted considering that most of the data of the studies included in this review were of low or very-low certainty.

While pioglitazone does decrease blood sugar levels, the main study that looked at the medication found no difference in the main cardiovascular outcomes that were looked at.[11] The secondary outcome of death from all causes, myocardial infarction, and stroke were lower.[11]

Pioglitazone has been found to reduce all-cause mortality in type 2 diabetic patients compared to other therapies, with a 60% reduction in mortality in those exposed to pioglitazone, compared to those never exposed.[12] Another study found an all-cause mortality hazard ratio of 0.33 for pioglitazone after adjusting for >40 covariates, compared to insulin.[13] Due to insufficient data on all-cause mortality, cardiovascular mortality, myocardial infarction and stroke, this was not possible to compare in a more recent review.[10]

Contraindications

Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone, other thiazolidinediones or any of components of its pharmaceutical forms. It is ineffective and possibly harmful in diabetes mellitus type 1 and diabetic ketoacidosis.[1] Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established.[1]

Given previous experiences with the related drug troglitazone, acute diseases of the liver are regarded as a contraindication for pioglitazone.

Side effects

A press release by GlaxoSmithKline in February 2007 noted that there is a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide. The information was based on data from the ADOPT trial. Following release of this statement, Takeda Pharmaceutical Company, the developer of pioglitazone (sold as Actos in many markets) admitted that it has similar implications for female patients.[14]

The risk of hypoglycemia is low in the absence of other drugs that lower blood glucose.

Pioglitazone can cause fluid retention and peripheral edema. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose tissue. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.

Chronic administration of the drug has led to occasional instances of cholestatic hepatitis, reversible upon drug discontinuation.[15]

On July 30, 2007, an Advisory Committee of the Food and Drug Administration concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of "myocardial ischemic events" when compared to placebo, but when compared to other diabetes drugs, there was no increased risk. Pioglitazone is currently being reviewed. A meta-analysis released subsequently showed that pioglitazone reduced the risk of ischemic cardiac events rather than increased the risk, but increased CHF.[16]

A 2020 Cochrane systematic review assessed occurrence of adverse effects with use of pioglitazone, but was not able to reach any conclusions due to insufficient data on included studies.[10]

Bladder cancer

On June 9, 2011, the French Agency for the Safety of Health Products decided to withdraw pioglitazone due to high risk of bladder cancer.[17] 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.[18] 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.[19]

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 two months later the label was updated with an additional warning about this risk.[20][8]

A 2017 meta-analysis found no difference in the rates of bladder cancer attributed to the pioglitazone.[21]

Drug interactions

Combination with sulfonylureas or insulin reciprocally exponentiate risk of hypoglycemia. Therapy with pioglitazone increase the chance of pregnancy in individuals taking oral contraception.

Mechanism of action

Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.[22][23] It modulates the transcription of the genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues, decreases gluconeogenesis in the liver, and reduces quantity of glucose and glycated hemoglobin in the bloodstream.

More recently,[when?] pioglitazone and other active TZDs have been shown to bind to the outer mitochondrial membrane protein mitoNEET with affinity comparable to that of pioglitazone for PPARγ.[24][25]

Leriglitazone is a metabolite.[26]

Society and culture

Economics

In 2008, it generated the tenth-highest amount of money for a medication in the U.S. in 2008, with sales exceeding $2.4 billion.[27]

To 2020, no study has examined the socioeconomic effects of utilization of pioglitazone.[10]

Brand names

Pioglitazone is marketed as Actos in the United States, Canada, the UK and Germany, Glustin in the European Union, Glizone and Pioz in India by Zydus Cadila and USV Limited, respectively and Zactos in Mexico by Takeda Pharmaceuticals. On August 17, 2012, the US FDA announced its approval of the first generic version of Actos.[28]

Research

Psychiatry

Bipolar disorder

Pioglitazone has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder.[29] However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of pioglitazone in the treatment of bipolar depression.[29]

Major depression

There is research that suggests that pioglitazone may be useful for treating major depression.[30]

Other illnesses

Pioglitazone has been found to exert anti-ageing effects in Drosophila.[31]

Because it is thought to reduce inflammatory activity in neuroglia, it was studied in a small clinical trial involving children with autism, under the autoimmune/inflammatory hypotheses of the causes of autism.[32]

Pioglitazone may improve symptoms of psoriasis.[33]

Pioglitazone also showed to be a potential treatment for Alzheimer's disease in preclinical studies, however testing for the efficacy of Pioglitazone has been fraught with failure and confusing results from clinical trials.[34]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Actos- pioglitazone tablet". 25 January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2ddc491-88a9-4063-9150-443b4fa4330c. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 694. ISBN 9780857113382. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Pioglitazone Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/pioglitazone-hydrochloride.html. 
  4. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 450. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA450. Retrieved 2020-09-23. 
  5. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Pioglitazone - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Pioglitazone. 
  7. ↑ Medical Management of Type 2 Diabetes. American Diabetes Association. 2012. p. 63. ISBN 9781580404570. https://books.google.com/books?id=b4osDQAAQBAJ&pg=PA63. Retrieved 2020-09-23. 
  8. ↑ 8.0 8.1 "Update to ongoing safety review of Actos". 18 June 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-ongoing-safety-review-actos-pioglitazone-and-increased-risk. 
  9. ↑ "Update on ongoing European review of pioglitazone–containing medicines". European Medicines Agency (EMA) (Press release). Archived from the original on 22 October 2020. Retrieved 8 November 2020.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews 2020 (11): CD013516. November 2020. doi:10.1002/14651858.CD013516.pub2. PMID 33210751. 
  11. ↑ 11.0 11.1 "Outcomes and lessons from the PROactive study". Diabetes Research and Clinical Practice 98 (2): 175–86. November 2012. doi:10.1016/j.diabres.2012.09.001. PMID 23020930. http://orbi.ulg.ac.be/jspui/handle/2268/132794. Retrieved 2019-09-18. "Since 2005, there has been much debate on the relative value of the statistically non-significant 10% reduction in the quite challenging primary composite endpoint (combining cardiovascular disease-driven and procedural events in all vascular beds) versus the statistically significant 16% decrease in the more robust and conventional main secondary endpoint (all-cause mortality, myocardial infarction, and stroke) observed with pioglitazone.". 
  12. ↑ "Pioglitazone and risk of mortality in patients with type 2 diabetes: results from a European multidatabase cohort study". BMJ Open Diabetes Research & Care 5 (1): e000364. 2017. doi:10.1136/bmjdrc-2016-000364. PMID 28761650. 
  13. ↑ "A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study". Current Medical Research and Opinion 30 (11): 2223–2231. 2014. doi:10.1185/03007995.2014.941054. PMID 24983744. 
  14. ↑ Takeda (March 2007). "Observation of an Increased Incidence of Fractures in Female Patients Who Received Long-Term Treatment with ACTOSO (pioglitazone HOI) Tablets for Type 2 Diabetes Mellitus". https://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM153896.pdf. 
  15. ↑ Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. 2008. pp. 1271–2. 
  16. ↑ "Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials". JAMA 298 (10): 1180–8. September 2007. doi:10.1001/jama.298.10.1180. PMID 17848652. 
  17. ↑ "L'antidiabétique Actos retiré du marché" (in fr). Le Figaro. 9 June 2011. http://www.lefigaro.fr/flash-actu/2011/06/09/97001-20110609FILWWW00505-info-le-figaro-lantidiabetique-actos-retire-du-marche.php. 
  18. ↑ "France and Germany Suspended Use of Actos for Bladder Cancer Risk". Medical-Reference. 1 January 2012. http://www.medical-reference.net/2011/12/france-and-germany-suspended-use-of.html. 
  19. ↑ "UPDATE 2-Germany joins France in suspending top Takeda drug". Reuters. June 10, 2011. https://www.reuters.com/article/takeda-germany-idUSL3E7HA0X920110610. 
  20. ↑ "FDA Drug Safety Communication: Updated drug labels for pioglitazone-containing medicines". U.S. Food and Drug Administration (FDA). 4 August 2011. https://www.fda.gov/Drugs/DrugSafety/ucm266555.htm. 
  21. ↑ "Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis". Diabetes Therapy 8 (4): 705–726. August 2017. doi:10.1007/s13300-017-0273-4. PMID 28623552. 
  22. ↑ "Pioglitazone". Drugs 60 (2): 333–43; discussion 344–5. August 2000. doi:10.2165/00003495-200060020-00009. PMID 10983737. 
  23. ↑ "Pioglitazone: mechanism of action". International Journal of Clinical Practice. Supplement (121): 13–8. September 2001. PMID 11594239. 
  24. ↑ "Identification of a novel mitochondrial protein ("mitoNEET") cross-linked specifically by a thiazolidinedione photoprobe". American Journal of Physiology. Endocrinology and Metabolism 286 (2): E252–60. February 2004. doi:10.1152/ajpendo.00424.2003. PMID 14570702. 
  25. ↑ "MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone". Proceedings of the National Academy of Sciences of the United States of America 104 (36): 14342–7. September 2007. doi:10.1073/pnas.0707189104. PMID 17766440. Bibcode: 2007PNAS..10414342P. 
  26. ↑ Monternier, Pierre-Axel; Singh, Jaspreet; Parasar, Parveen; Theurey, Pierre; DeWitt, Sheila; Jacques, Vincent; Klett, Eric; Kaur, Navtej et al. (July 2022). "Therapeutic potential of deuterium-stabilized ( R )-pioglitazone— PXL065 —for X-linked adrenoleukodystrophy". Journal of Inherited Metabolic Disease 45 (4): 832–847. doi:10.1002/jimd.12510. PMID 35510808. 
  27. ↑ "Details for Actos". Drug Patent Watch. http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=ACTOS. 
  28. ↑ "FDA approves first generic Actos to treat type 2 diabetes" (Press release). U.S. Food and Drug Administration (FDA). 17 August 2012. Archived from the original on 4 January 2016.
  29. ↑ 29.0 29.1 "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research 143: 230–238. September 2021. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090. 
  30. ↑ "Pioglitazone could induce remission in major depression: a meta-analysis". Neuropsychiatric Disease and Treatment 13: 9–16. 2017. doi:10.2147/NDT.S121149. PMID 28031713. 
  31. ↑ "Pioglitazone: an anti-diabetic compound with anti-aging properties". Biogerontology 8 (6): 639–51. December 2007. doi:10.1007/s10522-007-9105-7. PMID 17628757. https://escholarship.org/content/qt38j292g2/qt38j292g2.pdf?t=pgp1pw. 
  32. ↑ "Pharmacotherapy to control behavioral symptoms in children with autism". Expert Opinion on Pharmacotherapy 13 (11): 1615–29. August 2012. doi:10.1517/14656566.2012.674110. PMID 22550944. 
  33. ↑ "Lipid disturbances in psoriasis: an update". Mediators of Inflammation 2010: 535612. 2010. doi:10.1155/2010/535612. PMID 20706605. 
  34. ↑ "Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease". Aging and Disease 12 (8): 1964–1976. December 2021. doi:10.14336/AD.2021.0719. PMID 34881080. 

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