Pioglitazone

Pioglitazone
Clinical data
Trade names Actos
AHFS/Drugs.com Monograph
MedlinePlus a699016
License data
Pregnancy
category
  • C
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%
Metabolism liver (CYP2C8)
Elimination half-life 3–7 hours
Excretion in bile
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.114.441 Edit this at Wikidata
Chemical and physical data
Formula C19H20N2O3S
Molar mass 356.44 g/mol
3D model (JSmol)
Chirality Racemic mixture
Melting point 183 to 184 °C (361 to 363 °F)
  (verify)

Pioglitazone (brand name Actos) is a prescription drug of the thiazolidinedione (TZD) class with hypoglycemic (antihyperglycemic, antidiabetic) action to treat diabetes. While pioglitazone does decrease blood sugar levels, studies on the main cardiovascular outcomes have not yielded statistically significant results.[1]

Its cardiovascular safety profile compares favorably with that of rosiglitazone, which was withdrawn from some markets after concerns about an increased risk of cardiac events. Pioglitazone has been found to be associated with bladder tumors.[2] It has been withdrawn in some countries.

Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion.[3]

Medical uses

Pioglitazone is used to lower blood glucose levels in the treatment of diabetes mellitus type 2 (T2DM) either alone or in combination with a sulfonylurea, metformin, or insulin.[4]

The main study that looked at the medication, however, found no statistically significant difference in the main cardiovascular outcomes that were looked at.[1] The secondary outcome of death from all causes, myocardial infarction, and stroke were lower.[1]

Pioglitazone has also been used to treat non-alcoholic steatohepatitis (fatty liver), but this use is presently considered experimental.[5]

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.[6] Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established.

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

Pioglitazone and all other drugs of its class (thiazolidinediones) are absolutely contraindicated in patients with heart failure.[6]

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.[7]

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.[8]

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.[9]

Bladder cancer

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.[10] 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.[11] 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.[12]

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.[13]

A 2017 meta-analysis of diabetes found no difference in the rates of bladder cancer attributed to the pioglitazone.[14]

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.[15][16] 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, 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.[17][18]

Society and culture

Brand names

Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe, 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.[19]

Research

There is tentative research that suggests that pioglitazone may be useful for treating major depression.[20]

Because it is thought to reduce glial cell activity, it was studied in a small clinical treat in children with autism, under the autoimmune/inflammatory hypotheses of the cause of autism.[21]

References

  1. 1 2 3 Scheen AJ (November 2012). "Outcomes and lessons from the PROactive study". Diabetes Research and Clinical Practice. 98 (2): 175–86. doi:10.1016/j.diabres.2012.09.001. PMID 23020930. 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.
  2. Office of the Commissioner. "Safety Alerts for Human Medical Products - Pioglitazone-containing Medicines: Drug Safety Communication - Updated FDA Review, Increased Risk of Bladder Cancer". United States Food and Drug Administration. Retrieved 14 December 2016.
  3. "Details for Actos". Drug Patent Watch.
  4. "ACTOS (pioglitazone) Prescribing Information" (PDF). United States Food and Drug Administration. November 2013.
  5. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, et al. (November 2006). "A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis". The New England Journal of Medicine. 355 (22): 2297–307. doi:10.1056/NEJMoa060326. PMID 17135584.
  6. 1 2 U.S. National Library of Medicine (2010). "ACTOS (pioglitazone hydrochloride) tablet". National Institutes of Health. Retrieved 24 December 2012.
  7. 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" (PDF). Retrieved 2012-04-04.
  8. Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1271–1272.
  9. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (September 2007). "Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials". JAMA. 298 (10): 1180–8. doi:10.1001/jama.298.10.1180. PMID 17848652.
  10. "L'antidiabétique Actos retiré du marché" [Actos antidiabetic withdrawn from the market]. Le Figaro (in French). 9 June 2011.
  11. Alam II (1 January 2012). "France and Germany Suspended Use of Actos for Bladder Cancer Risk". Medical-Reference.
  12. Topham, James (June 10, 2011). "UPDATE 2-Germany joins France in suspending top Takeda drug". Reuters.
  13. "FDA Drug Safety Communication: Updated drug labels for pioglitazone-containing medicines". United States Food and Drug Administration. 4 August 2011.
  14. Filipova E, Uzunova K, Kalinov K, Vekov T (August 2017). "Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis". Diabetes Therapy. 8 (4): 705–726. doi:10.1007/s13300-017-0273-4. PMC 5544610. PMID 28623552.
  15. Gillies PS, Dunn CJ (August 2000). "Pioglitazone". Drugs. 60 (2): 333–43, discussion 344-5. doi:10.2165/00003495-200060020-00009. PMID 10983737.
  16. Smith U (September 2001). "Pioglitazone: mechanism of action". International Journal of Clinical Practice. Supplement (121): 13–8. PMID 11594239.
  17. Colca JR, McDonald WG, Waldon DJ, Leone JW, Lull JM, Bannow CA, Lund ET, Mathews WR (February 2004). "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. doi:10.1152/ajpendo.00424.2003. PMID 14570702.
  18. Paddock ML, Wiley SE, Axelrod HL, Cohen AE, Roy M, Abresch EC, Capraro D, Murphy AN, Nechushtai R, Dixon JE, Jennings PA (September 2007). "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. doi:10.1073/pnas.0707189104. PMC 1963346. PMID 17766440.
  19. "FDA approves first generic Actos to treat type 2 diabetes". United States Food and Drug Administration. 17 August 2012. Archived from the original on 4 January 2016.
  20. Colle R, de Larminat D, Rotenberg S, Hozer F, Hardy P, Verstuyft C, Fève B, Corruble E (2017). "Pioglitazone could induce remission in major depression: a meta-analysis". Neuropsychiatric Disease and Treatment. 13: 9–16. doi:10.2147/NDT.S121149. PMC 5182046. PMID 28031713.
  21. Doyle CA, McDougle CJ (August 2012). "Pharmacotherapy to control behavioral symptoms in children with autism". Expert Opinion on Pharmacotherapy. 13 (11): 1615–29. doi:10.1517/14656566.2012.674110. PMID 22550944.
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