Pioglitazone

Pioglitazone
Clinical data
Trade names Actos
AHFS/Drugs.com Monograph
MedlinePlus a699016
License data
Pregnancy
category
  • C
Routes of
administration		 Oral
ATC code A10BG03 (WHO)
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%
Metabolism liver (CYP2C8)
Biological half-life 3–7 hours
Excretion in bile
Identifiers
CAS Number 111025-46-8 YesY
PubChem (CID) 4829
IUPHAR/BPS 2694
DrugBank DB01132 YesY
ChemSpider 4663 YesY
UNII X4OV71U42S YesY
KEGG D08378 YesY
ChEBI CHEBI:8228 YesY
ChEMBL CHEMBL595 YesY
ECHA InfoCard 100.114.441
Chemical and physical data
Formula C19H20N2O3S
Molar mass 356.44 g/mol
3D model (Jmol) Interactive image
Chirality Racemic mixture
  (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Its cardiovascular safety profile compares favorably with that of rosiglitazone, which was withdrawn from some markets after concerns about an increased risk of cardiac events. Pioglitazone has been found to be associated with bladder tumors and has been withdrawn in some countries.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.[2]

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.[3] 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.[4]

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.[5] 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.[5]

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.[6]

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.[7]

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.[8] The PERISCOPE study compared pioglitazone with glimepiride in diabetics; atherosclerotic plaque volume was measured and followed over time. Glimepiride therapy had highly significant progression of plaque volume over time of 0.73 percent. In comparison, pioglitazone had a -0.16 percent regression in plaque volume. This is the first study to show that diabetic therapy slowed progression of atherosclerosis. Therapy with pioglitazone raised HDL, and lowered triglyceride and hsCRP; these are all beneficial effects on risk factors for coronary artery disease; however, to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications.[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]

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.

Pharmacology

Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.[14][15] 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.[16][17]

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.[18]

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. ↑ Details for Actos.
  3. ↑ Actos Label. Last updated November 2013. FDA index page for drug label. Index accessed February 10, 2016
  4. ↑ 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". N. Engl. J. Med. 355 (22): 2297–307. doi:10.1056/NEJMoa060326. PMID 17135584.
  5. 1 2 U.S. National Library of Medicine (2010). "ACTOS (pioglitazone hydrochloride) tablet". National Institutes of Health. Retrieved 24 December 2012.
  6. ↑ 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.
  7. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1271-1272.
  8. ↑ Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (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.
  9. ↑ Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochelliere R, et al. (2008). "Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes". JAMA. 299 (13): 1561–73. doi:10.1001/jama.299.13.1561. PMID 18378631.
  10. ↑ http://www.lefigaro.fr/flash-actu/2011/06/09/97001-20110609FILWWW00505-info-le-figaro-lantidiabetique-actos-retire-du-marche.php.
  11. ↑ http://www.medical-reference.net/2011/12/france-and-germany-suspended-use-of.html | France and Germany Suspended Use of Actos for Bladder Cancer Risk|
  12. ↑ Topham, James (June 10, 2011). "UPDATE 2-Germany joins France in suspending top Takeda drug". Reuters.
  13. ↑ FDA August 4, 2011. FDA Drug Safety Communication: Updated drug labels for pioglitazone-containing medicines.
  14. ↑ Gillies, PS; Dunn, CJ (August 2000). "Pioglitazone". Drugs. 60 (2): 333–43; discussion 344–5. doi:10.2165/00003495-200060020-00009. PMID 10983737.
  15. ↑ Smith U (September 2001). "Pioglitazone: mechanism of action". Int J Clin Pract Suppl (121): 13–8. PMID 11594239.
  16. ↑ 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" (PDF). Am. J. Physiol. Endocrinol. Metab. 286 (2): E252–60. doi:10.1152/ajpendo.00424.2003. PMID 14570702.
  17. ↑ Paddock, ML; Wiley, SE; Axelrod, HL; Cohen, AE; Roy, M; Abresch, EC; Capraro, D; Murphy, AN; et al. (September 2007). "MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone". Proc. Natl. Acad. Sci. U.S.A. 104 (36): 14342–7. doi:10.1073/pnas.0707189104. PMC 1963346Freely accessible. PMID 17766440.
  18. ↑ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315951.htm FDA approves first generic Actos to treat type 2 diabetes


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