|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Legal status||POM (UK) ℞-only (US)|
|Mol. mass||356.44 g/mol|
|(what is this?)|
Pioglitazone (Actos) is a prescription drug of the class thiazolidinedione (TZD) with hypoglycemic (antihyperglycemic, antidiabetic) action to treat diabetes. Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion. While pioglitazone does decrease blood sugar levels, studies on the main cardiovascular outcomes has not yielded statistically significant results. Its cardiovascular safety profile compares favorably with rosiglitazone (Avandia), which was withdrawn after concerns about an increased risk of cardiac events. There is an assumption that Pioglitazone is associated with bladder cancer. Pioglitazone has been withdrawn in France and India. In the US and the UK the medicine is sold with a warning on the packet.
- 1 Medical uses
- 2 Contraindications
- 3 Side effects
- 4 Drug interactions
- 5 Mechanism of Action
- 6 Society and culture
- 7 References
- 8 External links
Pioglitazone is used for the treatment of diabetes mellitus type 2 either alone or in combination with a sulfonylurea, metformin, or insulin. There was, however, no statistically significant difference in the main composite outcome studied: death, cardiovascular events and revascularisations, and a higher risk of heart failure in the Proactive trial. There is no conclusive evidence of macrovascular benefit with pioglitazone or any other antidiabetic medication, but metformin. There was no evidence of increased all-cause mortality or cardiovascular mortality found with pioglitazone; some studies suggest reduced risk of all-cause and cardiovascular mortality with pioglitazone (low strength of evidence)
Pioglitazone reduced the urinary albumin–creatinine ratio in 2 trials (by 15% and 19%) over metformin, suggesting less nephropathy (moderate strength of evidence).
- Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone and other thiazolidinediones.
- It is ineffective and possibly harmful in diabetes mellitus type 1. Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established.
- It is contraindicated in diabetic ketoacidosis.
- 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.
- Pioglitazone is contraindicated in current bladder cancer or a history of bladder cancer
Patients receiving pioglitazone in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycaemia. The risk of hypoglycaemia is reduced with thiazolidinediones (TZDs) when compared with sulfonylureas; the risk is similar to the risk with metformin.
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.
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) 
Heart failure and edema
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). Risk of heart failure was 20% higher than control. Numbers needed to harm 1/23. So for 23 people treated with the drug, 1 more should have heart failure against control therapy. It may cause anemia also. A meta-analysis showed that pioglitazone increased CHF. Both thiazolidinediones increase the risk of heart failure (high strength of evidence) and edema (high strength of evidence).
When the drug was approved in 1999, the FDA ordered a 10-year safety study to assess the drug's links to 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. 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. 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.
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.The FDA asked to conduct a clinical cohort study of Pioglitazone and Bladder Cancer in Patients with Diabetes. The study is conducted by Kaiser Permanente Northern California and University of Pennsylvania. The fourth interim analysis (8-Year) report with data from January 1, 1997 to December 31, 2010 has been published. The eight-year interim data from this study show that there is no overall statistically significant increased risk of bladder cancer among patients ever treated with Pioglitazone. But the risk of bladder cancer increased with increasing dose and duration of pioglitazone use and there was a numerically increased risk in people treated longer than 24 month.(Hazard Ratio: 1.4; 95% CI 0.9 to 2.1) 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.
A 2012 meta analysis found a numerically higher risk of bladder cancer in one trial and a 22% higher risk in three cohort studies. 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. 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.
Pioglitazone has been withdrawn in France and India.
April 2014 The U.S District Court in western Louisiana ordered a $6 billion penalty for Takeda Pharmaceutical Company and $3 billion for its business partner and co-defendant Eli Lilly and Company. It also ordered $1.5 million in compensatory damages in favour of the plaintiff. The legal fight turned on whether Actos, which is a drug used to treat type-two diabetes, caused a patient's bladder cancer and by implication was responsible for other cases of the cancer.
In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2–3 kg over one year. Both thiazolidinthiones cause a similar degree of weight gain to that caused by sulfonylureas (moderate strength of evidence).
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. A retrospective cohort study showed an association between the use of thiazolidinediones (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.
60% higher risks of pneumonia and lower respiratory tract infections were observed for pioglitazones compared with other active treatment or placebo. Following adverse events were common: upper respiratory tract infection and bronchitis.
Other adverse events
Following adverse events were common: hypo-aesthesie, joint pain, headache, muscle pain, backpain, erectile dysfunction.
Combination with sulfonylureas, metformin or insulin reciprocally exponentiate risk of hypoglycemia. Therapy with pioglitazone increased risk for pregnancy in those taking oral contraception by lowering the concentration of the contraceptive.
Mechanism of Action
It modulates the transcription of the insulin-sensitive 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; increases the expense of insulin-dependent glucose; decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated hemoglobin in the bloodstream. Although not clinically significant, pioglitazone decreases the level of triglycerides and increases that of high-density lipoproteins (HDL) without changing low-density lipoproteins (LDL) and total cholesterol in patients with disorders of lipid metabolism, although statins are the drug of choice for this.
Society and culture
Takeda is facing more than 3,000 suits alleging Actos caused bladder cancer or other ailments among patients, according to court records and that Takeda officials knew about this dangerous side effect and withheld that information. U.S. District Judge Rebecca Doherty said that officials of Takeda admitted they couldn’t find files compiled by 46 current and former employees involved with the development, marketing and sale of Actos, including those of two directors and that some files were deleted from company computers after executives warned employees to retain Actos-related material.
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.
- "Actos patent expiration date, patent status, and tentative generic approvals | TAKEDA PHARMS USA: pioglitazone hydrochloride".
- Scheen AJ (2012). "Outcomes and lessons from the PROactive study". Diabetes Res. Clin. Pract. 98 (2): 175–86. doi:10.1016/j.diabres.2012.09.001. PMID 23020930.
- "Doctors Concerned as India Suspends Diabetes Drug Pioglitazone". Medscape.
- Isley, William. "Pioglitazone did not reduce macrovascular complications and increased HF in type 2 diabetes with macrovascular disease". Evidence based medecine 11 (April 2006). doi:10.1136/ebm.11.2.47 http://ebm.bmj.com/content/11/2/47.extract
- "DailyMed". The National Library of Medicine.http://connection.ebscohost.com/c/articles/20488278/pioglitazone-did-not-reduce-macrovascular-complications-increased-hf-type-2-diabetes-macrovascular-disease
- 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.
- Bennett, Wendy L.; Maruthur, Nisa M.; Singh, Sonal; Segal, Jodi B.; Wilson, Lisa M.; Chatterjee, Ranee; Marinopoulos, Spyridon S.; Puhan, Milo A.; Ranasinghe, Padmini; Block, Lauren; Nicholson, Wanda K.; Hutfless, Susan; Bass, Eric B.; Bolen, Shari (3 May 2011). "Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations". Annals of Internal Medicine 154 (9): 602. doi:10.7326/0003-4819-154-9-201105030-00336.
- U.S. National Library of Medicine (2010). "ACTOS (pioglitazone hydrochloride) tablet". National Institutes of Health. Retrieved 24 December 2012.
- "Pioglitazone SUMMARY OF PRODUCT CHARACTERISTICS". EMA. Retrieved 29 March 2014.
- "DailyMed". The National Library of Medicine.
- 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.
- 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.
- Isley, William. "Pioglitazone did not reduce macrovascular complications and increased HF in type 2 diabetes with macrovascular disease". Evidence based medecine 11 (April 2006).
- 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.
- "INFO LE FIGARO - L'antidiabétique Actos retiré du marché".
- "France and Germany Suspended Use of Actos for Bladder Cancer Risk".
- Topham, James (June 10, 2011). "UPDATE 2-Germany joins France in suspending top Takeda drug". Reuters.
- "FDA Drug Safety Communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer".
- Kaiser Permanente (2012). Cohort study of Pioglitazone and bladder cancer in patients with diabetes: fourth interim analysis (8-year) report
- "European Medicines Agency recommends new contra-indications and warnings for pioglitazone to reduce small increased risk of bladder cancer". EMA. Retrieved 31 March 2014.
- 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.
- Singh S (July 17, 2012). "A Significantly increased risk of bladder cancer with Pioglitazone in the PROactive trial". CMAJ.
- Turner, RM; Kwok, CS; Chen-Turner, C; Maduakor, CA; Singh, S; Loke, YK (Dec 10, 2013). "Thiazolidinediones and associated risk of Bladder Cancer: a Systematic Review and Meta-analysis.". British journal of clinical pharmacology. PMID 24325197.
- IMS Quarterly MIDAS Data to: Dec 2013
- Singh S, Loke YK, Furberg CD (2011). "Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: systematic review and meta-analysis". Thorax 66 (5): 383–8. doi:10.1136/thx.2010.152777. PMID 21325145.
- Baselt RC (2008). Disposition of toxic drugs and chemicals in man (8th ed.). Foster City, Ca: Biomedical Publications. ISBN 978-0962652370.
- "Pioglitazone drug interactions". Medscape.
- Gillies PS, Dunn CJ (2000). "Pioglitazone". Drugs 60 (2): 333–43; discussion 344–5. doi:10.2165/00003495-200060020-00009. PMID 10983737.
- Smith U (September 2001). "Pioglitazone: mechanism of action". Int J Clin Pract Suppl (121): 13–8. PMID 11594239.
- Colca JR, McDonald WG, Waldon DJ, Leone JW, Lull JM, Bannow CA, Lund ET, Mathews WR (2004). "Identification of a novel mitochondrial protein ("mitoNEET") cross-linked specifically by a thiazolidinedione photoprobe". Am. J. Physiol. Endocrinol. Metab. 286 (2): E252–60. doi:10.1152/ajpendo.00424.2003. PMID 14570702.
- Paddock ML, Wiley SE, Axelrod HL, Cohen AE, Roy M, Abresch EC, Capraro D, Murphy AN, Nechushtai R, Dixon JE, Jennings PA (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 1963346. PMID 17766440.
- Reitman, Valerie (Apr 16, 2013). "Takeda’s Actos Diabetes Drug Tied to Cancer, Jury Is Told". Bloomberg.
- Feeley, Jef (Jan 30, 2014). "Takeda Jury Can Hear Claims Over Destroyed Actos Files". Bloomberg.
- "FDA approves first generic Actos to treat type 2 diabetes".
- Official site
- Pioglitazone FAQ
- U.S. National Library of Medicine: Drug Information Portal - Pioglitazonee