|Trade names||Actos, others|
|Elimination half-life||3–7 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||356.44 g/mol g·mol−1|
|3D model (JSmol)|
|Melting point||183 to 184 °C (361 to 363 °F)|
Pioglitazone, sold under the brand name Actos among others, is a medication used to treat diabetes mellitus type 2. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not recommended in diabetes mellitus type 1. It is taken by mouth.
Common side effects include headaches, muscle pains, inflammation of the throat, and swelling. Serious side effects may include bladder cancer, low blood sugar, heart failure, and osteoporosis. Use in not recommended in pregnancy or breastfeeding. It is in the thiazolidinedione (TZD) class and works by improving sensitivity of tissues to insulin.
Pioglitazone was patented in 1985 and came into medical use in 1999. It is available as a generic medication. A month supply in the United Kingdom costs the NHS less than £1 as of 2019. In the United States the wholesale cost of this amount is about 3.20 USD. In 2016 it was the 116th most prescribed medication in the United States with more than 6 million prescriptions. It was withdrawn in France and Germany in 2011.
Pioglitazone is used to lower blood glucose levels in diabetes mellitus type 2 (T2DM) either alone or in combination with a sulfonylurea, metformin, or insulin. 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. The secondary outcome of death from all causes, myocardial infarction, and stroke were lower.
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. Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established.
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.
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.
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.
On June 9, 2011 the French Agency for the Safety of Health Products decided to withdraw pioglitazone due 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 two months later the label was updated with an additional warning about this risk.
A 2017 meta-analysis of diabetes found no difference in the rates of bladder cancer attributed to the pioglitazone.
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Mechanism of action
Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. 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.
Society and culture
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.
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.
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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.
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