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| Trade names | Actos, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a699016 |
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| Routes of administration | By mouth |
| Drug class | Thiazolidinedione |
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| Pharmacokinetic data | |
| Protein binding | >99% |
| Metabolism | Liver (CYP2C8) |
| Eliminationhalf-life | 3–7 hours |
| Excretion | Bile duct |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.114.441 |
| Chemical and physical data | |
| Formula | C19H20N2O3S |
| Molar mass | 356.44 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
| Melting point | 183 to 184 °C (361 to 363 °F) |
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Pioglitazone, sold under the brand nameActos among others, is ananti-diabetic medication used to treattype 2 diabetes.[3] It may be used withmetformin, asulfonylurea, orinsulin.[3][4] Use is recommended together with exercise and diet.[4] It is not recommended intype 1 diabetes.[4] It is takenby mouth.[4]
Common side effects include headaches, muscle pains, inflammation of the throat, and swelling.[4] Serious side effects may includebladder cancer,low blood sugar,heart failure, andosteoporosis.[4][3] Use is not recommended inpregnancy orbreastfeeding.[3] It is in thethiazolidinedione (TZD) class and works by improving sensitivity of tissues to insulin.[3]
Pioglitazone was patented in 1985, and came into medical use in 1999.[5] It is available as ageneric medication.[3] In 2023, it was the 133rd most commonly prescribed medication in the United States, with more than 4 million prescriptions.[6][7] It was withdrawn in France and Germany in 2011.[8][9][10]
Pioglitazone is used to lower blood glucose levels intype 2 diabetes either alone or in combination withsulfonylurea,metformin, orinsulin.[1] The effects of pioglitazone have been compared in a Cochrane systematic review to that of other blood sugar lowering-medicine, including metformin,acarbose, andrepaglinide, 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.[11] It did, however, show reduction of risk of developing type 2 diabetes when compared to a placebo or to no treatment.[11] 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.[12] The secondary outcome of death from all causes, myocardial infarction, and stroke were lower.[12]
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.[13] Another study found an all-cause mortalityhazard ratio of 0.33 for pioglitazone after adjusting for >40 covariates, compared to insulin.[14] 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.[11]
Pioglitazone cannot be used in patients with a knownhypersensitivity to pioglitazone, otherthiazolidinediones or any of the components of itspharmaceutical forms. It is ineffective and possibly harmful indiabetes mellitus type 1 anddiabetic ketoacidosis.[1] Its safety in pregnancy,lactation (breastfeeding) and people under 18 is not established.[1]
Given previous experiences with the related drugtroglitazone, acute diseases of the liver are regarded as acontraindication for pioglitazone.[medical citation needed]
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 givenrosiglitazone 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.[15]
The risk ofhypoglycemia is low in the absence of other drugs that lower blood glucose.[medical citation needed]
Pioglitazone can causefluid retention and peripheraledema. As a result, it may precipitatecongestive heart failure (which worsens with fluid overload in those at risk). It may causeanemia. Mild weight gain is common due to increase in subcutaneousadipose tissue. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.[medical citation needed]
Chronic administration of the drug has led to occasional instances ofcholestatic hepatitis, reversible upon drug discontinuation.[16]
On 30 July 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. Ameta-analysis released subsequently showed that pioglitazone reduced the risk of ischemic cardiac events rather than increased the risk, but increasedCHF.[17]
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.[11]
On 9 June 2011, theFrench Agency for the Safety of Health Products decided to withdraw pioglitazone due to high risk ofbladder cancer.[18] 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.[19] On 10 June 2011, Germany'sFederal Institute for Drugs and Medical Devices also advised doctors not to prescribe the medication until further investigation of the cancer risk had been conducted.[20]
On 15 June 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.[21][9]
A 2017 meta-analysis found no difference in the rates of bladder cancer attributed to pioglitazone.[22]
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Combination withsulfonylureas orinsulin reciprocally exponentiate risk ofhypoglycemia. Therapy with pioglitazone increases the chance of pregnancy in individuals taking oral contraception.
Pioglitazone selectively stimulates thenuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extentPPAR-α.[23][24] It modulates the transcription of the genes involved in the control of glucose andlipid metabolism in themuscle,adipose tissue, and theliver. As a result, pioglitazone reducesinsulin resistance in the liver and peripheral tissues, decreases gluconeogenesis in the liver, and reduces quantity of glucose andglycated hemoglobin in the bloodstream.
Since 2004, pioglitazone and other active TZDs have been shown to bind to theouter mitochondrial membrane proteinmitoNEET with affinity comparable to that of pioglitazone for PPARγ.[25][26]
Leriglitazone is a metabolite.[27]
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.[28]
To 2020, no study has examined the socioeconomic effects of utilization of pioglitazone.[11]
Pioglitazone is marketed asActos in the United States, Canada, the UK and Germany,Glustin in the European Union,Glizone andPioz in India byZydus Cadila andUSV Limited, respectively andZactos in Mexico byTakeda Pharmaceuticals. On 17 August 2012, the US FDA announced its approval of the firstgeneric version of Actos.[29]
Pioglitazone has been repurposed as an add-on treatment for depressive episodes in subjects withbipolar disorder.[30] However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of pioglitazone in the treatment of bipolar depression.[30]
There is research that suggests that pioglitazone may be useful for treatingmajor depression.[31]
Pioglitazone has been found to exert anti-ageing effects inDrosophila.[32]
Pioglitazone has been tried fornon-alcoholic fatty liver disease, showing promising results according to several meta-analyses.[33]
Because it is thought to reduce inflammatory activity in neuroglia, it was studied in a small clinical trial involving children withautism, under the autoimmune/inflammatory hypotheses of thecauses of autism.[34]
Pioglitazone may improve symptoms ofpsoriasis.[35]
Pioglitazone is also being researched as 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.[36]
Pioglitazone has been shown in animal models to be a possible treatment forOpioid use disorder.[37]
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.
