pioglitazone

Pioglitazone is used to lower blood glucose levels in type 2 diabetes either alone or in combination with sulfonylurea, metformin, or insulin.{{cite web | title=Actos- pioglitazone tablet | website=DailyMed | date=25 January 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2ddc491-88a9-4063-9150-443b4fa4330c | access-date=13 February 2020 | archive-date=6 September 2015 | archive-url=https://web.archive.org/web/20150906115408/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2ddc491-88a9-4063-9150-443b4fa4330c | url-status=live }} The effects of pioglitazone have been compared in a Cochrane systematic review to that of other blood sugar lowering-medicine, including metformin, acarbose, and repaglinide, 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.{{cite journal | vauthors = Ipsen EØ, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B | title = Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 11 | pages = CD013516 | date = November 2020 | pmid = 33210751 | pmc = 8092670 | doi = 10.1002/14651858.CD013516.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }} It did, however, show reduction of risk of developing type 2 diabetes when compared to a placebo or to no treatment. 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.{{cite journal | vauthors = Scheen AJ | title = Outcomes and lessons from the PROactive study | journal = Diabetes Research and Clinical Practice | volume = 98 | issue = 2 | pages = 175–86 | date = November 2012 | pmid = 23020930 | doi = 10.1016/j.diabres.2012.09.001 | hdl = 2268/132794 | quote = 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. | url = http://orbi.ulg.ac.be/jspui/handle/2268/132794 | access-date = 18 September 2019 | archive-date = 28 January 2021 | archive-url = https://web.archive.org/web/20210128055222/https://orbi.uliege.be//handle/2268/132794 | url-status = live | hdl-access = free }} The secondary outcome of death from all causes, myocardial infarction, and stroke were lower.

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.{{cite journal | vauthors=Strongman H, Korhonen P, Williams R, et al | date=2017 | title=Pioglitazone and risk of mortality in patients with type 2 diabetes: results from a European multidatabase cohort study | journal=BMJ Open Diabetes Research & Care | volume=5 | issue=1 | pages=e000364 | doi=10.1136/bmjdrc-2016-000364 | pmid=28761650 | pmc=5530248 }} Another study found an all-cause mortality hazard ratio of 0.33 for pioglitazone after adjusting for >40 covariates, compared to insulin.{{cite journal | vauthors=Yang J, Vallarino C, Bron M, Perez A, Liang H, Joseph G, Yu S | date=2014| title= A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study|volume=30|issue=11|pages=2223–2231|doi=10.1185/03007995.2014.941054 |journal=Current Medical Research and Opinion| pmid=24983744| s2cid=35665797}} 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.

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.

Given previous experiences with the related drug troglitazone, acute diseases of the liver are regarded as a contraindication for pioglitazone.{{medcn|date=February 2020}}

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.{{cite web | url = https://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM153896.pdf | title = 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 | access-date = 4 April 2012 | work = Takeda | publisher = Food and Drug Administration | date = March 2007 | archive-url = https://web.archive.org/web/20120516103123/http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM153896.pdf | archive-date = 16 May 2012 | url-status = dead }}

The risk of hypoglycemia is low in the absence of other drugs that lower blood glucose.{{medcn|date=February 2020}}

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.{{medcn|date=February 2020}}

Chronic administration of the drug has led to occasional instances of cholestatic hepatitis, reversible upon drug discontinuation.{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | date = 2008 | pages = 1271–2 }}

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. A meta-analysis released subsequently showed that pioglitazone reduced the risk of ischemic cardiac events rather than increased the risk, but increased CHF.{{cite journal | vauthors = Lincoff AM, Wolski K, Nicholls SJ, Nissen SE | title = Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials | journal = JAMA | volume = 298 | issue = 10 | pages = 1180–8 | date = September 2007 | pmid = 17848652 | doi = 10.1001/jama.298.10.1180 }}

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.

On 9 June 2011, the French Agency for the Safety of Health Products decided to withdraw pioglitazone due to high risk of bladder cancer.{{cite web | title = L'antidiabétique Actos retiré du marché | trans-title = Actos antidiabetic withdrawn from the market | language = fr | url = http://www.lefigaro.fr/flash-actu/2011/06/09/97001-20110609FILWWW00505-info-le-figaro-lantidiabetique-actos-retire-du-marche.php | work = Le Figaro | date = 9 June 2011 | access-date = 9 June 2011 | archive-date = 12 June 2011 | archive-url = https://web.archive.org/web/20110612001536/http://www.lefigaro.fr/flash-actu/2011/06/09/97001-20110609FILWWW00505-info-le-figaro-lantidiabetique-actos-retire-du-marche.php | url-status = live }} 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.{{cite web | vauthors = Alam II | date = 1 January 2012 | url = http://www.medical-reference.net/2011/12/france-and-germany-suspended-use-of.html | title = France and Germany Suspended Use of Actos for Bladder Cancer Risk | work = Medical-Reference | access-date = 27 August 2012 | archive-date = 2 September 2012 | archive-url = https://web.archive.org/web/20120902222645/http://www.medical-reference.net/2011/12/france-and-germany-suspended-use-of.html | url-status = live }} On 10 June 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.{{cite news | url=https://www.reuters.com/article/takeda-germany-idUSL3E7HA0X920110610 | work=Reuters | vauthors = Topham J | title=UPDATE 2-Germany joins France in suspending top Takeda drug | date=10 June 2011 | access-date=1 July 2017 | archive-date=13 November 2015 | archive-url=https://web.archive.org/web/20151113074307/http://www.reuters.com/article/2011/06/10/takeda-germany-idUSL3E7HA0X920110610 | url-status=live }}

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.{{cite web | title = FDA Drug Safety Communication: Updated drug labels for pioglitazone-containing medicines | date = 4 August 2011 | url = https://www.fda.gov/Drugs/DrugSafety/ucm266555.htm | publisher = U.S. Food and Drug Administration (FDA) | access-date = 16 December 2019 | archive-date = 24 April 2019 | archive-url = https://web.archive.org/web/20190424012237/https://www.fda.gov/Drugs/DrugSafety/ucm266555.htm | url-status = live }}{{cite web | title=Update to ongoing safety review of Actos | website=U.S. Food and Drug Administration | date=18 June 2019 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-ongoing-safety-review-actos-pioglitazone-and-increased-risk | access-date=8 November 2020 | archive-date=28 September 2020 | archive-url=https://web.archive.org/web/20200928032722/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-ongoing-safety-review-actos-pioglitazone-and-increased-risk | url-status=live }}

A 2017 meta-analysis found no difference in the rates of bladder cancer attributed to pioglitazone.{{cite journal | vauthors = Filipova E, Uzunova K, Kalinov K, Vekov T | title = Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis | journal = Diabetes Therapy | volume = 8 | issue = 4 | pages = 705–726 | date = August 2017 | pmid = 28623552 | pmc = 5544610 | doi = 10.1007/s13300-017-0273-4 }}

{{Unreferenced section|date=March 2011}}

Combination with sulfonylureas or insulin reciprocally exponentiate risk of hypoglycemia. Therapy with pioglitazone increase the chance of pregnancy in individuals taking oral contraception.

Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.{{cite journal | vauthors = Gillies PS, Dunn CJ | title = Pioglitazone | journal = Drugs | volume = 60 | issue = 2 | pages = 333–43; discussion 344–5 | date = August 2000 | pmid = 10983737 | doi = 10.2165/00003495-200060020-00009 | s2cid = 265781287 }}{{cite journal | vauthors = Smith U | title = Pioglitazone: mechanism of action | journal = International Journal of Clinical Practice. Supplement | issue = 121 | pages = 13–8 | date = September 2001 | pmid = 11594239 }} 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.

Since 2004, 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.{{cite journal | vauthors = Colca JR, McDonald WG, Waldon DJ, Leone JW, Lull JM, Bannow CA, Lund ET, Mathews WR | title = Identification of a novel mitochondrial protein ("mitoNEET") cross-linked specifically by a thiazolidinedione photoprobe | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 286 | issue = 2 | pages = E252–60 | date = February 2004 | pmid = 14570702 | doi = 10.1152/ajpendo.00424.2003 | doi-access=free | s2cid=20550873 | s2cid-access=free }}{{cite journal | vauthors = Paddock ML, Wiley SE, Axelrod HL, Cohen AE, Roy M, Abresch EC, Capraro D, Murphy AN, Nechushtai R, Dixon JE, Jennings PA | title = MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 36 | pages = 14342–7 | date = September 2007 | pmid = 17766440 | pmc = 1963346 | doi = 10.1073/pnas.0707189104 | bibcode = 2007PNAS..10414342P | doi-access = free }}

Leriglitazone is a metabolite.{{cite journal | vauthors = Monternier PA, Singh J, Parasar P, Theurey P, DeWitt S, Jacques V, Klett E, Kaur N, Nagaraja TN, Moller DE, Hallakou-Bozec S | title = Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy | journal = Journal of Inherited Metabolic Disease | volume = 45 | issue = 4 | pages = 832–847 | date = July 2022 | pmid = 35510808 | pmc = 9545763 | doi = 10.1002/jimd.12510 }}

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.{{cite web | url = http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=ACTOS | title = Details for Actos | work = Drug Patent Watch | access-date = 14 December 2009 | archive-date = 15 August 2011 | archive-url = https://web.archive.org/web/20110815065919/http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=ACTOS | url-status = live }}

To 2020, no study has examined the socioeconomic effects of utilization of pioglitazone.

Pioglitazone is marketed as Actos in the United States, Canada, the UK and Germany, Glustin in the European Union, Glizone and Pioz in India by Zydus Cadila and USV Limited, respectively and Zactos in Mexico by Takeda Pharmaceuticals. On 17 August 2012, the US FDA announced its approval of the first generic version of Actos.{{cite press release | title = FDA approves first generic Actos to treat type 2 diabetes | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315951.htm | archive-url = https://web.archive.org/web/20160104163520/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315951.htm | url-status = dead | archive-date = 4 January 2016| publisher = U.S. Food and Drug Administration (FDA) | date = 17 August 2012}}

Pioglitazone has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder.{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials | journal = Journal of Psychiatric Research | date = September 2021 | volume = 143 | pages = 230–238 | doi = 10.1016/j.jpsychires.2021.09.018| pmid = 34509090 | s2cid = 237485915 }} However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of pioglitazone in the treatment of bipolar depression.

There is research that suggests that pioglitazone may be useful for treating major depression.{{cite journal | vauthors = Colle R, de Larminat D, Rotenberg S, Hozer F, Hardy P, Verstuyft C, Fève B, Corruble E | title = Pioglitazone could induce remission in major depression: a meta-analysis | journal = Neuropsychiatric Disease and Treatment | volume = 13 | pages = 9–16 | year = 2017 | pmid = 28031713 | doi = 10.2147/NDT.S121149 | pmc=5182046 | doi-access = free }}

Pioglitazone has been found to exert anti-ageing effects in Drosophila.{{cite journal | vauthors = Jafari M, Khodayari B, Felgner J, Bussel II, Rose MR, Mueller LD | title = Pioglitazone: an anti-diabetic compound with anti-aging properties | journal = Biogerontology | volume = 8 | issue = 6 | pages = 639–51 | date = December 2007 | pmid = 17628757 | doi = 10.1007/s10522-007-9105-7 | s2cid = 9714773 | url = https://escholarship.org/content/qt38j292g2/qt38j292g2.pdf?t=pgp1pw }}

Pioglitazone has been tried for non-alcoholic fatty liver disease, showing promising results according to several meta-analyses.{{cite journal | vauthors = Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, Kassir R, Singhal R, Mahawar K, Ramnarain D | title = Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss | journal = BMC Endocrine Disorders | volume = 22 | issue = 1 | pages = 63 | date = March 2022 | pmid = 35287643 | pmc = 8919523 | doi = 10.1186/s12902-022-00980-1 | doi-access = free }}

Because it is thought to reduce inflammatory activity in neuroglia, it was studied in a small clinical trial involving children with autism, under the autoimmune/inflammatory hypotheses of the causes of autism.{{cite journal | vauthors = Doyle CA, McDougle CJ | title = Pharmacotherapy to control behavioral symptoms in children with autism | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 11 | pages = 1615–29 | date = August 2012 | pmid = 22550944 | doi = 10.1517/14656566.2012.674110 | s2cid = 32144885 }}

Pioglitazone may improve symptoms of psoriasis.{{cite journal | vauthors = Pietrzak A, Michalak-Stoma A, Chodorowska G, Szepietowski JC | title = Lipid disturbances in psoriasis: an update | journal = Mediators of Inflammation | volume = 2010 | pages = 535612 | date = 2010 | pmid = 20706605 | pmc = 2914266 | doi = 10.1155/2010/535612 | doi-access = free }}

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.{{cite journal | vauthors = Abyadeh M, Gupta V, Gupta V, Chitranshi N, Wu Y, Amirkhani A, Meyfour A, Sheriff S, Shen T, Dhiman K, Ghasem HS, Paul AH, Stuart LG, Mirzaei M | title = Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease | journal = Aging and Disease | volume = 12 | issue = 8 | pages = 1964–1976 | date = December 2021 | pmid = 34881080 | pmc = 8612603 | doi = 10.14336/AD.2021.0719 }}

Pioglitazone has been shown in animal models to be a possible treatment for Opioid use disorder. {{cite journal | vauthors = de Guglielmo G, Kallupi M, Scuppa G, Demopulos G, Gaitanaris G, Ciccocioppo R | title = Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents | journal = Psychopharmacology | volume = 234 | issue = 2 | pages = 223–234 | date = January 2017 | pmid = 27714428 | doi = 10.1007/s00213-016-4452-1 }}

{{Reflist}}

{{Oral hypoglycemics}}

{{PPAR modulators}}

{{Portal bar | Medicine}}

Category:3β-Hydroxysteroid dehydrogenase inhibitors

Category:CYP3A4 inducers

Category:CYP17A1 inhibitors

Category:Drugs developed by Eli Lilly and Company

Category:IARC Group 2A carcinogens

Category:Phenol ethers

Category:PPAR agonists

Category:Pyridines

Category:Drugs developed by Takeda Pharmaceutical Company

Category:Thiazolidinediones

Category:Wikipedia medicine articles ready to translate

Category:Withdrawn drugs