Pioglitazone was patented in 1985, and came into medical use in 1999.[5] It is available as a generic medication.[3] In 2022, it was the 120th most commonly prescribed medication in the United States, with more than 5million prescriptions.[6][7] It was withdrawn in France and Germany in 2011.[8][9][10]
Medical uses
Pioglitazone is used to lower blood glucose levels in type 2 diabetes either alone or in combination with sulfonylurea, metformin, or insulin.[1] 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.[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 mortality hazard 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]
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.[15]
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.[medical citation needed]
Chronic administration of the drug has led to occasional instances of cholestatic 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. A meta-analysis released subsequently showed that pioglitazone reduced the risk of ischemic cardiac events rather than increased the risk, but increased CHF.[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]
Bladder cancer
On 9 June 2011, the French Agency for the Safety of Health Products decided to withdraw pioglitazone due to high risk of bladder 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'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.[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]
Combination with sulfonylureas or insulin reciprocally exponentiate risk of hypoglycemia. Therapy with pioglitazone increase the chance of pregnancy in individuals taking oral contraception.
Mechanism of action
Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.[23][24] 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,[when?] 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.[25][26]
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]
Brand names
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.[29]
Research
Psychiatry
Bipolar disorder
Pioglitazone has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar 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]
Major depression
There is research that suggests that pioglitazone may be useful for treating major depression.[31]
Other illnesses
Pioglitazone has been found to exert anti-ageing effects in Drosophila.[32]
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.[34]
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 for Opioid use disorder. [37]
^ abScheen 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. hdl:2268/132794. PMID23020930. Archived from the original on 28 January 2021. Retrieved 18 September 2019. 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.
^Yang J, Vallarino C, Bron M, Perez A, Liang H, Joseph G, et al. (2014). "A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study". Current Medical Research and Opinion. 30 (11): 2223–2231. doi:10.1185/03007995.2014.941054. PMID24983744. S2CID35665797.
^Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1271–2.
^Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (September 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. PMID17848652.
^ abBartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, et al. (September 2021). "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 of Psychiatric Research. 143: 230–238. doi:10.1016/j.jpsychires.2021.09.018. PMID34509090. S2CID237485915.
^de Guglielmo G, Kallupi M, Scuppa G, Demopulos G, Gaitanaris G, Ciccocioppo R (January 2017). "Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents". Psychopharmacology. 234 (2): 223–234. doi:10.1007/s00213-016-4452-1. PMID27714428.
