Pioglitazone

Last updated

Pioglitazone
Pioglitazone.svg
Pioglitazone ball-and-stick model.png
Clinical data
Trade names Actos, others
AHFS/Drugs.com Monograph
MedlinePlus a699016
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
Drug class Thiazolidinedione
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [1]
  • EU:Rx-only [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding >99%
Metabolism Liver (CYP2C8)
Elimination half-life 3–7 hours
Excretion Bile duct
Identifiers
  • (RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.114.441 OOjs UI icon edit-ltr-progressive.svg
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)
  • O=C1NC(=O)SC1Cc3ccc(OCCc2ncc(cc2)CC)cc3
  • InChI=1S/C19H20N2O3S/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23) Yes check.svgY
  • Key:HYAFETHFCAUJAY-UHFFFAOYSA-N Yes check.svgY
   (verify)

Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. [3] It may be used with metformin, a sulfonylurea, or insulin. [3] [4] Use is recommended together with exercise and diet. [4] It is not recommended in type 1 diabetes. [4] It is taken by mouth. [4]

Contents

Common side effects include headaches, muscle pains, inflammation of the throat, and swelling. [4] Serious side effects may include bladder cancer, low blood sugar, heart failure, and osteoporosis. [4] [3] Use is not recommended in pregnancy or breastfeeding. [3] It is in the thiazolidinedione (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 a generic medication. [3] In 2021, it was the 129th 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 [6] [7] It was withdrawn in France and Germany in 2011.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]

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]

Contraindications

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. [1] Its safety in pregnancy, lactation (breastfeeding) and people under 18 is not established. [1]

Given previous experiences with the related drug troglitazone, acute diseases of the liver are regarded as a contraindication for pioglitazone.[ medical citation needed ]

Side effects

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]

The risk of hypoglycemia is low in the absence of other drugs that lower blood glucose.[ medical citation needed ]

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 the pioglitazone. [22]

Drug interactions

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]

Leriglitazone is a metabolite. [27]

Society and culture

Economics

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]

Pioglitazone has been tried for non-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 with autism, under the autoimmune/inflammatory hypotheses of the causes of autism. [34]

Pioglitazone may improve symptoms of psoriasis. [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 for Opioid use disorder. [37]

Related Research Articles

<span class="mw-page-title-main">Type 2 diabetes</span> Form of diabetes mellitus

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal. Often symptoms develop slowly. Long-term complications from high blood sugar include heart disease, stroke, diabetic retinopathy, which can result in blindness, kidney failure, and poor blood flow in the lower-limbs, which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

<span class="mw-page-title-main">Metformin</span> Medication used to treat diabetes

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. Metformin is not associated with weight gain and is taken by mouth.

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Thiazolidinedione</span> Class of chemical compounds

The thiazolidinediones, abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in the treatment of diabetes mellitus type 2 that were introduced in the late 1990s.

<span class="mw-page-title-main">Rosiglitazone</span> Chemical compound

Rosiglitazone is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis in 2007 that linked the drug's use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drug's patent expired in 2012.

<span class="mw-page-title-main">Sulfonylurea</span> Class of organic compounds used in medicine and agriculture

Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea, a dehydrogenated derivative of urea). The side chains R1 and R2 distinguish various sulfonylureas. Sulfonylureas are the most widely used herbicide.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin.

<span class="mw-page-title-main">Meglitinide</span> Chemical substance

Meglitinides or glinides are a class of drugs used to treat type 2 diabetes.

<span class="mw-page-title-main">Dipeptidyl peptidase-4 inhibitor</span> Enzyme blocker and diabetes treatment drug

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.

<span class="mw-page-title-main">Sitagliptin</span> Diabetes medication

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<span class="mw-page-title-main">Dapagliflozin</span> Diabetes medication

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.

<span class="mw-page-title-main">Muraglitazar</span> Chemical compound

Muraglitazar is a dual peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

<span class="mw-page-title-main">Canagliflozin</span> Chemical compound

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Empagliflozin, sold under the brand name Jardiance, among others, is an antidiabetic medication used to improve glucose control in people with type 2 diabetes. It is taken by mouth.

<span class="mw-page-title-main">Diabetes</span> Group of endocrine diseases characterized by high blood sugar levels

Diabetes mellitus, often known simply as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body becoming unresponsive to the hormone's effects. Classic symptoms include thirst, polyuria, weight loss, and blurred vision. If left untreated, the disease can lead to various health complications, including disorders of the cardiovascular system, eye, kidney, and nerves. Diabetes accounts for approximately 4.2 million deaths every year, with an estimated 1.5 million caused by either untreated or poorly treated diabetes.

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Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

SGLT2 inhibitors are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium/glucose cotransporter 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Pioglitazone/glimepiride, sold under the brand name Duetact among others, is a fixed-dose combination anti-diabetic medication for the treatment of type 2 diabetes. It contains the thiazolidinedione pioglitazone and the sulfonylurea glimepiride. It is taken by mouth.

References

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  12. 1 2 Scheen 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 . PMID   23020930. 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.
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