PIOGLITAZONE

Pioglitazone is a member of thiazolidinediones, an aromatic ether and a member of pyridines.
Pioglitazone is an oral antidiabetic medication that belongs to the thiazolidinedione class of drugs, which are commonly prescribed for the treatment of type 2 diabetes mellitus, particularly in patients who have insulin resistance and inadequate blood sugar control with diet, exercise, or other medications. 
Pioglitazone works primarily by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) in adipose tissue, skeletal muscle, and the liver, which leads to an increase in insulin sensitivity, improved glucose uptake by peripheral tissues, and a reduction in hepatic glucose production, thereby helping to lower blood sugar levels over time.

CAS Number: 105355-27-9
Molecular Formula: C19H20N2O3S
Molecular Weight: 356.44

Synonyms: Pioglitazone, 111025-46-8, Glustin, Zactos, Pioglitazona, Pioglitazonum, AD-4833, 5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, CHEBI:8228, 5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, X4OV71U42S, U-72107, 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione, 5-[4-[2-(5-ETHYL-2-PYRIDYL)ETHOXY]BENZYL]-2,4-THIAZOLIDINEDIONE, DTXSID3037129, 5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 5-((4-(2-(5-Ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-2,4-thiazolidinedione, 5-({4-[2-(5-ethyl-2-pyridin-2-yl)ethoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione, (+/-)-5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-2,4-thiazolidinedione, 2,4-Thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, (+/-)-, U72,107A, 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione, 5-(4-(2-(5-ethyl-pyridin-2-yl)ethoxy)benzyl)-1,3-thiazolidine-2,4-dione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-1,3-thiazolidine-2,4-dione, AD4833, U72107A, RefChem:56525, DTXCID1017129, A10BG03, 601-029-7, 921-004-7, Actos, 105355-27-9, Pioglitazonum [INN-Latin], Pioglitazona [INN-Spanish], 5-(4-(2-(5-ethyl-pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione, Pioglitazone (Actos), U 72107, MFCD00865504, C19H20N2O3S, pioglitazone (INN), 105390-47-4, Actos (TN), 2,4-thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-, 5-[4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione, PIOGLITAZONE [INN], Pioglitazone [BAN:INN], Pioglitazone [INN:BAN], Piozone, Pioglu, 2,4-Thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, HSDB 7322, U-72107E, UNII-X4OV71U42S, Pioglitazone?, SR-01000763737, Pioglitazone base, 5-(4-(2-(5-ETHYL-2-PYRIDYL)ETHOXY)BENZYL)THIAZOLIDINE-2,4-DIONE, 2,4-Thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-, (+/-)-, [( inverted exclamation markA)-5-[[4-[2-(5-ethyl-2-pyridyl)]ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochlorid, 2,4-THIAZOLIDINEDIONE, 5-((4-(2-(5-ETHYL-2-PYRIDINYL)ETHOXY)PHENYL)METHYL)-, (+/-)-, Pioglitazone-[d4], HS-0047, Spectrum_001623, Pioglitazone (Standard), Spectrum2_001679, Spectrum3_001002, Spectrum4_001130, Spectrum5_001480, Spectrum5_002067, PIOGLITAZONE [MI], PIOGLITAZONE [HSDB], PIOGLITAZONE [IARC], SCHEMBL4121, PIOGLITAZONE [VANDF], BSPBio_002723, KBioGR_001619, KBioSS_002103, MLS006011848, PIOGLITAZONE [WHO-DD], SPBio_001897, GTPL2694, orb1310828, PIOGLITAZONE [EMA EPAR], SCHEMBL29364546, KBio2_002103, KBio2_004671, KBio2_007239, KBio3_001943, Pioglitazone - Bio-X trade mark, HYAFETHFCAUJAY-UHFFFAOYSA-N, BDBM724000, GLXC-05211, HMS2089H14, HMS3651D09, HMS3712E16, HMS3884L10, HMS5081P07, Pharmakon1600-01504401, BCP26474, MSK11071, BBL029068, BDBM50103521, HB4139, HY-13956R, NSC758876, s2590, STL309607, STL373406, (+/-)-5-[p-[2-(ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl]methyl]thiazolidine-2,4-dione, AKOS015894953, AKOS022109420, AC-1021, CCG-220107, CS-1700, DB01132, FP39372, SB17323, (+/-)-5-[[4-[2-(5-Ethyl-2-pyridinyl)-ethoxy]phenyl]methyl]-2,4-thiazolidinedione, NCGC00163128-01, NCGC00163128-02, NCGC00163128-03, NCGC00163128-04, NCGC00163128-05, NCGC00163128-06, NCGC00163128-07, BP164273, HY-13956, SMR002204015, SY017473, SBI-0206791.P001, US20250064791, DB-027350, NS00000599, SW197561-3, C07675, D08378, EN300-117258, AB00698454-10, AB00698454_11, AB00698454_12, AB00698454_13, 355P279, F386732, Q417765, SR-01000763737-5, BRD-A48430263-001-07-7, BRD-A48430263-003-02-4, BRD-A48430263-003-06-5, BRD-A48430263-003-16-4, BRD-A48430263-003-17-2, Z1501480426, 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]-2,4-thiazolidinedione, 5-[4-[2-(5-ethyl-2-pyridyl)eth-oxy]benzyl]-2,4-thiazolidinedione, 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4thiazolidinedione, 5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-thiazolidine-2,4-dione, 5-[[4-[2-(5-ethyl-2-pyridyl)ethoxy] phenyl]methyl]-2,4-thiazolidinedione, (+/-)-5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-2,4-thiazolidinedione, (+/-)-5-(P-(2-(5-ETHYL-2-PYRIDYL)ETHOXY)BENZYL)-2,4-THIAZOLIDINEDIONE, (RS)-5-(4-(2-(5-ETHYLPYRIDIN-2-YL)ETHOXY)BENZYL)THIAZOLIDINE-2,4-DIONE, 2,4-Thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]- (9CI), 5-[[4-[2-[(5-ethyl-2-pyridyl)]ethoxy]phenyl]methyl]thiazolidine-2,4-dione, 5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-4-hydroxy-1,3-thiazol-2(5H)-one, [()-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochlorid, 198077-89-3, 5-[[4-[2-(5-Ethylpyridin-2-yl)ethoxy]phenyl]methyl]thiazolidine-2,4-dione, Pioglitazone, 5-({4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}Methyl)-1,3-thiazolidine-2,4-dione hydrochloride, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]thiazolidine-2,4-dione

Pioglitazone is a member of the class of thiazolidenediones that is 1,3-thiazolidine-2,4-dione substituted by a benzyl group at position 5 which in turn is substituted by a 2-(5-ethylpyridin-2-yl)ethoxy group at position 4 of the phenyl ring. 
Pioglitazone exhibits hypoglycemic activity. 
Pioglitazone has a role as an insulin-sensitizing drug, an EC 2.7.1.33 (pantothenate kinase) inhibitor, a xenobiotic, an EC 6.2.1.3 (long-chain-fatty-acid--CoA ligase) inhibitor, a ferroptosis inhibitor, a cardioprotective agent, a PPARgamma agonist, an antidepressant, a geroprotector and a hypoglycemic agent. 

Chemically, Pioglitazone is defined as 5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione, and it contains a thiazolidinedione ring linked to a substituted benzyl group and a pyridinyl-ethoxy moiety, which together confer its pharmacological activity and influence its pharmacokinetics, including absorption, metabolism, and excretion. 
The drug is metabolized primarily in the liver by the cytochrome P450 enzymes, mainly CYP2C8 and CYP3A4, producing active metabolites that contribute to its therapeutic effect, and it has a relatively long half-life, which allows for once-daily dosing in most patients.

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation mainly via cytochrome P450 2C8 to form active and inactive metabolites. 
Three of the six identified metabolites are active (M-II, M-III, and M-IV). 
Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45%).

Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes.
Pioglitazone may be used with metformin, a sulfonylurea, or insulin.
Use is recommended together with exercise and diet.

Pioglitazone is not recommended in type 1 diabetes.
Pioglitazone 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 is 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.
Pioglitazone is available as a generic medication.
In 2023, it was the 133rd most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Pioglitazone was withdrawn in France and Germany in 2011.
Pioglitazone is a medication that treats type 2 diabetes. 
It helps your body use insulin more effectively and decreases your blood sugar. 

A healthcare provider may recommend changes to your diet and exercise if you take this medication. 
The brand name of this medication is Actos.
Pioglitazone is an antihyperglycemic used as an adjunct to diet, exercise, and other antidiabetic medications to manage type 2 diabetes mellitus.4,5,6,7.

It is administered as a racemic mixture, though there is no pharmacologic difference between the enantiomers and they appear to interconvert in vivo with little consequence.
The thiazolidinedione class of medications, which also includes rosiglitazone and troglitazone, exerts its pharmacological effect primarily by promoting insulin sensitivity and the improved uptake of blood glucose4 via agonism at the peroxisome proliferator-activated receptor-gamma (PPARγ).
Pioglitazones are ligand-activated transcription factors that are involved in the expression of more than 100 genes and affect numerous metabolic processes, most notably lipid and glucose homeostasis.2

Thiazolidinediones, including pioglitazone, have fallen out of favor in recent years due to the presence of multiple adverse effects and warnings regarding their use (e.g. congestive heart failure, bladder cancer) and the availability of safer and more effective alternatives for patients with type 2 diabetes mellitus.
Pioglitazone, a widely prescribed medication for diabetes, has gained huge acclaim for its unique approach to managing diabetes and improving insulin sensitivity. 
This drug plays a crucial role in helping individuals with type 2 diabetes mellitus control their blood sugar levels and diminish the likelihood of complications associated with the disease.

Protein binding    >99%
Excreted unchanged in urine    <1%
Volume of distribution    0.25(L/kg)
Biological half-life    5-6 (active metabolites: 16-23) / Unchanged

Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.
Pioglitazone 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.

Pioglitazone has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder.
However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of pioglitazone in the treatment of bipolar depression.
Pioglitazone is an oral antidiabetic agent belonging to the drug class known as the thiazolidinediones (TZD) or "insulin sensitizers". 

Pioglitazone is used alone or in combination with other diabetic drug for the treatment of diabetes mellitus type 2. 
Similar to other thiazolidinediones, Pioglitazone selectively stimulates nuclear receptor peroxisone proliferator-activated receptor gamma (PPAR-gamma/PPARG). 
Pioglitazone acts by improving sensitivity to insulin in muscle and adipose tissue and inhibiting hepatic gluconeogenesis. 

Pioglitazone improves glycemic control while reducing circulating insulin levels. 
Pioglitazone is not recommended in patients with symptomatic heart failure. 
Pioglitazone and other similar medications for diabetes may cause or worsen congestive heart failure (http://www.rxlist.com/actos-drug.htm#).

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). 

Pioglitazone 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.
Pioglitazone has been found to exert anti-ageing effects in Drosophila.

Pioglitazone has been tried for non-alcoholic fatty liver disease, showing promising results according to several meta-analyses.
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.
Pioglitazone may improve symptoms of psoriasis.

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.
Pioglitazone has been shown in animal models to be a possible treatment for Opioid use disorder.
Pioglitazone treats type 2 diabetes. 

Pioglitazone helps your body use insulin effectively, which decreases your blood sugar (glucose). 
Changes to diet and exercise are often combined with this medication.
Take this medication by mouth with a glass of water follow the directions on the prescription label. 

Clinically, Pioglitazone is used not only to control hyperglycemia but also to improve lipid profiles, as it can modestly reduce triglycerides and increase high-density lipoprotein (HDL) cholesterol, which may provide additional cardiovascular benefits for patients with type 2 diabetes. 
Pioglitazone is frequently prescribed either as monotherapy for patients intolerant to other oral antidiabetic drugs or in combination with metformin, sulfonylureas, or insulin to achieve better glycemic control.

Pioglitazone also has a number of therapeutic and pharmacological considerations. 
While it improves insulin sensitivity, it may cause weight gain due to fluid retention and increased adiposity, and it carries a potential risk of edema and heart failure exacerbation in susceptible individuals. 
Rarely, it has been associated with bladder cancer after long-term use, which has led to regulatory warnings and restrictions in some countries. 

Because of these risks, careful patient selection, monitoring of liver function, and assessment of cardiovascular status are recommended before and during therapy.
In addition to its glucose-lowering effects, Pioglitazone has been studied for potential benefits in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome, due to its insulin-sensitizing and anti-inflammatory effects, although these uses are off-label and require careful clinical judgment. 
Pioglitazone is considered a potent, long-acting insulin sensitizer that addresses one of the root causes of type 2 diabetes—insulin resistance—while offering additional metabolic benefits, but it must be used cautiously due to its associated safety considerations.

Uses Of Pioglitazone:
Pioglitazone is used to lower blood glucose levels in type 2 diabetes either alone or in combination with sulfonylurea, metformin, or insulin.
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.

Pioglitazone 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.

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.
Another study found an all-cause mortality hazard ratio of 0.33 for pioglitazone after adjusting for >40 covariates, compared to insulin.

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. 
Pioglitazone is ineffective and possibly harmful in diabetes mellitus type 1 and diabetic ketoacidosis.

Pioglitazones 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.
Pioglitazone is primarily used in the management of type 2 diabetes mellitus, a chronic condition characterized by insulin resistance and impaired glucose metabolism, where it functions to lower blood sugar levels by improving insulin sensitivity in peripheral tissues such as skeletal muscle and adipose tissue while simultaneously reducing hepatic glucose production. 

Because it targets insulin resistance—a core defect in type 2 diabetes—Pioglitazone is often prescribed to patients who are unable to achieve adequate glycemic control through lifestyle measures alone, such as diet and exercise, and it can also be used in combination with other antidiabetic agents, including metformin, sulfonylureas, and basal insulin, to enhance overall glucose regulation in patients with persistent hyperglycemia.
Beyond its primary use in glucose control, Pioglitazone has additional metabolic benefits that extend to lipid regulation and cardiovascular risk management. 
Studies have shown that it can modestly increase high-density lipoprotein (HDL) cholesterol, lower triglycerides, and sometimes reduce small dense low-density lipoprotein (LDL) particles, which together contribute to improved cardiovascular risk profiles in patients with type 2 diabetes, particularly those who have dyslipidemia or are at heightened risk for atherosclerotic disease.

Pioglitazone has also been investigated for use in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) because of its insulin-sensitizing and anti-inflammatory effects. 
By improving insulin resistance and reducing hepatic fat accumulation, Pioglitazone may help reduce liver inflammation, improve liver enzyme levels, and slow the progression of fatty liver disease in selected patients, although its use in this context is generally considered off-label and requires careful clinical monitoring.

In addition, Pioglitazone has been used in certain cases of polycystic ovary syndrome (PCOS), where insulin resistance contributes to hyperandrogenism and irregular menstrual cycles. 
By improving insulin sensitivity, Pioglitazone can help regulate menstrual cycles, improve ovulatory function, and potentially reduce androgen-related symptoms, although this indication is also off-label and typically considered when first-line therapies are insufficient.
Pioglitazone may have ancillary benefits in broader components of metabolic syndrome, including central obesity, hypertension, and dyslipidemia, by enhancing insulin sensitivity and exerting modest effects on lipid metabolism. 

While these benefits are secondary to its primary action as a blood glucose-lowering agent, they make Pioglitazone a potentially valuable option for patients with multiple metabolic abnormalities who require an integrated therapeutic approach.
Pioglitazone extend beyond simple glucose lowering to encompass improvements in lipid metabolism, liver health, reproductive function in select conditions, and certain cardiovascular risk factors, making it a multifunctional medication in the treatment of metabolic disorders, although careful monitoring and patient selection are essential due to potential side effects.

Safety Profile Of Pioglitazone:
Pioglitazone, while effective in improving insulin sensitivity and controlling blood glucose, carries several potential hazards and side effects that must be carefully considered by healthcare providers and patients. 
One of the most common adverse effects is weight gain, which is primarily due to fluid retention and, in some cases, an increase in subcutaneous fat. 
This fluid retention can also contribute to peripheral edema, which may worsen or precipitate congestive heart failure, particularly in patients with pre-existing cardiovascular conditions. 

Because of this, Pioglitazone is generally contraindicated in patients with symptomatic heart failure or a history of significant cardiac dysfunction.
Another notable hazard is bone fracture risk, especially in postmenopausal women. 
Clinical studies have shown that long-term Pioglitazone use can reduce bone mineral density, making bones more fragile and increasing susceptibility to fractures of the wrist, arm, and foot. 

Therefore, patients at risk for osteoporosis must be monitored closely when using this medication.
Pioglitazone has also been associated, although rarely, with bladder cancer. 

Long-term exposure has been linked to an increased incidence of bladder tumors in some epidemiological studies, which has prompted regulatory agencies to issue warnings and recommend that the drug be avoided in patients with active bladder cancer or a history of bladder malignancy. 
Routine monitoring and limiting treatment duration may be advised to mitigate this risk.