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Pioglitazone
Pioglitazone
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Pioglitazone
Clinical data
Trade namesActos, others
AHFS/Drugs.comMonograph
MedlinePlusa699016
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
Drug classThiazolidinedione
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%
MetabolismLiver (CYP2C8)
Elimination half-life3–7 hours
ExcretionBile 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 InfoCard100.114.441 Edit this at Wikidata
Chemical and physical data
FormulaC19H20N2O3S
Molar mass356.44 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point183 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) checkY
  • Key:HYAFETHFCAUJAY-UHFFFAOYSA-N checkY
  (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]

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 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133rd most commonly prescribed medication in the United States, with more than 4 million prescriptions.[6][7] It was withdrawn in France and Germany in 2011.[8][9][10]

Medical uses

[edit]

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

[edit]

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

[edit]

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

[edit]

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]

Drug interactions

[edit]

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

Mechanism of action

[edit]

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.

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.[25][26]

Leriglitazone is a metabolite.[27]

Society and culture

[edit]

Economics

[edit]

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

[edit]

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

[edit]

Psychiatry

[edit]

Bipolar disorder

[edit]

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

[edit]

There is research that suggests that pioglitazone may be useful for treating major depression.[31]

Other illnesses

[edit]

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]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pioglitazone

View on Grokipedia
from Grokipedia
Pioglitazone is an oral antidiabetic medication from the class, primarily used to manage mellitus in adults by improving insulin sensitivity and reducing blood glucose levels. It acts as an agonist for (PPAR-γ), which enhances in peripheral tissues and decreases hepatic , thereby lowering without directly stimulating insulin secretion. Marketed under the brand name Actos by Takeda Pharmaceuticals, pioglitazone was approved by the U.S. (FDA) on July 15, 1999, as an adjunct to diet and exercise for glycemic control, and it remains available in generic forms. It is typically administered once daily in doses ranging from 15 to 45 mg, either as monotherapy or in combination with other agents like metformin, , or insulin, making it a versatile option for patients with insulin-resistant diabetes. While effective for long-term blood sugar management, pioglitazone carries notable risks, including fluid retention, , and an increased risk of congestive , particularly in patients with pre-existing cardiac conditions. It is contraindicated in individuals with New York Heart Association Class III or IV , active , or , and the FDA has required updated labeling since 2011 to warn of a potential association with based on observational studies, though a 2016 review concluded the benefits outweigh this risk for most patients. Other adverse effects may include , bone fractures, and , necessitating regular monitoring of renal, hepatic, and cardiac function during treatment. Despite these concerns, pioglitazone continues to be prescribed globally, with ongoing research exploring its potential benefits in conditions like non-alcoholic (NASH) due to its effects on and .

Medical Uses

Glycemic Control in Type 2 Diabetes

Pioglitazone was approved by the U.S. in 1999 as an adjunct to diet and exercise to improve glycemic control in adults with mellitus. It is indicated for use as monotherapy or in combination with metformin, , or insulin when diet and exercise alone do not provide adequate control. Clinical trials have demonstrated that pioglitazone monotherapy reduces HbA1c levels by 0.5% to 1.4% over 16 to 26 weeks, with greater reductions observed in combination regimens, such as an additional 0.6% to 1.0% when added to metformin or . The recommended starting dose is 15 mg or 30 mg orally once daily, which may be titrated in increments of 15 mg at intervals of 4 to 8 weeks based on glycemic response, up to a maximum of 45 mg daily. Therapy should always be integrated with modifications, including calorie-controlled diet and regular physical exercise, to optimize outcomes and minimize the need for higher doses. Lower starting doses of 15 mg are advised for patients with New York Heart Association Class I or II to reduce fluid retention risks. Long-term use of pioglitazone has shown cardiovascular benefits in high-risk patients with . The PROactive trial, a 3-year prospective study involving over 5,000 participants with a history of macrovascular disease, found that pioglitazone reduced the main secondary composite endpoint of all-cause mortality, non-fatal , and non-fatal by 16% (HR 0.84, 95% CI 0.72-0.98) compared to , alongside improvements in glycemic control. Individual components showed a trend toward reduced non-fatal (HR 0.83, 95% CI 0.65-1.06) and a significant reduction in all (HR 0.77, 95% CI 0.59-1.00). Updated meta-analyses as of 2025 confirm these findings, indicating pioglitazone's association with lower risks of recurrent and overall cardiovascular adverse events in patients with , supporting its role in secondary prevention. Pioglitazone is approved exclusively for adults with and is not indicated for or , as it does not promote insulin secretion and may exacerbate in insulin-deficient states. Its efficacy relies on improving insulin sensitivity via (PPAR-γ) agonism, making it unsuitable for pediatric populations or non-type 2 diabetic conditions.

Off-Label Use in Non-Alcoholic Steatohepatitis

Pioglitazone, a that activates (PPAR-γ), exerts its effects in non-alcoholic (NASH) primarily through insulin sensitization, which reduces hepatic fat accumulation () and attenuates by modulating secretion and in the liver. This mechanism addresses core pathophysiological features of NASH, such as insulin resistance-driven and inflammatory cascades, independent of its antidiabetic actions. The landmark Pioglitazone vs. vs. for the Treatment of Nondiabetic Patients with Nonalcoholic (PIVENS) trial, a multicenter randomized controlled study, demonstrated histological benefits of pioglitazone at 30 mg daily for 96 weeks in nondiabetic adults with biopsy-proven . In this trial, 47% of pioglitazone-treated patients achieved resolution of (defined as absence of , , and ballooning without worsening), compared to 21% in the placebo group (P=0.001), alongside significant improvements in steatosis and lobular scores. Although the primary composite endpoint of NAFLD activity score reduction did not reach prespecified significance (34% vs. 19%, P=0.04), these findings established pioglitazone's potential to improve key histological features. More recent evidence from 2025 supports sustained benefits, particularly in patients with and . A Brazilian multicenter retrospective study of 65 patients with metabolic dysfunction-associated steatotic (MASLD, formerly ) receiving pioglitazone (30-45 mg daily) for 1-10 years reported significant reductions in controlled attenuation parameter () scores indicative of hepatic (P=0.002 in the 4-10 year group) and improvements in assessment using the FAST score (P=0.042 for 1-3 years; P=0.012 for 4-10 years), alongside lowered liver enzymes like ALT and GGT. The ongoing AIM 2 trial (NCT04501406) is evaluating low-dose pioglitazone (15 mg daily) in patients with biopsy-proven , aiming to confirm histological improvements with reduced side effects through paired liver biopsies after 72 weeks. Typical off-label dosing for ranges from 30-45 mg daily for 6-24 months, often starting at 15-30 mg to minimize adverse effects, with efficacy monitored via non-invasive fibrosis markers such as the FIB-4 index to track regression. However, pioglitazone remains unapproved by the FDA for treatment, limiting its use to specialists who weigh benefits against risks like and fluid retention, particularly in patients without contraindications. In comorbid , it may concurrently support glycemic control.

Contraindications and Precautions

Heart Failure Risks

Pioglitazone carries an absolute contraindication for initiation or continuation in patients with established New York Heart Association (NYHA) Class III or IV , due to the risk of fluid retention leading to exacerbation or precipitation of congestive . This restriction stems from a black box warning issued by the U.S. in 2007, which highlights that thiazolidinediones like pioglitazone can cause or worsen , particularly in patients with underlying cardiac dysfunction. In patients with NYHA Class I or II , pioglitazone should only be used with caution, starting at the lowest effective dose, and requires close monitoring for signs of deterioration. The risk of heart failure is linked to pioglitazone's activation of (PPAR-γ), which can lead to fluid retention through mechanisms including increased and vascular changes, resulting in that can overload the cardiovascular system. Clinical trials have reported an incidence of new or worsening heart failure ranging from approximately 1% to 2.3% in pioglitazone-treated patients, compared to 1.8% in controls, with the risk appearing dose-related and lower at 15 mg daily versus 45 mg daily. This incidence increases notably when pioglitazone is co-administered with insulin, where rates can reach 15% or higher, amplifying the potential for heart failure hospitalization without elevating overall cardiovascular mortality. Current guidelines, as updated in 2025 by sources such as , emphasize proactive monitoring for in all patients starting pioglitazone, including assessment of baseline cardiac status through symptoms and physical exam, followed by regular surveillance for signs of such as dyspnea, peripheral edema, or rapid weight gain (e.g., exceeding 2 kg in a week), which may warrant immediate dose reduction or discontinuation. Per the 2025 Standards of Care, pioglitazone may still be considered in patients with for cardiovascular risk reduction, with careful monitoring in those with risk factors. If develops or worsens, pioglitazone should be stopped, and management aligned with standard protocols, underscoring the need for individualized risk-benefit evaluation in vulnerable populations.

Bladder Cancer and Malignancy Concerns

In 2011, the U.S. (FDA) issued a safety warning about pioglitazone based on interim results from a large observational conducted by Northern California, which suggested a potential increased risk of with prolonged use. The study, involving over 193,000 diabetic patients, reported a dose- and duration-dependent association, with adjusted hazard ratios of 1.4 (95% CI 1.03–2.0) for use exceeding 24 months and 1.4 (95% CI 0.96–2.1) for cumulative doses greater than 28 g, compared to non-users. Epidemiological reassessments, including the European Medicines Agency's (EMA) 2011 review and more recent analyses up to 2024, have affirmed a small absolute risk of , estimated at approximately 1 excess case per 10,000 patient-years among long-term users, though the association remains controversial in some randomized trials and meta-analyses. As a result, pioglitazone is contraindicated in patients with active or a history of uninvestigated macroscopic , with cautious use recommended for those with prior after weighing benefits and risks. Patient monitoring guidelines emphasize vigilance for early signs of , prompt evaluation of any urinary symptoms such as , , or urgency, and immediate discontinuation of pioglitazone if is confirmed. Studies on other malignancies indicate no consistent evidence of increased risk with pioglitazone use, such as for , pancreatic, or colorectal cancers, though the theoretical role of PPAR-γ agonism in modulating tumor suppression or promotion continues to be investigated in preclinical models without clear clinical implications.

Adverse Effects

Common Side Effects

Pioglitazone is associated with several common side effects, primarily affecting metabolic and , as observed in clinical trials involving patients with . These effects are generally mild and occur at higher rates than with , though many are also prevalent in the general . Upper infections were reported in approximately 13-15% of patients on pioglitazone monotherapy or , compared to 8-9% with . Headaches occurred in 5-9% of patients, versus 6-7% on , suggesting a possible but not definitively causal association. Weight gain is a frequent , with patients experiencing an average increase of 2-4 kg over one year of treatment, primarily due to fat redistribution from visceral to subcutaneous depots and enhanced mediated by (PPAR-γ) activation. This affects about 10-15% of users noticeably, though overall incidence is higher when including minor changes. , manifesting as swelling in the legs or ankles, occurs in 5-15% of patients and is often dose-dependent, resolving upon dose reduction or discontinuation. Mild , characterized by a 2-4% decrease in levels due to hemodilution from increased plasma volume, has been noted in clinical studies but is typically and without . Management strategies include counseling on diet and exercise to mitigate , as these interventions can help counteract fat accumulation. For , cautious use of diuretics may be employed under medical supervision to address retention, while monitoring for signs of .

Serious Adverse Effects

Pioglitazone use has been associated with an increased risk of bone fractures, particularly in postmenopausal women, due to its activation of peroxisome proliferator-activated receptor gamma (PPAR-γ), which promotes adipocyte differentiation at the expense of osteoblast activity and bone formation. A 2025 meta-analysis of randomized clinical trials reported a risk ratio of 1.21 (95% CI 1.01-1.45) overall, with the effect more pronounced in women (RR 1.56; 95% CI 1.20-2.02). A 2020 meta-analysis reported odds approximately doubled in women (MH-OR 2.05; 95% CI 1.28-3.27). Post-marketing surveillance and long-term studies indicate a 1.5- to 2-fold higher incidence in women over 65 years, often involving peripheral fractures like those in the distal forearm or foot, necessitating consideration of bone density screening in at-risk patients prior to initiation. Diabetic macular edema (DME) represents another serious ocular complication, occurring in approximately 0.1-1% of pioglitazone-treated patients, with higher rates (up to 1.3%) observed in those concurrently using insulin or with preexisting . This fluid accumulation in the can lead to vision loss and is thought to stem from pioglitazone-induced fluid retention exacerbating retinal . Guidelines recommend prompt ophthalmologic evaluation, including fundus examination and , for any patient reporting visual changes while on therapy, with discontinuation considered if DME is confirmed and attributable to the drug. Hepatotoxicity is rare with pioglitazone, manifesting as asymptomatic elevations in (ALT) levels exceeding three times the upper limit of normal (ULN) in less than 1% of patients (0.26% incidence), though it is contraindicated in those with active or baseline ALT greater than 2.5 times ULN. Prior data show rates comparable to (0.25%). Monitoring of (LFTs), including ALT, is advised prior to starting therapy and quarterly during the first year, followed by periodic checks, with immediate discontinuation if ALT exceeds three times ULN or develops. The risk of with pioglitazone monotherapy is low, affecting fewer than 1% of patients, as it enhances insulin sensitivity without stimulating insulin secretion. However, this risk increases in combination regimens, particularly with or insulin, where enhanced glucose-lowering effects can precipitate symptomatic or severe episodes requiring intervention.

Drug Interactions

Interactions with Antidiabetic Agents

Pioglitazone, when combined with insulin or , exhibits pharmacodynamic interactions that increase the risk of due to additive effects on glucose lowering. In a 16-week placebo-controlled trial, the incidence of reported was 3.7% with pioglitazone 30 mg added to compared to 0.5% with ; rates reached up to 15.7% in a 24-week study, while rates reached up to 48% when added to insulin. To mitigate this risk, a dose reduction of insulin by 10-25% or by up to 20% is recommended upon initiation of pioglitazone if occurs, with adjustments individualized based on glycemic response. In contrast, pioglitazone combined with metformin shows no significant pharmacokinetic interaction, as evidenced by minimal changes in pioglitazone exposure (AUC decreased by 3%, Cmax by 5%). This combination provides synergistic pharmacodynamic effects, achieving an additional HbA1c reduction of approximately 0.8% beyond metformin monotherapy without elevating the risk of adverse events, including . Gemfibrozil, a strong inhibitor of CYP2C8 (the primary for pioglitazone ), causes a pharmacokinetic interaction by increasing pioglitazone AUC approximately 3-fold and prolonging its from 8 to 23 hours. Consequently, the pioglitazone dose should be limited to 15 mg daily when co-administered with to avoid excessive exposure. When pioglitazone is used with insulin secretagogues such as , frequent of blood glucose (SMBG) is advised to detect and manage potential early. Pioglitazone is primarily metabolized via CYP2C8 and in the liver, which underpins these interaction profiles.

Interactions with Other Medications

Pioglitazone is primarily metabolized by the cytochrome P450 enzyme CYP2C8, with minor contributions from CYP3A4, making it susceptible to interactions with drugs that induce or inhibit these enzymes. Rifampin, a potent inducer of CYP2C8 and CYP3A4, significantly reduces pioglitazone exposure, decreasing its area under the curve (AUC) by 54% and maximum concentration (C_max) by 5%. This interaction may necessitate an increase in pioglitazone dosage up to a maximum of 45 mg daily, with adjustments based on clinical glycemic response. Coadministration with oral contraceptives containing results in a modest reduction of ethinyl estradiol levels, with AUC decreased by 11% and C_max by 13%, potentially impacting contraceptive efficacy; patients should consider alternative or additional contraception methods. Topiramate, another CYP2C8 inducer, moderately decreases pioglitazone AUC by 15% without altering C_max, while , a strong CYP2C8 inhibitor, increases pioglitazone AUC by 34% and C_max by 14%; in both cases, close monitoring of glycemic control is recommended to guide any necessary dose adjustments. Despite shared metabolism via , coadministration with results in a 24% decrease in pioglitazone AUC and 31% decrease in C_max, but this interaction is not considered clinically significant and requires no routine dose modification. As of 2025, no new major drug interactions involving pioglitazone have been identified.

Pharmacology

Mechanism of Action

Pioglitazone acts primarily as a selective of the (PPARγ), a ligand-activated nuclear expressed in adipocytes, hepatocytes, and other insulin-sensitive tissues. By binding to the ligand-binding domain of PPARγ, pioglitazone induces a conformational change that promotes heterodimerization with the (RXR). This complex then binds to specific peroxisome proliferator response elements (PPREs) in the DNA, facilitating the recruitment of coactivators and the transcriptional activation of target genes involved in glucose and lipid metabolism. The simplified model of receptor activation can be represented as: PPARγ+Pioglitazone→PPARγ/RXR heterodimer→Transcriptional activation of target genes (e.g., [adiponectin](/page/Adiponectin) upregulation)\text{PPAR}\gamma + \text{Pioglitazone} \to \text{PPAR}\gamma/\text{RXR heterodimer} \to \text{Transcriptional activation of target genes (e.g., [adiponectin](/page/Adiponectin) upregulation)} This process upregulates genes that enhance glucose uptake, such as those promoting translocation to the plasma in adipocytes and cells, thereby increasing insulin-dependent glucose disposal. In hepatocytes, it suppresses gluconeogenic enzymes like and glucose-6-phosphatase, reducing hepatic glucose output. Overall, pioglitazone improves peripheral and hepatic insulin sensitivity without directly stimulating beta-cell insulin secretion or acting as an insulin secretagogue. Additionally, pioglitazone promotes by inducing differentiation and expression of fatty acid-binding proteins, contributing to fat redistribution. It also exhibits weak at PPARα, which supports its lipid-modifying effects, including reductions in triglycerides and increases in HDL , while having variable impacts on LDL . The onset of glycemic effects typically begins within 1 to 2 weeks, with full therapeutic benefits on insulin sensitivity and glucose control achieved after 2 to 3 months of continuous treatment, reflecting the time required for changes and metabolic adaptations.

Pharmacokinetics

Pioglitazone is well absorbed following , with a mean absolute of approximately 83%. Peak plasma concentrations (T_max) are achieved within 2 hours in the fasting state, though slightly delays this to 3-4 hours without altering the overall extent of absorption (area under the curve, AUC). Steady-state concentrations of the parent drug and its active metabolites are reached after about 7 days of once-daily dosing, and the drug exhibits linear over the therapeutic dose range of 15-45 mg. The apparent (V_d/F) of pioglitazone is approximately 0.63 L/kg following single-dose administration, indicating moderate tissue distribution. The drug is highly bound to plasma proteins (>99%), primarily , as are its major active metabolites M-III and M-IV (>98% bound). Pioglitazone undergoes extensive hepatic metabolism primarily via enzymes CYP2C8 and , forming several metabolites, including the active keto-derived M-III and hydroxy-derived M-IV. These active metabolites contribute significantly to the drug's efficacy, with M-III providing roughly equivalent activity to the parent compound and M-IV accounting for about 50% of the total pharmacological effect when considering concentrations, activity, and protein binding. The elimination of the parent pioglitazone is 3-7 hours, while that of M-III and M-IV ranges from 16-24 hours, leading to prolonged exposure primarily through these metabolites. Excretion occurs mainly via biliary secretion into feces (65-80% of dose as metabolites), with 15-30% recovered in urine, predominantly as metabolites and less than 2% as unchanged parent drug. The mean apparent oral clearance (CL/F) is 5-7 L/h. No dose adjustment is required for mild to moderate renal impairment (creatinine clearance ≥30 mL/min); in severe renal impairment, elimination half-lives remain unchanged but exposure (AUC) to active metabolites M-III and M-IV is increased (by approximately 116% and 137%, respectively). Pharmacokinetic data indicate unchanged half-lives but increased exposure in hemodialysis patients; data are not available for peritoneal dialysis. No dose adjustment is necessary in renal impairment, though caution is advised in severe cases due to higher metabolite exposure and limited clinical data. In hepatic impairment (Child-Pugh class B or C), peak concentrations are reduced by about 45%, but AUC is unaffected, with no dose adjustment needed. Pharmacokinetic variability exists across populations. In females, C_max and AUC values for pioglitazone are increased by 20-60% compared to males, corresponding to approximately 23% longer and slower clearance, though no dose adjustment is recommended. Elderly patients exhibit about a 21% increase in AUC and a prolonged (around 10 hours versus 7 hours in younger adults), but these changes are not clinically significant. No specific pharmacokinetic data are available for pediatric or ethnic differences, and pioglitazone is not indicated for use in children.

Society and Culture

Brand Names and Availability

Pioglitazone is marketed under the primary brand name Actos by Takeda Pharmaceuticals, available in tablet formulations of 15 mg, 30 mg, and 45 mg for oral administration. These dosages allow for flexible titration based on patient response and tolerability, with the maximum recommended daily dose being 45 mg. Following the expiration of key U.S. patents in 2012, generic versions of pioglitazone became widely available, significantly increasing and reducing costs for patients. In the , generic pioglitazone is approved and distributed through multiple manufacturers, often in the same 15 mg, 30 mg, and 45 mg strengths as the branded product. In , generic brands such as Pioz (USV Limited) and GlitaZone () are commonly prescribed, alongside numerous combination formulations tailored to local markets. As of 2025, generic pioglitazone dominates the global market, comprising the vast majority of prescriptions due to patent expirations and established . Fixed-dose combination products enhance convenience for patients requiring multiple antidiabetic agents. Actoplus Met combines pioglitazone with metformin hydrochloride in strengths such as 15 mg/500 mg and 15 mg/850 mg tablets. Duetact pairs pioglitazone with glimepiride (a sulfonylurea) in formulations like 30 mg/2 mg and 30 mg/4 mg. Oseni integrates pioglitazone with alogliptin (a DPP-4 inhibitor) in options including 15 mg/25 mg and 30 mg/25 mg tablets. These combinations are available in various countries, including the U.S. and EU, with generic equivalents emerging post-patent expiry. Pioglitazone is approved for use in over 50 countries worldwide, including the , member states, , , and many in and , primarily as a prescription for management. It remains strictly prescription-only globally, with no over-the-counter availability as of 2025. Regulatory scrutiny has occurred in select regions; for instance, suspended pioglitazone in June 2011 due to concerns over a potential increased of based on observational data, but following an EMA review confirming benefits outweigh risks with appropriate warnings, the suspension was lifted in September 2011 under restricted conditions. Similar warnings for long-term use and have been added to labels in the U.S. and since 2011, without full withdrawals.

Economics and Patent History

Pioglitazone was developed by , a Japanese firm, as part of a series of compounds aimed at treating . The drug, marketed under the brand name Actos, underwent extensive clinical development, including Phase III trials that demonstrated its efficacy in improving glycemic control. It received approval from the (FDA) on July 15, 1999, marking its entry into the U.S. market as an adjunct to diet and exercise for adults with . The commercial success of pioglitazone peaked in the late 2000s, with global sales reaching approximately $3.4 billion in , driven primarily by strong demand in the U.S. and other developed markets where it became a leading oral antidiabetic agent. Takeda's on the active ingredient expired in 2012, allowing generic manufacturers such as Ranbaxy, , and Teva to launch versions in the U.S. starting August 17, 2012. This led to a significant price reduction, with generic pioglitazone tablets dropping by about 80% compared to the brand-name product; for instance, 30 mg tablets fell from over $4 each to $0.50–$1, enhancing accessibility for patients. As of 2025, the global market for pioglitazone hydrochloride remains substantial, with annual sales estimated at around $1 billion, largely propelled by demand in emerging markets where prevalence is rising rapidly. Cost-effectiveness analyses underscore its value in , with incremental cost-effectiveness ratios typically ranging from $10,000 to $20,000 per (QALY) gained, depending on dosage and patient population; for example, long-term modeling from the PROactive trial showed an incremental cost of $44,105 per QALY for pioglitazone versus in high-risk patients. These metrics position pioglitazone as a favorable option in resource-limited settings. The drug's history includes notable controversies, particularly around data disclosure. In , Takeda agreed to a $2.4 billion settlement to resolve over 9,000 lawsuits in the U.S., primarily alleging that the company concealed risks of associated with long-term pioglitazone use and promoted the drug off-label for conditions like . This payout, one of the largest in pharmaceutical litigation, covered claims without admitting liability but highlighted ongoing of the drug's risk-benefit profile.

Research Directions

Psychiatric Applications

Pioglitazone, a (PPAR-γ) agonist primarily used for , has been investigated as an adjunctive therapy for mood disorders, including bipolar depression and (MDD), due to its potential to address overlapping metabolic and inflammatory pathways in psychiatric conditions. Early proof-of-concept studies from 2014 explored its use in patients with and comorbid , showing improvements in depressive symptoms when added to mood stabilizers at doses of 15-30 mg/day over 8 weeks. Subsequent randomized controlled trials (RCTs) between 2015 and 2019 tested doses of 30-45 mg/day as adjunct to antidepressants or mood stabilizers, reporting mixed results on depression severity, with some evidence of benefit in patients exhibiting or metabolic disturbances. The hypothesized mechanism involves PPAR-γ activation modulating and central , which may contribute to mood dysregulation. By enhancing insulin sensitivity in the brain, pioglitazone is thought to reduce pro-inflammatory levels and improve in regions like the hippocampus, potentially alleviating depressive symptoms in metabolically compromised individuals. Preclinical models support this, demonstrating anti-inflammatory effects in the hippocampus that correlate with antidepressant-like behaviors. Key trials include an open-label study (NCT00835120) in 37 patients with and /, where adjunctive pioglitazone (15-30 mg/day) led to significant mood improvement, with Inventory of Depressive Symptomatology scores decreasing by approximately 17 points from baseline over 8 weeks. A 2015 double-blind RCT (n=44) in bipolar depression without found 30 mg/day adjunctive pioglitazone reduced Hamilton Depression Rating Scale (HAM-D) scores significantly more than (p<0.01 at weeks 2-6), with reductions of 5-10 points observed in responders. However, a 2019 RCT (n=37) reported no benefit at 15-45 mg/day, with showing greater HAM-D reductions (approximately 12 points vs. 7 points). A 2024 of RCTs indicated moderate effect sizes (standardized mean difference 0.4-0.6) for pioglitazone in MDD and bipolar depression subgroups with metabolic features, though overall effects were small and limited by heterogeneous, small-sample studies (total n<200 across trials). Despite these findings, pioglitazone is not approved for psychiatric indications, and its use remains investigational due to inconsistent across trials and concerns over cardiometabolic risks, such as fluid retention and exacerbation, particularly in patients with prevalent comorbidities like or . Benefit-risk profiles favor cautious application in those with co-occurring , but larger confirmatory trials are needed.

Metabolic and Neurodegenerative Diseases

Pioglitazone has been extensively studied for its potential role in treating non-alcoholic steatohepatitis (), a progressive form of metabolic dysfunction-associated steatotic (MASLD), through its ability to enhance insulin sensitivity and reduce hepatic inflammation via (PPARγ) activation. In a phase II randomized -controlled trial evaluating low-dose deuterium-stabilized pioglitazone (PXL065, 7.5–22.5 mg daily), 35–50% of patients achieved at least a one-stage improvement in liver without worsening of , compared to 17% in the group, alongside reductions in liver fat content and favorable changes in non-invasive fibrosis markers like procollagen III N-terminal propeptide (PIIINP). A multicenter Brazilian retrospective study of 65 patients with MASLD treated with pioglitazone (30–45 mg daily) for up to 10 years reported significant reductions in liver stiffness measured by vibration-controlled transient (from median 8.9 kPa to 6.5 kPa, p < 0.001) and hepatic grade (from 2.4 to 1.8, p < 0.001), suggesting histological benefits including regression in a substantial proportion of cases. These findings indicate pioglitazone's superiority over in improving liver . Pioglitazone remains off-label for , following the FDA's approval of in March 2024 as the first treatment for NASH with moderate to advanced . In neurodegenerative contexts, pioglitazone's investigation for (AD) centers on its capacity to address , a key factor in AD pathogenesis, by modulating PPARγ to decrease , enhance cerebral blood flow, and reduce amyloid-beta accumulation. The phase III TOMORROW trial (2015), involving over 3,400 at-risk individuals, tested low-dose pioglitazone (0.8 mg daily) but failed to demonstrate a delay in onset overall; however, post-hoc analyses in insulin-resistant subsets suggested modest stabilization of cognitive function, with smaller phase II pilots showing mean improvements of 1–3 points on scales like the (ADAS-Cog) in treated groups versus . As of November 2025, no large-scale ongoing monotherapy trials for pioglitazone in AD were identified, though a November 2025 study explored its use in combination with and , reporting potential benefits in preventing AD progression through metabolic and inflammatory targeting. Earlier observational data suggested a 20–30% for in pioglitazone users with , but a 2025 found no significant association. Despite these mechanistic insights, no regulatory approval for AD exists. The shared therapeutic rationale for pioglitazone in both and AD lies in overcoming organ-specific —hepatic in NASH and cerebral in AD—leading to reduced progression in the liver and attenuated neuronal loss in the , with modest effect sizes observed across studies (e.g., of 0.80 for disease progression in meta-analyses of diabetic cohorts). However, gaps persist, including the need for large-scale randomized controlled trials to confirm and in non-diabetic populations, as current evidence derives from smaller or post-hoc analyses; as of November 2025, pioglitazone remains unapproved for these indications.

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