Pioglitazone

Generic Name: Pioglitazone
Brand Names: Actos, Glustin, Glitaz, Pioz, Zactos (international variations)

Drug Class: Thiazolidinedione (TZD); Insulin sensitizer
Pharmaceutical Category: Oral antidiabetic agent
Formulations: Oral tablets (15 mg, 30 mg, 45 mg)
Route of Administration: Oral

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1. Pharmacological Classification

Pioglitazone is an oral antihyperglycemic agent of the thiazolidinedione class. It acts primarily as an insulin sensitizer, improving glycemic control in type 2 diabetes mellitus (T2DM) by targeting insulin resistance, a core pathophysiological defect in T2DM. Pioglitazone is not used in type 1 diabetes or diabetic ketoacidosis.

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2. Mechanism of Action

Pioglitazone selectively activates peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor predominantly expressed in adipose tissue, muscle, and the liver.

Upon activation, PPAR-γ modulates the transcription of insulin-responsive genes involved in:

• Glucose uptake

• Lipid metabolism

• Adipocyte differentiation

Key pharmacodynamic effects include:

• Increased peripheral glucose uptake (primarily in adipose and muscle tissue)

• Reduced hepatic glucose production

• Improved insulin sensitivity without increasing insulin secretion

• Reduction in circulating free fatty acids and triglycerides

• Shift in fat distribution from visceral to subcutaneous stores

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3. Therapeutic Indications

A. Approved Indications

• Type 2 Diabetes Mellitus (T2DM)

  • As monotherapy (if metformin is contraindicated or not tolerated)

  • As dual or triple oral therapy in combination with:

    • Metformin

    • Sulfonylureas

    • DPP-4 inhibitors

    • SGLT2 inhibitors

  • In combination with insulin (when metformin is insufficient)

B. Off-label Uses

• Polycystic Ovary Syndrome (PCOS)

• Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)

• Prediabetes (insulin resistance prevention)

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4. Dosage and Administration

Initial Dose

• 15 mg or 30 mg once daily with or without food

• Titrate up at intervals of 4–8 weeks based on glycemic response

Maximum Dose

• 45 mg once daily

Renal Impairment

• No dose adjustment needed in mild to moderate renal impairment

• Use with caution in end-stage renal disease due to fluid retention risk

Hepatic Impairment

• Avoid in patients with active liver disease or significantly elevated LFTs

• Baseline and periodic liver function monitoring required

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5. Pharmacokinetics

• Absorption: Well absorbed orally; not affected by food

• Bioavailability: ~83%

• Peak plasma level: ~2 hours

• Distribution: High protein binding (~99%)

• Metabolism: Hepatic via CYP2C8 and to a lesser extent CYP3A4

• Active metabolites: Yes (contribute to efficacy)

• Elimination: Bile and feces (~55%), urine (~15%)

• Half-life: 3–7 hours (pioglitazone), up to 24 hours (active metabolites)

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6. Contraindications

• Heart failure (NYHA class III or IV) due to risk of fluid retention

• Active bladder cancer or history of bladder cancer

• Uninvestigated macroscopic hematuria

• Severe hepatic impairment

• Type 1 diabetes mellitus or diabetic ketoacidosis

• Hypersensitivity to pioglitazone or any excipients

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7. Warnings and Precautions

Cardiac Risk

• Fluid retention leading to congestive heart failure (CHF)

• Monitor for signs of dyspnea, edema, weight gain

• Combination with insulin increases CHF risk

Bladder Cancer

• Long-term use (especially >1 year) associated with increased bladder cancer risk in some studies

• Contraindicated in active bladder cancer or unexplained hematuria

Hepatotoxicity

• Baseline and periodic LFT monitoring required

• Discontinue if ALT levels >3x upper normal limit

Fracture Risk

• Increased risk of bone fractures in women (particularly distal limb fractures)

• Mechanism thought to be PPAR-γ–mediated suppression of osteoblastogenesis

Macular Edema

• Rare cases of diabetic macular edema with visual disturbances

• Regular ophthalmologic monitoring advised

Weight Gain

• Common due to fluid retention and adipogenesis

• Advise lifestyle modification to mitigate effect

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8. Adverse Effects

Common (≥5%)

• Peripheral edema

• Weight gain

• Headache

• Fatigue

• Sinusitis or upper respiratory infection

• Myalgia

Less Common (1–5%)

• Increased ALT or liver enzymes

• Dizziness

• Hypoglycemia (especially with sulfonylureas or insulin)

• Anemia

• Arthralgia

Serious (<1%)

• Heart failure

• Bladder cancer

• Liver injury

• Macular edema

• Rhabdomyolysis (rare)

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9. Drug Interactions

CYP2C8 Substrates/Inhibitors

• Gemfibrozil: Inhibits CYP2C8 → increases pioglitazone levels (↑ toxicity risk)

• Rifampin: Induces CYP2C8 → decreases efficacy of pioglitazone

• Dose adjustments may be required based on clinical response

Insulin and Secretagogues

• Additive risk of hypoglycemia and fluid retention when used with insulin or sulfonylureas

Oral Contraceptives (ethinyl estradiol/norethindrone)

• Pioglitazone may reduce plasma concentrations and efficacy

• Alternative contraception may be advised

Diuretics

• Monitor for worsening edema or weight gain

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10. Pregnancy and Lactation

Pregnancy

• Category C (old classification)

• Animal studies show fetal harm; human data limited

• Not recommended in pregnancy; insulin preferred

Lactation

• Unknown if excreted in human milk

• Discontinue drug or breastfeeding based on risk-benefit analysis

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11. Use in Special Populations

Elderly

• Higher risk of heart failure, edema, and bone fractures

• Use with caution; monitor closely

Renal Impairment

• No dose adjustment required in mild/moderate impairment

• Use with caution due to fluid retention risk

Hepatic Impairment

• Avoid in active liver disease or ALT >2.5x ULN

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12. Monitoring Parameters

• Fasting blood glucose and HbA1c every 3–6 months

• Liver function tests at baseline, then periodically

• Weight and signs of fluid retention regularly

• Hematuria or urinary symptoms (bladder cancer screening)

• Ophthalmologic exam for visual changes

• Fracture risk assessment, especially in postmenopausal women

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13. Formulations and Brand Availability

• Tablets: 15 mg, 30 mg, 45 mg

• Combination formulations:

  • Pioglitazone + Metformin (e.g., Actoplus Met)

  • Pioglitazone + Glimepiride (e.g., Duetact)

  • Pioglitazone + Alogliptin (e.g., Oseni)

• Brands:

  • Actos (Takeda)

  • Glustin (Europe)

  • Pioz, Zactos, Glitaz (Asia, generics)

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14. Comparative Notes and Clinical Pearls

• Compared to rosiglitazone, pioglitazone is associated with improved lipid profile (↓ triglycerides, ↑ HDL) and lower CV risk

• Unlike metformin, pioglitazone is weight-positive and causes fluid retention

• Effect on glycemic control takes several weeks to manifest due to nuclear receptor mechanism

• TZDs are the only oral antidiabetics with proven durability in glycemic control (e.g., per ADOPT trial)