Pioglitazone

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
• Used as monotherapy or in combination with other antidiabetic agents (e.g., metformin, sulfonylureas, insulin) to improve glycemic control in adults.
• Suitable for patients who are intolerant to metformin or in whom metformin is contraindicated.

Clinically Accepted Off-label Uses:

• Polycystic Ovary Syndrome (PCOS):
• Used to improve insulin sensitivity and menstrual regularity.
• Nonalcoholic Steatohepatitis (NASH):
• May reduce hepatic inflammation and fibrosis in biopsy-proven NASH, especially in patients with coexisting T2DM or insulin resistance.
• Type 1 Diabetes (Adjunct):
• Occasionally studied as an adjunct to insulin in selected patients to reduce insulin requirements, though not officially approved.

Route: Oral
Available Dosage Forms: 15 mg, 30 mg, and 45 mg tablets

Adults with Type 2 Diabetes Mellitus:

• Initial Dose:
• 15 mg or 30 mg once daily, with or without food.
• Maintenance Dose:
• May be increased in 15 mg increments at intervals of at least 3 months based on glycemic response.
• Maximum Dose:
• 45 mg once daily.

Combination Therapy:

• When combined with insulin or sulfonylureas, monitor closely for hypoglycemia. Consider reducing the dose of sulfonylurea or insulin accordingly.

Elderly:

• No specific dose adjustment required, but monitor renal function and signs of fluid retention.

Renal Impairment:

• No dose adjustment necessary. However, use with caution in patients with renal dysfunction when used in combination with insulin or other agents causing hypoglycemia.

Hepatic Impairment:

• Contraindicated in active liver disease or elevated ALT >2.5 times ULN. Monitor LFTs regularly during treatment.

Pioglitazone is a thiazolidinedione (TZD) and acts as an agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-γ). This nuclear receptor modulates the transcription of insulin-responsive genes involved in glucose and lipid metabolism. Activation of PPAR-γ enhances insulin sensitivity in adipose tissue, skeletal muscle, and the liver, leading to improved glucose uptake and reduced hepatic glucose output. Pioglitazone also redistributes fat from visceral to subcutaneous depots and may exert anti-inflammatory effects, contributing to improved metabolic outcomes in insulin-resistant patients.

• Absorption:
• Rapidly absorbed after oral administration.
• Peak plasma concentration: ~2 hours (Tmax)
• Bioavailability: ~83%
• Distribution:
• Widely distributed; plasma protein binding ~99% (mainly to albumin)
• Metabolism:
• Extensively metabolized in the liver via CYP2C8 (major) and CYP3A4 (minor) pathways.
• Major metabolites (M-III and M-IV) are active.
• Elimination:
• Mainly excreted in the feces (55%) and urine (15%) as metabolites.
• Terminal half-life:
• Pioglitazone: ~3–7 hours
• Active metabolites: up to 16–24 hours

• Pregnancy:
• FDA Category C
• Animal studies have shown fetal harm at high doses; no adequate data in pregnant women.
• Should be used during pregnancy only if the potential benefit outweighs the potential risk.
• Insulin is preferred for glycemic control during pregnancy.
• Lactation:
• Unknown whether Pioglitazone is excreted into human breast milk.
• Use caution in breastfeeding women; avoid if safer alternatives are available.

• Primary Class: Antidiabetic Agent
• Subclass: Thiazolidinedione (Insulin Sensitizer)

• Known hypersensitivity to Pioglitazone or any tablet component
• NYHA Class III or IV Heart Failure
• Active liver disease or elevated serum ALT >2.5 times upper limit of normal
• History of bladder cancer
• Diabetic ketoacidosis

• Heart Failure Risk:
• May cause or exacerbate congestive heart failure; monitor for edema, weight gain, and shortness of breath.
• Bladder Cancer:
• Long-term use associated with increased risk; avoid in patients with active bladder cancer or history of bladder tumors.
• Liver Toxicity:
• Monitor liver enzymes before initiation and periodically thereafter.
• Fracture Risk:
• Increased risk of bone fractures, particularly in postmenopausal women.
• Ovulation in Anovulatory Women:
• May restore ovulation in premenopausal anovulatory women, increasing pregnancy risk.
• Macular Edema:
• Rare reports; monitor visual symptoms.
• Weight Gain:
• Dose-dependent and more common when used with insulin.

Common (≥5%):

• Endocrine/Metabolic:
• Weight gain
• Hypoglycemia (especially in combination therapy)
• Edema
• Musculoskeletal:
• Myalgia
• Bone fractures (mainly in women)
• Gastrointestinal:
• Upper respiratory tract infection
• Sinusitis
• Pharyngitis

Serious:

• Congestive heart failure
• Hepatotoxicity
• Bladder cancer
• Macular edema
• Severe hypoglycemia (when used with insulin or sulfonylureas)

Timing:
Edema and weight gain typically occur within the first 4–12 weeks. Hepatic or cardiac complications may occur any time during therapy.

• CYP2C8 inhibitors (e.g., gemfibrozil):
• May increase Pioglitazone plasma levels; reduce dose if needed.
• CYP2C8 inducers (e.g., rifampin):
• May reduce efficacy by decreasing Pioglitazone levels.
• Insulin or sulfonylureas:
• Increased risk of hypoglycemia; dosage adjustment may be necessary.
• Oral contraceptives (containing ethinyl estradiol/norethindrone):
• Pioglitazone may reduce plasma concentrations; consider alternative birth control.
• Alcohol:
• May exacerbate risk of hypoglycemia, especially when combined with insulin or sulfonylureas.

• Guideline Revisions:
• ADA (American Diabetes Association) guidelines confirm Pioglitazone as a second-line therapy, especially for patients with insulin resistance but without heart failure.
• Safety Alerts:
• Continued recommendations for monitoring bladder cancer risk, especially with long-term use (>1 year).
• Labeling Updates:
• Enhanced warnings regarding fracture risk and CHF monitoring, especially in women and elderly.
• New evidence for NASH:
• Clinical trials continue to support Pioglitazone’s efficacy in biopsy-proven NASH, leading to broader off-label acceptance.

• Storage Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Permitted Range: 15°C to 30°C (59°F to 86°F)
• Humidity & Light: Store in a dry place, away from moisture and direct light
• Handling Precautions:
• Do not split or crush tablets
• Keep out of reach of children
• Store in original container with lid tightly closed