Generic Name

Pioglitazone

Mechanism

• PPAR‑γ agonist – binds nuclear receptor, alters gene transcription (GLUT‑4, adiponectin, lipoprotein lipase).
• Enhances *glucose uptake* in adipose tissue, skeletal muscle, and liver.
• Down‑regulates hepatic gluconeogenesis and decreases hepatic insulin resistance.
• Improves lipid profile: ↑HDL‑C, ↓triglycerides, modest ↑LDL‑C but less atherogenic variant.

Pharmacokinetics

• Absorption: ~64% bioavailability; peak plasma at 1–3 h post‑dose.
• Distribution: ~80% protein‑bound, large volume of distribution (≈95 L).
• Metabolism: Hepatic N‑oxidation via CYP2C8, CYP3A4 → inactive 1,4‑dihydroxylated metabolites.
• Elimination: Renal excretion of metabolites; half‑life 3–7 h after single dose; ~12 h with chronic therapy.
• Drug interactions: CYP2C8 inhibitors (e.g., gemfibrozil) ↑ pioglitazone levels; inhibitors of CYP3A4 (ketoconazole) similarly affect clearance.

Indications

• Type 2 diabetes mellitus (T2DM) as monotherapy or add‑on to metformin, sulfonylureas, or insulin.
• Off‑label: rosiglitazone‑resistant cases, pre‑diabetes in insulin‑resistance syndromes (comprehensive lifestyle therapy indicated first).

Contraindications

• Contraindications:
• Known hypersensitivity to pioglitazone or other TZDs.
• Untreated heart failure (NYHA III‑IV).
• Warnings:
• Fluid retention → risk of heart failure; use cautiously in patients with renal/hepatic impairment.
• Weight gain, edema, edema‑related complications.
• Possible increase in risk of bone fractures (especially in postmenopausal women).
• Tumor promotion (preclinical evidence) → avoid in patients with active bladder cancer or at high risk.

Dosing

• Initial dose: 15 mg orally once daily (preferably at bedtime).
• Titration: Increase to 30 mg once daily after 3–4 weeks if glycemic control insufficient and no contraindications.
• Maximum: 45 mg/day (30 mg + 15 mg).
• Special populations:
• Renal impairment: normal dose; monitor.
• Hepatic impairment: not recommended in Child‑Pugh C; use caution in B.
• Administration advice: Take with a meal to reduce GI upset; avoid concomitant diuretics unless heart‑failure monitor.

Adverse Effects

Common (≤5 % incidence)
• Peripheral edema
• Weight gain (≈2–3 kg)
• Nausea, dyspepsia
• Hepatic enzyme elevation (monitor LFTs)

Serious (≤1 %)
• Severe heart failure exacerbation
• Pulmonary edema
• Lactic acidosis (rare in T2DM)
• Hepatotoxicity (transaminases ↑10× ULN or jaundice)
• Bladder–10 % with prolonged use)
• Bone fractures (women >50 yrs)

Monitoring

• Baseline: HbA1c, fasting plasma glucose, weight, BP, renal/ hepatic function (ALT, AST, creatinine), urinalysis (protein).
• Follow‑up:
• LFTs every 3 months (first year), then annually.
• Weight and edema assessment every visit.
• HbA1c 3–6 months after initiation or dose change.
• BNP/ment patient-reported edema or dyspnea for early heart strain detection.

Clinical Pearls

• Edema management: Initiate low‑dose diuretic (e.g., thiazide) concurrently if patient has mild CHF; consider switching TZD if heart failure develops.
• Contra‑cox: To mitigate fracture risk, combine pioglitazone with calcium/vitamin D or bisphosphonates in postmenopausal women.
• Drug interactions: Advise patients on metformin to separately schedule dose due to potential overlapping myotoxicity; combine only if monitored.
• Race/ethnicity: Black patients often require higher doses; adjust titration accordingly.
• Education: Emphasize regular urinary catheter checks for men—bladder cancer risk.

*All recommendations reflect current 2024 pharmacology literature; adjust for individual patient profile and local guidelines.*