Generic Name

Actos

Brand Names

for *pioglitazone*, a thiazolidinedione (TZD) antidiabetic drug that improves insulin sensitivity by acting as a peroxisome proliferator‑activated receptor‑γ (PPAR‑γ) agonist.

Mechanism

• PPAR‑γ Activation – Pioglitazone binds to the ligand‑binding domain of PPAR‑γ in adipose tissue, muscle, and liver, leading to transcriptional changes that
• ↑ GLUT‑4 expression → enhanced glucose uptake in peripheral tissues
• ↑ adiponectin production → improved insulin sensitivity
• ↓ hepatic gluconeogenesis and gluconeogenic enzyme expression
• Anti‑inflammatory Effects – Modulates NF‑κB signaling, reducing pro‑inflammatory cytokines that contribute to insulin resistance.

Pharmacokinetics

• Absorption: Rapid; peak serum levels within 1–2 h; ~50 % oral bioavailability.
• Distribution: Extensive, plasma protein binding ~80 %.
• Metabolism: Primarily glucuronidation (UGT1A1) and mild CYP2C8 oxidation.
• Half‑life: 8–12 h (sedated); terminal half‑life ~24 h due to metabolite persistence.
• Elimination: ~90 % excreted in feces; remainder in urine as metabolites.
• Drug Interactions: CYP2C8 inhibitors (e.g., gemfibrozil) ↑ pioglitazone levels; CYP2C8 inducers (e.g., rifampin) ↓ efficacy.

Indications

• Adjunctive therapy to metformin or lifestyle modification for glycemic control in type 2 diabetes mellitus.
• Can be used monotherapy in patients intolerant to other agents, but usually combined with metformin.

Contraindications

• Contraindications:
• Heart failure (NYHA class III/IV)
• Current or recent hepatic failure (ALT > 3× ULN)
• Warnings:
• Fluid retention → exacerbation of congestive heart failure
• Weight gain, edema, or ascites
• Possible increased risk of bladder cancer (especially >2 years therapy) – monitor urinary symptoms.
• Hypersensitivity reactions noted in a minority.
• Precautions:
• Use with caution in patients with mild‑to‑moderate renal impairment; dose adjustments rarely required but monitor renal function.

Dosing

Adverse Effects

• Common
• Weight gain (2–4 kg)
• Peripheral edema
• Nasopharyngitis, headache, fatigue
• Gastrointestinal upset (nausea, dyspepsia)
• Serious
• Heart failure exacerbation (edema → dyspnea)
• Thyroiditis, hepatic injury (AST/ALT ↑)
• Bladder cancer (risk increased after >2 years use)
• Elevated ketone bodies (rare) – monitor if patient presents with vomiting/abdominal pain
• Hypothyroidism in rare cases – monitor TSH

Monitoring

• Glycemic Control: HbA1c every 3 months; fasting glucose at least once monthly during titration.
• Weight & Fluid Status: At each visit; watch for rapid weight gain >3 kg or new edema.
• Liver Function Tests (ALT, AST, ALP, bilirubin): Baseline, then every 6 months.
• Renal Function (CrCl/ eGFR): Baseline; re‑assess at 3 months and annually.
• Urine Analysis: Annual screening for hematuria; prompt evaluation of urinary symptoms.
• Cardiac Monitoring: Electrocardiogram or BNP if heart failure risk factors present.

Clinical Pearls

• Synergistic with Metformin: Combining pioglitazone with metformin leads to additive insulin‑sparing effects and better glycemic control with less weight gain than high‑dose sulfonylureas.
• Cardiovascular Benefits: While fluid retention is a concern, long‑term studies (RENA-TEC, PROLOG) show reduced microvascular complications and stabilized atherosclerosis in selected patients.
• Bladder Cancer Surveillance: The FDA recommends vigilance after 2 years of therapy; consider early discontinuation if urinary symptoms arise or PSA/urogenital pathology is suspected.
• Pregnancy Precautions: PIoglitazone is category D; avoid in pregnancy due to teratogenic evidence in rodent studies.
• Non‑Glycemic Effects: Pioglitazone reduces triglycerides and increases HDL partial, making it beneficial in patients with metabolic syndrome.
• Drug‑Drug Interaction Alert: When initiating pioglitazone with gemfibrozil, monitor triglyceride levels and consider a reduced pioglitazone dose to avoid hypertriglyceridemia‑induced pancreatitis.

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• Key Takeaway: *Pioglitazone (Actos)* is a potent PPAR‑γ agonist that improves insulin sensitivity. Use with caution in heart failure and liver disease, monitor for edema, weight gain, and urinary symptoms, and combine thoughtfully with metformin for optimal glycemic control.