Pioglitazone + Glimepiride

• Type 2 Diabetes Mellitus (T2DM):
  Used as an adjunct to diet and exercise to improve glycemic control in adults with T2DM who are inadequately controlled on monotherapy with either pioglitazone or glimepiride, or as initial combination therapy for patients with significantly elevated blood glucose.

• Route: Oral
• Dosage forms: Fixed-dose tablets combining pioglitazone (15 mg or 30 mg) with glimepiride (1 mg, 2 mg, or 4 mg).
• Adult dosing:
  Initial dose generally starts with pioglitazone 15 mg + glimepiride 1 or 2 mg once daily, taken with breakfast or the first main meal.
  Dose may be adjusted every 2 to 4 weeks based on glycemic response, not exceeding pioglitazone 45 mg and glimepiride 8 mg daily.
• Elderly:
  Initiate at lowest glimepiride dose due to increased hypoglycemia risk; monitor closely.
• Renal impairment:
  Use with caution or avoid due to hypoglycemia risk from glimepiride.
• Hepatic impairment:
  Contraindicated in active liver disease or elevated liver enzymes (>2.5 times upper normal limit).

Pioglitazone improves insulin sensitivity by activating peroxisome proliferator-activated receptor gamma (PPAR-γ), which regulates gene expression involved in glucose and lipid metabolism. This enhances peripheral glucose uptake and reduces hepatic glucose production. Glimepiride stimulates pancreatic β-cells to release insulin by closing ATP-sensitive potassium channels, leading to cell depolarization and increased calcium influx, triggering insulin secretion. The combination provides complementary glucose-lowering effects through increased insulin availability and improved insulin sensitivity.

• Pioglitazone:
  Well absorbed orally with peak plasma levels in ~2 hours. Metabolized primarily via CYP2C8 and CYP3A4 to active metabolites with longer half-lives (16–24 hours). Eliminated mainly in feces.
• Glimepiride:
  Rapid absorption with peak concentration at 2–3 hours. Metabolized mainly by CYP2C9 to active and inactive metabolites. Excreted primarily in urine.

• Pregnancy: FDA category C. Use only if potential benefits justify potential risks. Insulin preferred during pregnancy.
• Lactation: Insufficient data; may cause hypoglycemia in nursing infants due to glimepiride; use caution or avoid.

• Antidiabetic Agents
• Pioglitazone: Thiazolidinedione (insulin sensitizer)
• Glimepiride: Sulfonylurea (insulin secretagogue)

• Hypersensitivity to either pioglitazone, glimepiride, or sulfonylureas
• Type 1 diabetes or diabetic ketoacidosis
• NYHA Class III or IV heart failure
• Active liver disease or significant hepatic impairment
• Severe renal impairment
• History or risk of bladder cancer (pioglitazone)

• Monitor for congestive heart failure due to fluid retention risk (pioglitazone).
• Risk of hypoglycemia with glimepiride, especially in elderly, renal impairment, or reduced caloric intake.
• Regular liver function monitoring recommended.
• Increased risk of bone fractures, mainly in postmenopausal women.
• Avoid use in patients with active bladder cancer or high risk of bladder tumors.
• May cause weight gain and peripheral edema.
• Monitor for visual disturbances due to possible macular edema.

• Common: Hypoglycemia, weight gain, peripheral edema, nausea, upper respiratory infections, headache.
• Serious: Heart failure exacerbation, bladder cancer, hepatotoxicity, macular edema, bone fractures.

• CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone levels; dose adjustment may be needed.
• CYP2C9 inhibitors (e.g., fluconazole) increase glimepiride levels; monitor for hypoglycemia.
• Rifampin decreases pioglitazone levels via CYP2C8 induction.
• Beta-blockers may mask hypoglycemia symptoms.
• Alcohol and other hypoglycemic agents can potentiate glimepiride effects.

• ADA guidelines recommend pioglitazone + glimepiride as a second-line option after metformin failure or intolerance.
• Emphasis on monitoring for bladder cancer and heart failure during long-term pioglitazone therapy.
• Updated safety information on fracture risk and liver monitoring.

• Store at 20°C to 25°C (68°F to 77°F), with permitted excursions between 15°C and 30°C.
• Protect from moisture and direct sunlight.
• Keep in original container, tightly closed, and out of reach of children.