Metglip Plus

• Type 2 Diabetes Mellitus (T2DM):
  • Indicated as an adjunct to diet and exercise to improve glycemic control in patients whose blood glucose levels are not adequately controlled by either glipizide or metformin monotherapy alone.
  • Suitable for patients who require combination therapy due to progressive disease or inadequate response to single agents.
  • Used in patients with sufficient pancreatic beta-cell function to respond to sulfonylurea stimulation.
• Important Off-Label Uses:
  • Occasionally used in selected cases of MODY (maturity-onset diabetes of the young), under specialist supervision.
  • Not indicated for type 1 diabetes or diabetic ketoacidosis.

• Adults:

• Initial dose usually contains glipizide 5 mg + metformin 500 mg, taken orally twice daily with meals to reduce gastrointestinal side effects.
• Dose titration is based on blood glucose response and tolerance; maximum daily doses vary depending on formulation but typically do not exceed glipizide 20 mg + metformin 2000 mg per day.
• Dosage adjustments should be made gradually, usually every 1 to 2 weeks.

• Elderly:

• Start at lower doses due to increased risk of hypoglycemia and renal impairment.
• Careful monitoring of renal function and glucose levels is essential.

• Renal Impairment:

• Contraindicated or dose-adjusted depending on severity: metformin is contraindicated if eGFR <30 mL/min/1.73 m²; glipizide requires caution with dose reduction.
• Regular renal monitoring is mandatory.

• Hepatic Impairment:

• Combination use is contraindicated in severe hepatic dysfunction due to increased risk of lactic acidosis (metformin) and hypoglycemia (glipizide).

• Pediatrics:
  • Safety and efficacy not established; not generally recommended.
• Administration:

• Tablets should be taken with meals to reduce gastrointestinal adverse effects and improve tolerability.
• Do not crush or chew extended-release formulations.

This combination combines two complementary antihyperglycemic mechanisms:

• Glipizide: Stimulates pancreatic beta cells to release insulin by binding to sulfonylurea receptors on ATP-sensitive potassium channels, causing depolarization and calcium influx, which triggers insulin exocytosis. This reduces blood glucose by increasing insulin availability.
• Metformin: Primarily reduces hepatic glucose production (gluconeogenesis), enhances insulin sensitivity in peripheral tissues (muscle and adipose), and improves peripheral glucose uptake and utilization without increasing insulin secretion. It also reduces intestinal glucose absorption to a minor extent.

Together, these effects lower both fasting and postprandial blood glucose levels effectively without causing excessive insulin release beyond physiological needs.

• Glipizide:

• Absorbed rapidly with bioavailability near 90–100%.
• Peak plasma concentration reached in 1–3 hours (immediate-release).
• Half-life of 2–5 hours.
• Metabolized primarily by CYP2C9 in the liver to inactive metabolites.
• Excreted mainly via urine (metabolites).

• Metformin:

• Absorption bioavailability ~50–60%; delayed and incomplete absorption.
• Peak plasma concentration reached in ~2–3 hours.
• Half-life approximately 6 hours.
• Not metabolized; excreted unchanged by kidneys via tubular secretion.
• Steady-state plasma levels achieved in 24–48 hours.

• Combined Use: No significant pharmacokinetic interactions altering absorption or elimination.

• Pregnancy:

• Metformin is FDA Category B (no proven risk in humans), but glipizide is Category C (animal studies show adverse effects, no adequate human data).
• Insulin remains preferred during pregnancy for glycemic control.
• Use only if benefits outweigh risks and under specialist supervision.

• Lactation:

• Both drugs are excreted in small amounts into breast milk.
• Risk of hypoglycemia in the infant is low but monitoring is advised.
• Caution is warranted when administered during breastfeeding.

• Primary Class: Oral Antidiabetic Agents
• Subclass: Combination therapy of Second-generation Sulfonylurea (glipizide) + Biguanide (metformin)

• Known hypersensitivity to glipizide, metformin, or any excipients.
• Type 1 diabetes mellitus or diabetic ketoacidosis.
• Severe renal impairment (eGFR <30 mL/min/1.73 m²).
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• Severe hepatic impairment.
• Conditions predisposing to hypoxia (e.g., congestive heart failure, respiratory failure).
• Excessive alcohol intake.
• Use of contrast media requiring iodinated contrast (temporary discontinuation recommended).

• Hypoglycemia Risk:
  • Increased risk due to glipizide, especially in elderly, malnourished, or renal-impaired patients.
  • Educate patients about signs of hypoglycemia.
• Lactic Acidosis (Metformin):
  • Rare but serious; associated with metformin accumulation in renal impairment or hypoxic states.
  • Monitor renal function regularly.
• Cardiovascular Considerations:
  • Use cautiously in patients with cardiac disease.
• Gastrointestinal Effects:
  • Metformin may cause GI intolerance; start low and titrate.
• Surgery and Acute Illness:
  • Temporary discontinuation recommended.
• Monitoring:
  • Periodic assessment of blood glucose, HbA1c, renal and hepatic function.

• Common:

• Hypoglycemia (due to glipizide)
• Gastrointestinal disturbances (nausea, vomiting, diarrhea, abdominal discomfort - mainly metformin)
• Weight gain (glipizide)
• Metallic taste (metformin)
• Headache, dizziness

• Serious/Rare:

• Lactic acidosis (metformin)
• Severe hypoglycemia (glipizide)
• Hematologic reactions: leukopenia, thrombocytopenia (rare)
• Hepatic dysfunction
• Allergic skin reactions (rash, photosensitivity)

• Potentiation of Hypoglycemia:

• Other antidiabetics, ACE inhibitors, angiotensin receptor blockers, beta-blockers (mask symptoms), fluconazole, sulfonamides, alcohol.

• Reduced Efficacy:

• Corticosteroids, diuretics, oral contraceptives, phenytoin, rifampin.

• Metformin-specific:

• Cimetidine may increase metformin plasma levels.

• Glipizide-specific:

• CYP2C9 inhibitors (fluconazole) increase glipizide levels; inducers (rifampin) decrease effectiveness.

• Food:

• Take with meals to minimize GI side effects.

• Alcohol:

• Risk of hypoglycemia and lactic acidosis increased; avoid or limit intake.

• ADA/EASD Consensus (Recent):
  • Metformin remains first-line for T2DM.
  • Sulfonylurea combinations (like glipizide + metformin) remain acceptable when cost or tolerance limits other options.
  • Increased emphasis on hypoglycemia risk minimization in elderly or comorbid patients.
  • Monitoring of renal function for metformin safety is underscored.
• FDA and EMA Warnings:
  • Updated contraindications for metformin in severe renal impairment.
  • Stronger recommendations to temporarily discontinue metformin around iodinated contrast procedures.

• Store tablets at 20°C to 25°C (68°F to 77°F).
• Protect from excessive moisture and light.
• Keep tablets in original container, tightly closed.
• Do not freeze or expose to high humidity.
• Keep out of reach of children.
• Discard expired tablets properly.