Introduction
Glipizide is a second-generation sulfonylurea oral hypoglycemic agent approved by the FDA in 1984 for the management of type 2 diabetes mellitus. As an insulin secretagogue, it remains a cornerstone therapy in the treatment algorithm for type 2 diabetes when glycemic control cannot be achieved through diet and exercise alone.
Mechanism of Action
Glipizide exerts its primary therapeutic effect by binding to ATP-sensitive potassium channels on pancreatic beta cells. This binding causes depolarization of the cell membrane, opening voltage-dependent calcium channels, and subsequent calcium influx. The increased intracellular calcium concentration stimulates insulin secretion from pancreatic beta cells. Unlike first-generation sulfonylureas, glipizide has minimal effect on cardiovascular potassium channels, potentially reducing cardiovascular side effects.
Indications
- Primary Indication: Management of type 2 diabetes mellitus as an adjunct to diet and exercise
- Monotherapy: When glycemic control cannot be achieved by nonpharmacological interventions alone
- Combination Therapy: May be used with other oral antidiabetic agents (e.g., metformin) or insulin when dual therapy is indicated
Dosage and Administration
Initial Dose: 5 mg once daily, 30 minutes before breakfast Maintenance Dose: May be increased in increments of 2.5-5 mg at weekly intervals Maximum Dose: 40 mg daily (divided doses if >15 mg daily) Special Populations:- Geriatric: Start with 2.5 mg daily due to increased hypoglycemia risk
- Renal Impairment: Use with caution; consider alternative agents in severe impairment
- Hepatic Impairment: Use with caution; monitor closely for hypoglycemia
Pharmacokinetics
- Absorption: Rapid and complete gastrointestinal absorption; bioavailability approaches 100%
- Distribution: Extensive protein binding (92-99%), primarily to albumin
- Metabolism: Hepatic metabolism via cytochrome P450 2C9 to inactive metabolites
- Elimination: Renal excretion (80-90% as metabolites); half-life 2-4 hours
- Onset/Duration: Onset within 1-3 hours; duration 12-24 hours
Contraindications
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Hypersensitivity to glipizide or sulfonylureas
- Concomitant use with bosentan
Warnings and Precautions
- Hypoglycemia: Risk increased with renal/hepatic impairment, elderly, malnourished patients
- Cardiovascular Mortality: Possible increased risk as suggested by UGDP study
- Hemolytic Anemia: Possible in patients with glucose-6-phosphate dehydrogenase deficiency
- Syndrome of Inappropriate Antidiuretic Hormone (SIADH): Has been reported
- Hepatic Porhyria: May precipitate acute attacks in susceptible individuals
Drug Interactions
Significant Interactions:- Beta-blockers: Mask hypoglycemic symptoms, potentiate hypoglycemia
- Alcohol: May cause disulfiram-like reaction and potentiate hypoglycemia
- Warfarin: Increased anticoagulant effect possible
- NSAIDs, sulfonamides, MAOIs: May enhance hypoglycemic effect
- Thiazides, corticosteroids: May decrease hypoglycemic effect
- CYP2C9 inhibitors/inducers: May affect glipizide concentrations
Adverse Effects
Common (≥1%):- Hypoglycemia (dose-related)
- Gastrointestinal disturbances (nausea, diarrhea, constipation)
- Dizziness
- Headache
- Severe hypoglycemia requiring intervention
- Hemolytic anemia
- Hyponatremia/SIADH
- Hepatic toxicity
- Disulfiram-like reactions with alcohol
- Photosensitivity reactions
Monitoring Parameters
- Glycemic Control: Fasting blood glucose, HbA1c (every 3 months until stable)
- Hypoglycemia: Regular assessment for signs and symptoms
- Renal Function: Serum creatinine at baseline and periodically
- Hepatic Function: Liver enzymes at baseline and as clinically indicated
- Complete Blood Count: At baseline and if anemia suspected
Patient Education
- Timing: Take medication 30 minutes before meals
- Hypoglycemia Recognition: Educate about symptoms (sweating, tremor, confusion)
- Hypoglycemia Management: Always carry quick-acting glucose source
- Consistency: Maintain regular meal patterns and exercise schedule
- Alcohol: Avoid excessive consumption; may cause reaction
- Sick Days: Contact provider during illness; may need dose adjustment
- Monitoring: Regular blood glucose monitoring as directed
- Pregnancy: Use effective contraception; notify provider if planning pregnancy
References
1. American Diabetes Association. (2023). Standards of Medical Care in Diabetes. Diabetes Care. 46(Suppl 1):S1-S291. 2. Glipizide [package insert]. New York, NY: Pfizer; 2022. 3. Inzucchi SE, et al. (2015). Management of Hyperglycemia in Type 2 Diabetes. Diabetes Care. 38(1):140-149. 4. Lexicomp Online. Glipizide: Drug Information. Wolters Kluwer Clinical Drug Information. 5. UK Prospective Diabetes Study (UKPDS) Group. (1998). Lancet. 352(9131):837-853. 6. FDA-approved drug labeling for Glucotrol (glipizide).