Introduction
Repaglinide is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. It belongs to the meglitinide class of medications and functions as a rapid-acting insulin secretagogue. First approved by the FDA in 1997, repaglinide offers a unique pharmacokinetic profile that makes it particularly suitable for controlling postprandial glucose excursions.
Mechanism of Action
Repaglinide stimulates pancreatic beta cells to release insulin by binding to specific ATP-sensitive potassium channels on beta cell membranes. This binding causes depolarization of the beta cell membrane, opening voltage-dependent calcium channels, resulting in calcium influx and subsequent insulin exocytosis. Unlike sulfonylureas, which bind to a different site on the sulfonylurea receptor, repaglinide has a more rapid onset and shorter duration of action, making it particularly effective for controlling postprandial hyperglycemia.
Indications
Repaglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It may be used as monotherapy or in combination with metformin or thiazolidinediones when glycemic control is not achieved with single-agent therapy. Repaglinide is not indicated for use in type 1 diabetes mellitus or diabetic ketoacidosis.
Dosage and Administration
The recommended starting dose is 0.5 mg taken orally 15-30 minutes before each meal. For patients previously treated with other oral hypoglycemic agents, the starting dose is 1-2 mg before each meal. The dosage may be titrated at weekly intervals based on glycemic response, up to a maximum of 4 mg per meal or 16 mg daily.
Dosing should be skipped if a meal is missed and added if an extra meal is consumed. For patients with renal impairment, no initial dosage adjustment is required, but careful titration is recommended. In hepatic impairment, the initial dose should be 0.5 mg before meals with careful monitoring.
Pharmacokinetics
Absorption: Rapidly absorbed from the gastrointestinal tract with peak plasma concentrations occurring within 1 hour. Absolute bioavailability is approximately 56%. Food intake delays absorption but does not affect overall bioavailability. Distribution: Volume of distribution is approximately 31 L. Protein binding is greater than 98%, primarily to albumin. Metabolism: Extensively metabolized in the liver via cytochrome P450 3A4 and possibly 2C8 enzymes. The major metabolites are inactive. Elimination: Primarily excreted in feces (90%) via biliary elimination, with less than 8% excreted in urine. The elimination half-life is approximately 1 hour.Contraindications
- Hypersensitivity to repaglinide or any component of the formulation
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Concomitant use with gemfibrozil
- Severe hepatic impairment
- Pregnancy and breastfeeding (due to lack of safety data)
Warnings and Precautions
Hypoglycemia: Repaglinide can cause significant hypoglycemia, particularly in elderly patients, those with renal or hepatic impairment, and those who are malnourished. Hepatic impairment: Use with caution in patients with liver dysfunction due to reduced metabolism and increased risk of hypoglycemia. Cardiovascular effects: As with other insulin secretagogues, caution is advised in patients with cardiovascular disease due to potential increased cardiovascular mortality. Secondary failure: Like other antidiabetic agents, repaglinide may show decreasing effectiveness over time. Stress conditions: During periods of stress such as fever, trauma, infection, or surgery, temporary insulin therapy may be required.Drug Interactions
Major interactions:- Gemfibrozil: Contraindicated due to significant increase in repaglinide exposure (8-fold increase)
- Clarithromycin, ketoconazole, itraconazole: CYP3A4 inhibitors that increase repaglinide levels
- Rifampin, carbamazepine: CYP3A4 inducers that decrease repaglinide efficacy
- Beta-blockers: May mask hypoglycemia symptoms
- Thiazides, corticosteroids: May reduce hypoglycemic effect
- NSAIDs, salicylates: May enhance hypoglycemic effect
- Monoamine oxidase inhibitors: May enhance hypoglycemic effect
Adverse Effects
Common (≥5%):- Hypoglycemia (16-31%)
- Upper respiratory infection (10-16%)
- Headache (5-11%)
- Arthralgia (3-6%)
- Back pain (4-6%)
- Diarrhea (3-5%)
- Severe hypoglycemia
- Hepatitis, abnormal liver function tests
- Acute coronary syndrome (rare)
- Hemolytic anemia (rare)
- Hypersensitivity reactions
Monitoring Parameters
- Blood glucose: Preprandial and postprandial, especially during dose titration
- HbA1c: Every 3 months until stabilized, then every 6 months
- Liver function tests: Baseline and periodically
- Renal function: Baseline and periodically
- Signs and symptoms of hypoglycemia
- Weight changes
- Cardiovascular status in high-risk patients
Patient Education
- Take medication 15-30 minutes before meals
- Skip dose if meal is skipped; add dose if extra meal is consumed
- Recognize symptoms of hypoglycemia (sweating, trembling, hunger, confusion)
- Carry quick-acting glucose source at all times
- Regular self-monitoring of blood glucose
- Importance of diet and exercise adherence
- Report any signs of liver dysfunction (jaundice, dark urine, abdominal pain)
- Inform all healthcare providers about repaglinide use
- Avoid alcohol consumption due to increased risk of hypoglycemia
- Regular follow-up with healthcare provider
References
1. American Diabetes Association. (2023). Standards of Medical Care in Diabetes. Diabetes Care, 46(Supplement_1), S1-S291. 2. FDA Prescribing Information for Repaglinide (2022) 3. Hatorp, V., et al. (1998). Pharmacokinetics and pharmacodynamics of repaglinide in patients with type 2 diabetes. Diabetes Care, 21(Suppl 2), B36-B40. 4. Moses, R. G., et al. (1999). Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. Diabetes Care, 22(5), 789-792. 5. Niemi, M., et al. (2003). The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clinical Pharmacology & Therapeutics, 74(3), 249-255. 6. Van Gaal, L. F., & De Leeuw, I. H. (2003). Rationale and options for combination therapy in the treatment of type 2 diabetes. Diabetologia, 46(Suppl 1), M44-M50. 7. Pharmacotherapy: A Pathophysiologic Approach, 11th Edition (2020) 8. Lexicomp Online, Repaglinide Monograph (2023)