What is the recommended dosing regimen for repaglinide, including initial dose, titration schedule, maximum dose, adjustments for elderly or patients with mild to moderate renal or hepatic impairment, and instructions for missed meals?

Repaglinide Dosing

Repaglinide should be initiated at 0.5 mg taken 15-30 minutes before each meal (typically three times daily), with careful upward titration to a maximum of 4 mg per meal based on glycemic response, and dose adjustments are required for patients with renal impairment (eGFR <30 mL/min/1.73 m²) or hepatic dysfunction. 1

Initial Dosing

• Treatment-naive patients or those with HbA1c <8%: Start with 0.5 mg before each meal 2
• Patients previously treated with other oral antihyperglycemic agents: May initiate at 1-2 mg before each meal 2
• Timing: Administer 15-30 minutes before meals (typically three times daily) 3, 2

Titration Schedule

• Wait at least 1 week between dose adjustments to assess glycemic response 2
• Titrate in increments of 0.5-1 mg per meal based on preprandial glucose monitoring 4
• Adjust doses based on individual meal-related glucose excursions, as repaglinide specifically targets postprandial hyperglycemia 5, 2

Maximum Dosing

• Maximum single dose: 4 mg per meal 4, 2
• Maximum daily dose: 16 mg/day (4 mg × 4 meals) 2
• Most patients achieve adequate control with 0.5-4 mg three times daily 2

Renal Impairment Adjustments

This is a critical safety consideration, as repaglinide can accumulate with declining kidney function despite hepatic metabolism. 1

• eGFR >30 mL/min/1.73 m²: No dose adjustment required 1
• eGFR <30 mL/min/1.73 m²:
  • Initiate conservatively at 0.5 mg with meals 1
  • Titrate upward cautiously with close glucose monitoring 1
  • Repaglinide can accumulate when kidney function decreases, increasing hypoglycemia risk 1
• Dialysis patients: Repaglinide may be used with careful monitoring, as it offers an advantage over sulfonylureas in patients with severe renal impairment 5, 2

Hepatic Impairment Adjustments

• Repaglinide is primarily metabolized by the liver 1
• Use with caution in patients with hepatic dysfunction 1
• Start at 0.5 mg with meals and titrate slowly with frequent glucose monitoring 1

Elderly Patients

• No specific dose adjustment required based on age alone, as pharmacokinetics are similar between young adults and elderly subjects 6
• However, initiate at 0.5 mg before meals and titrate cautiously due to increased hypoglycemia risk in this population 4, 2
• The flexible dosing schedule of repaglinide is particularly advantageous in elderly patients with variable meal patterns 5

Missed Meals

A key advantage of repaglinide over sulfonylureas is its meal-dependent dosing. 4, 3

• If a meal is skipped, skip that dose of repaglinide 4, 3
• If an extra meal is consumed, an additional dose may be taken (up to maximum daily dose) 4
• This flexibility reduces hypoglycemia risk compared to glibenclamide when meals are missed 4, 3
• Repaglinide allows patients to vary their meal schedule (2,3, or 4 meals daily) while maintaining glycemic control 4

Important Clinical Considerations

Drug Interactions

• Cyclosporine significantly increases repaglinide levels (up to 2.5-fold), requiring dose reduction and close monitoring 1
• CYP3A4 inhibitors may increase repaglinide exposure 2

Hypoglycemia Risk

• The incidence of serious hypoglycemia is lower with repaglinide than with sulfonylureas 4, 2
• Risk is similar to or slightly less than sulfonylureas overall (16-18% incidence) 4
• Patients with advanced CKD (stages 4-5) have increased hypoglycemia risk due to impaired renal gluconeogenesis and drug accumulation 1

Combination Therapy

• Repaglinide shows additive effects when combined with metformin, thiazolidinediones, or bedtime NPH insulin 4, 2
• When used in combination, monitor closely and adjust doses of both agents as needed 2