Is repaglinide safe to use in patients with renal failure and how should the dose be adjusted according to estimated glomerular filtration rate?

Repaglinide Use in Renal Failure

Repaglinide can be used safely in patients with renal failure, including those with severe renal impairment and on dialysis, but requires a conservative starting dose of 0.5 mg before each meal when GFR is ≤40 mL/min/1.73 m², with cautious upward titration based on blood glucose monitoring. 1, 2

Dosing Recommendations by Renal Function

Mild to Moderate Renal Impairment (GFR >40 mL/min/1.73 m²)

• No dose adjustment is required for patients with mild to moderate renal dysfunction 3, 4
• Standard starting doses apply: 0.5 mg if HbA1c <8%, or 1-2 mg if HbA1c ≥8% before each meal 2
• Pharmacokinetic studies demonstrate no significant differences in drug clearance compared to patients with normal renal function 3, 4

Severe Renal Impairment (GFR 20-40 mL/min/1.73 m²)

• Start with 0.5 mg orally before each meal 1, 2
• Titrate upward cautiously based on blood glucose measurements 1
• The half-life of repaglinide is prolonged after multiple dosing in this population, though this does not significantly increase hypoglycemia risk 3, 4
• Area under the curve (AUC) values are significantly higher in severe renal impairment, necessitating more careful dose escalation 4

End-Stage Renal Disease and Dialysis

• Repaglinide can be used in dialysis patients 5
• Start with 0.5 mg before meals and titrate cautiously 1
• Hemodialysis does not significantly affect repaglinide clearance, so no additional dosing adjustments are needed around dialysis sessions 4

Key Safety Considerations

Hypoglycemia Risk

• The risk of hypoglycemia is increased in advanced CKD (stages 4-5) due to decreased drug clearance and impaired renal gluconeogenesis 1
• Instruct patients to skip the dose if a meal is skipped to reduce hypoglycemia risk 2
• If hypoglycemia occurs, reduce the dose rather than discontinue the medication 2
• Rates of minor hypoglycemia were similar across all levels of renal function in clinical studies, with no major hypoglycemic episodes reported 3

Advantages Over Other Agents

• Unlike nateglinide (which accumulates active metabolites in renal failure), repaglinide does not produce problematic active metabolites 1
• Repaglinide is preferred over first-generation sulfonylureas, which should be avoided entirely in CKD 1
• Among second-generation sulfonylureas, glipizide is preferred, but repaglinide offers more flexibility in severe renal impairment 1

Clinical Monitoring

• Monitor blood glucose closely when initiating or adjusting doses in patients with severe renal impairment 1, 2
• Allow at least one week between dose adjustments to assess glycemic response 2
• Doses can be doubled up to 4 mg per meal until satisfactory control is achieved, with maximum daily dose of 16 mg 2
• Take repaglinide within 30 minutes before meals 2

Important Caveats

Drug Interactions Requiring Dose Modification

• Avoid concomitant use with gemfibrozil (contraindicated) 2
• Limit daily dose to 6 mg when co-administered with cyclosporine 2
• CYP2C8 and CYP3A4 inhibitors may require dose reductions and increased glucose monitoring 2

Hepatic Metabolism

• Repaglinide is primarily hepatically metabolized, which explains its relative safety in renal impairment 5
• This hepatic clearance pathway remains intact even in severe renal dysfunction 3, 4