Is repaglinide safe for use in patients with renal failure (eGFR < 30 mL/min/1.73 m² or on dialysis) and what dose adjustments are recommended?

Repaglinide in Renal Failure

Repaglinide is safe and can be used in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) and those on dialysis, but must be initiated at a reduced dose of 0.5 mg before each meal with careful upward titration guided by blood glucose monitoring. 1

Dosing Recommendations by Renal Function

eGFR ≥ 30 mL/min/1.73 m²

• No dose adjustment required – standard dosing may be used 1
• Patients with mild to moderate renal impairment show no significant pharmacokinetic differences compared to those with normal renal function 2

eGFR < 30 mL/min/1.73 m² (Severe Renal Impairment)

• Initiate conservatively at 0.5 mg with each meal 1, 3
• Titrate cautiously based on self-monitored blood glucose readings 4, 3
• Pharmacokinetic studies demonstrate significantly higher drug exposure (area under the curve) in patients with severe renal impairment, though peak concentrations and time to peak remain unchanged 5
• The elimination half-life is prolonged after multiple doses in this population 2

End-Stage Renal Disease (ESRD) and Dialysis

• Start at 0.5 mg before meals and titrate gradually 4, 3
• Hemodialysis does not significantly affect repaglinide clearance – no additional dose adjustments needed around dialysis sessions 5, 3
• The drug is not dialyzable, so timing relative to hemodialysis is not critical 3

Safety Profile and Hypoglycemia Risk

Repaglinide demonstrates a favorable safety profile even in advanced renal impairment, with hypoglycemia rates comparable across all levels of renal function. 6

• Clinical trials showed that the percentage of patients experiencing hypoglycemic episodes during repaglinide treatment was not significantly related to renal function (P = 0.074) 6
• No major hypoglycemic episodes were reported in studies of patients with varying degrees of renal impairment 2, 6
• Minor hypoglycemia rates were similar across normal, mild-to-moderate, and severe renal dysfunction groups 2
• The drug was safe and well tolerated across all degrees of renal impairment in multiple studies 5, 6

Advantages Over Other Oral Agents in Renal Failure

Repaglinide is preferred over many other oral hypoglycemics in renal failure because it is primarily metabolized by the liver and does not generate active metabolites that accumulate. 1, 4

Comparison with Sulfonylureas

• Glyburide is contraindicated in renal impairment and should be avoided entirely 1
• Glimepiride and glipizide require conservative initiation (1 mg and 2.5 mg daily, respectively) with slow titration in severe renal impairment 1
• Repaglinide's hepatic metabolism makes it safer than renally-cleared sulfonylureas 1, 7

Comparison with Nateglinide

• Unlike nateglinide (another meglitinide), repaglinide does not produce active metabolites that accumulate in renal failure 4
• Both meglitinides require conservative initiation at reduced doses when eGFR < 30 mL/min/1.73 m² 1

Practical Advantages

• Meal-related dosing allows flexibility – patients can skip a dose if they miss a meal, reducing hypoglycemia risk 7
• Rapid absorption and elimination provide more physiological insulin coverage compared to once- or twice-daily sulfonylureas 7
• Particularly attractive for elderly diabetic patients with diminished kidney function 7

Clinical Monitoring Requirements

Close blood glucose monitoring is essential when initiating or adjusting repaglinide doses in patients with severe renal impairment. 4, 3

• Monitor for hypoglycemia symptoms, especially during dose titration 3, 6
• Assess renal function periodically, as changes may necessitate dose adjustments 3
• In clinical trials, final repaglinide doses tended to be lower in patients with severe and extreme renal impairment (P = 0.032) 6
• Longer intervals between dose adjustments may be needed in patients with hepatic impairment to allow full assessment of response 3

Important Caveats and Pitfalls

• Severe hypoglycemia requires immediate hospitalization – patients should be monitored for 24-48 hours as hypoglycemia may recur after apparent recovery 3
• Studies were not conducted in patients with creatinine clearance below 20 mL/min outside of dialysis populations, so extra caution is warranted in this range 3
• The 2022 ADA/KDIGO guidelines do not specifically list repaglinide in their dosing tables, focusing instead on newer agents like SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular and renal protection 1
• While repaglinide is safe in renal failure, consider alternative agents (DPP-4 inhibitors, GLP-1 receptor agonists, or insulin) that may offer additional cardiovascular or renal benefits in patients with CKD 1