What is the appropriate dosing, contraindications, and precautions for repaglinide in an adult with type 2 diabetes?

Repaglinide: Dosing, Contraindications, and Precautions in Type 2 Diabetes

Repaglinide is a rapid-acting insulin secretagogue that should be dosed 0.5–4 mg before each meal (up to 4 times daily, maximum 16 mg/day), with the key advantage of flexible meal-related dosing that reduces severe hypoglycemia risk when meals are skipped. 1

Starting Dose Selection

• For patients with HbA1c <8%: Start with 0.5 mg orally before each meal 1
• For patients with HbA1c ≥8%: Start with 1–2 mg orally before each meal 1
• For patients with severe renal impairment (CrCl 20–40 mL/min): Initiate at 0.5 mg before each meal and titrate gradually 1

The starting dose should be taken within 30 minutes before meals, and the medication follows the eating pattern rather than forcing patients to eat on a fixed schedule 1, 2.

Dose Titration and Maintenance

• Titration schedule: Double the dose up to 4 mg with each meal until satisfactory glycemic control is achieved 1
• Timing between adjustments: Allow at least one week to assess response after each dose adjustment 1
• Recommended dose range: 0.5–4 mg before meals 1
• Maximum daily dose: 16 mg total per day 1

Repaglinide may be dosed 2,3, or 4 times daily depending on the patient's meal pattern 1. This flexibility is a hallmark advantage over sulfonylureas 2.

Administration Guidelines

• Timing: Take within 30 minutes before meals 1
• Missed meals: If a meal is skipped, skip the corresponding dose to reduce hypoglycemia risk 1, 2
• Meal-related dosing advantage: A study demonstrated that when patients on repaglinide skipped lunch (and the corresponding dose), zero hypoglycemic events occurred, whereas 24% of patients on glibenclamide (who took their fixed morning dose) developed severe hypoglycemia 2

Absolute Contraindications

• Concomitant use with gemfibrozil is absolutely contraindicated due to significant drug interactions that increase repaglinide exposure 1
• Known hypersensitivity to repaglinide or any inactive ingredients 1
• Type 1 diabetes mellitus – repaglinide should not be used 1
• Diabetic ketoacidosis – repaglinide is not indicated for treatment 1

Critical Drug Interactions Requiring Dose Modification

• Clopidogrel: Avoid concomitant use; if unavoidable, initiate repaglinide at 0.5 mg before each meal and do not exceed 4 mg total daily dose 1
• Cyclosporine: Do not exceed 6 mg total daily dose of repaglinide 1
• Strong CYP3A4 or CYP2C8 inhibitors/inducers: Dosage adjustments are required 1

Hypoglycemia Risk and Management

• All glinides, including repaglinide, can cause hypoglycemia that may be severe enough to cause seizures, be life-threatening, or cause death 1
• Hypoglycemia impairs concentration and reaction time, placing patients at risk in situations requiring these abilities (e.g., driving) 1
• If hypoglycemia occurs: Reduce the dose of repaglinide 1
• Long-term hypoglycemia prevalence: Similar to other insulin secretagogues in long-term studies, though the risk of severe hypoglycemia with missed meals is substantially lower 2

Special Populations

Renal Impairment

• Severe renal impairment (CrCl 20–40 mL/min): Start at 0.5 mg before each meal and titrate gradually 1
• Safety profile: Repaglinide has a good safety and efficacy profile even in patients with severe renal impairment, as it is metabolized primarily in the liver and >90% excreted via bile 2, 3
• Hypoglycemia risk: The percentage of patients with hypoglycemic episodes increased significantly with increasing severity of renal impairment during run-in on other medications (P=0.007), but not during repaglinide treatment (P=0.074) 3
• Dose requirements: Final repaglinide dose tends to be lower for patients with severe and extreme renal impairment (P=0.032) 3

Elderly Patients

• Repaglinide is generally well tolerated in elderly patients 4
• The American Diabetes Association guidelines note that insulin secretagogues including repaglinide should be used with caution in older adults due to hypoglycemia, bone loss, and fracture risk 5

Clinical Efficacy

• HbA1c reduction: Repaglinide decreases HbA1c by 0.5–1.5% 5
• Postprandial glucose control: Repaglinide caused a decrease of 5.8 mmol/L in peak postprandial glucose levels and 3.1 mmol/L in fasting levels, with HbA1c reduction of 1.8% compared to placebo 2
• Meal-related dosing superiority: Dosing repaglinide with each main meal (breakfast, lunch, dinner) caused significantly better improvement in fasting and 24-hour glucose profiles and greater HbA1c decrease compared to the same total daily dose given only morning and evening 2, 6

Comparison to Sulfonylureas

• Lower hypoglycemia risk during Ramadan fasting: A study showed repaglinide was associated with less hypoglycemia compared with glibenclamide in patients who fasted 5
• Mechanism advantage: Repaglinide has a distinct binding site at the β-cell membrane that differs from sulfonylureas, corresponding to greater insulinotropic effects and more rapid onset of action 4
• Flexibility advantage: Repaglinide follows the eating pattern rather than forcing patients to eat on a fixed schedule, reducing severe hypoglycemia risk with missed meals 2

Common Pitfalls to Avoid

• Do not use repaglinide in type 1 diabetes or diabetic ketoacidosis 1
• Do not combine with gemfibrozil – this is an absolute contraindication 1
• Do not continue the dose when a meal is skipped – this is a critical safety feature that distinguishes repaglinide from sulfonylureas 1, 2
• Do not exceed maximum doses when using concomitant medications that interact with repaglinide (4 mg/day with clopidogrel, 6 mg/day with cyclosporine) 1
• Monitor closely in renal impairment and start with lower doses, though repaglinide is safer than many alternatives in this population 1, 3

Role in Older Adults

• The American Diabetes Association notes that sulfonylureas and meglitinides (including repaglinide) are associated with hypoglycemia, bone loss, and fracture risk and should be used with caution in older adults 5
• If used, frequency of hypoglycemia should be monitored at each visit 5
• Repaglinide may be safer than sulfonylureas during fasting periods (e.g., Ramadan) due to its meal-related dosing flexibility 5