Repaglinide

Repaglinide is an oral short-acting meglitinide insulin secretagogue taken before each main meal. It mainly lowers post-prandial glucose, lowers HbA1c by about 1%, suits irregular meal patterns, and is cleared largely by the liver, which makes it usable in advanced kidney disease.

Classification. Meglitinide (glinide), benzoic acid derivative. Tablets 0.5, 1 and 2 mg.

Mechanism. Binds SUR1 at a site distinct from sulphonylureas, closing beta-cell ATP-sensitive potassium channels and releasing insulin.

Pharmacodynamics. Onset within 30 minutes and duration 4 to 6 hours, giving a meal-linked insulin pulse and less late hypoglycaemia than sulphonylureas.

Pharmacokinetics. Rapid absorption; peak about 1 hour; bioavailability about 60%; over 98% protein bound. Metabolised by CYP2C8 and CYP3A4 to inactive metabolites, about 90% excreted in faeces. Half-life about 1 hour.

Type 2 diabetes, adults.

• Start 0.5 mg orally within 15 minutes before each main meal (up to 30 minutes before).
• Start 1 mg with each meal when switching from another oral agent or when HbA1c is 8% (64 mmol/mol) or higher.
• Titrate every 1 to 2 weeks, doubling the dose up to 4 mg with each meal.
• Maximum 4 mg as a single dose and 16 mg daily. No loading dose.
• One meal, one dose: skip the dose when a meal is skipped; add a dose with an extra meal.

Combination use. Licensed with metformin and pioglitazone. Do not combine with sulphonylureas (same mechanism). Avoid with NPH insulin.

Adjustments.

• Kidney: no adjustment in mild to moderate impairment. With eGFR 20 to 40 mL/min/1.73 m2, start 0.5 mg with meals and titrate carefully. Limited data under 20 and on dialysis.
• Liver: use longer titration intervals in mild to moderate impairment; avoid in severe impairment.
• Older adults: start 0.5 mg; data over 75 years are limited.
• Weight: no weight-based dosing.

Contraindications. Type 1 diabetes; diabetic ketoacidosis; severe hepatic impairment; co-administration with gemfibrozil; pregnancy and breastfeeding.

Adverse effects. Hypoglycaemia, less prolonged than with sulphonylureas; weight gain of about 1 to 2 kg; abdominal pain, diarrhoea; arthralgia; rare raised liver enzymes and hypersensitivity.

Major interactions.

• Gemfibrozil (CYP2C8 inhibitor) raises exposure about eightfold: contraindicated.
• Clopidogrel inhibits CYP2C8: avoid; if unavoidable, keep the total repaglinide dose at 4 mg daily or less.
• Ciclosporin, itraconazole, clarithromycin, trimethoprim and deferasirox raise levels.
• Rifampicin and other inducers lower levels; hypoglycaemia can follow when rifampicin stops.
• Beta-blockers mask warning symptoms.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid.
• Children: not licensed.
• Older adults: low hypoglycaemia risk relative to sulphonylureas makes it useful with erratic eating, but start low.
• Kidney and liver impairment: no change in mild to moderate renal impairment, start 0.5 mg when eGFR is 20 to 40; avoid in severe hepatic impairment.
• East Africa: useful for Ramadan fasting because dosing follows meals. Rifampicin during TB treatment and trimethoprim in co-trimoxazole alter levels. Clopidogrel use after stroke or coronary events limits the dose.

Administration. Swallow before each main meal, usually within 15 minutes. During Ramadan, take before iftar and suhoor only.

Baseline. HbA1c, eGFR, liver enzymes, list of interacting medicines.

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• Capillary glucose before and 2 hours after meals during titration.
• Liver enzymes if symptoms suggest liver injury.

Dose reduction and stopping. Reduce after hypoglycaemia. Stop if gemfibrozil is needed, with severe hepatic impairment, or with hypersensitivity.

Referral and escalation. Admit severe hypoglycaemia; observation for 12 to 24 hours is usually enough given the short half-life, longer with interacting drugs or liver disease.