Glibenclamide

Glibenclamide is an oral long-acting second-generation sulphonylurea with active, renally cleared metabolites. It is inexpensive and widely available, but has the highest risk of severe and prolonged hypoglycaemia in its class, so it is a poor choice in older adults and in kidney disease.

Classification. Sulphonylurea, insulin secretagogue. Tablets 2.5 mg and 5 mg; micronised tablets and an oral suspension for neonatal diabetes exist in some markets.

Mechanism. Binds SUR1 with high affinity, closing beta-cell ATP-sensitive potassium channels and releasing insulin. It also binds SUR1-regulated channels outside the pancreas.

Pharmacodynamics. Glucose-lowering effect lasts at least 24 hours. Slow dissociation from SUR1 and active metabolites prolong hypoglycaemia.

Pharmacokinetics. Well absorbed; over 99% protein bound. Hepatic metabolism (CYP3A4 and CYP2C9) to active hydroxy metabolites, excreted roughly equally in urine and bile. Half-life about 10 hours, prolonged in renal impairment.

Type 2 diabetes, adults.

• Start 2.5 to 5 mg orally once daily with breakfast.
• Increase by 2.5 mg every 1 to 2 weeks.
• Doses over 10 mg daily may be divided twice daily.
• Maximum 15 mg daily in most labels; 20 mg daily in some. No loading dose.

Gestational diabetes (where insulin is unavailable or declined).

• Start 2.5 mg orally once daily with breakfast; titrate every few days to glucose targets.
• Maximum 20 mg daily in divided doses. Insulin and metformin give fewer neonatal complications and are preferred.

Neonatal diabetes due to KCNJ11 or ABCC8 mutations (specialist).

• High weight-based doses, usually starting around 0.2 mg/kg daily in divided doses and escalating every few days to effect; many children need about 0.5 to 1 mg/kg daily. Transfer from insulin is directed by a specialist unit.

Adjustments.

• Kidney: avoid when eGFR is under 60 mL/min/1.73 m2 where an alternative exists; contraindicated in severe renal impairment.
• Liver: avoid in severe hepatic impairment.
• Older adults: avoid; switch to gliclazide or a non-secretagogue.
• Weight: weight-based only in neonatal diabetes.

Contraindications. Type 1 diabetes; diabetic ketoacidosis; severe renal or hepatic impairment; hypersensitivity to sulphonylureas or sulphonamides; co-administration with bosentan (liver injury).

Adverse effects. Severe and prolonged hypoglycaemia, which may need several days of glucose infusion; weight gain; gastrointestinal upset; rash and photosensitivity; rare cholestatic jaundice, blood dyscrasias, haemolytic anaemia in G6PD deficiency, and hyponatraemia.

Major interactions.

• Increased effect: fluconazole, clarithromycin, co-trimoxazole, fluoroquinolones, alcohol, ACE inhibitors.
• Reduced effect: rifampicin and other inducers, corticosteroids, thiazides.
• Bosentan: raised liver enzymes; avoid the combination.
• Ciclosporin levels may rise.

Special groups.

• Pregnancy: crosses the placenta; associated with more neonatal hypoglycaemia and macrosomia than insulin or metformin. Use only when those are not available or acceptable, and plan neonatal glucose checks.
• Breastfeeding: little transfer into milk on limited data; if used, observe the infant for hypoglycaemia.
• Children: specialist use in neonatal diabetes only.
• Older adults: avoid.
• East Africa: remains common and cheap in many facilities, so it is often what patients are taking. Switch high-risk patients (older, kidney disease, poor intake, TB or HIV co-medication) to gliclazide where available. Watch for haemolysis in G6PD deficiency.

Administration. Take with breakfast; omit when the meal is skipped. Avoid during Ramadan fasting where an alternative exists; if continued, move the dose to the sunset meal and reduce it.

Baseline. HbA1c, eGFR, liver enzymes, G6PD status where indicated.

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• Capillary glucose, especially in pregnancy and during dose changes.
• eGFR at least annually.

Dose reduction and stopping. Switch when eGFR falls under 60, with any severe hypoglycaemia, or in older adults. Stop with jaundice, severe rash or blood dyscrasia.

Referral and escalation. Admit all severe glibenclamide hypoglycaemia. Give intravenous glucose 10% by infusion, octreotide 50 to 100 micrograms subcutaneously every 6 to 12 hours for recurrence, and observe for at least 24 to 72 hours after the last glucose infusion.