Glipizide

Glipizide is an oral short-acting second-generation sulphonylurea. Its metabolites are inactive, so it carries less risk of prolonged hypoglycaemia in chronic kidney disease than glibenclamide or glimepiride, while sharing the class effects of weight gain and secondary failure.

Classification. Sulphonylurea, insulin secretagogue. IR tablets (5 and 10 mg) and extended-release (XL) osmotic tablets (2.5, 5 and 10 mg) where available.

Mechanism. Binds SUR1 on beta-cell ATP-sensitive potassium channels, depolarising the cell and releasing insulin.

Pharmacodynamics. Rapid onset within 30 minutes; glucose-lowering effect lasts 12 to 24 hours despite a short half-life.

Pharmacokinetics. Bioavailability close to 100%; food delays absorption of IR. About 98% protein bound. Metabolised in the liver, mainly by CYP2C9, to inactive metabolites excreted mostly in urine. Half-life 2 to 4 hours.

Type 2 diabetes, adults (IR).

• Start 2.5 to 5 mg orally once daily, 30 minutes before breakfast.
• Increase by 2.5 to 5 mg every few days to 1 week.
• Divide doses over 15 mg into twice daily before breakfast and evening meal.
• Maximum 20 mg daily in some labels and 40 mg daily in others; little extra benefit occurs over 20 mg. No loading dose.

Type 2 diabetes, adults (XL).

• Start 5 mg orally once daily with breakfast; 2.5 mg in older adults.
• Usual 5 to 10 mg daily; maximum 20 mg daily.

Adjustments.

• Kidney: start 2.5 mg daily when eGFR is under 60 mL/min/1.73 m2 and titrate slowly. Usable in severe impairment with close glucose monitoring where no alternative exists, though some labels advise avoiding it.
• Liver: start 2.5 mg; avoid in severe impairment.
• Older adults and malnourished patients: start 2.5 mg.
• Weight: no weight-based dosing.

Contraindications. Type 1 diabetes; diabetic ketoacidosis; severe hepatic impairment; hypersensitivity to sulphonylureas or sulphonamides; pregnancy and breastfeeding.

Adverse effects. Hypoglycaemia (less prolonged than with long-acting agents); weight gain; nausea, diarrhoea; rash and photosensitivity; rare cholestatic jaundice, blood dyscrasias and haemolysis in G6PD deficiency. XL tablets can cause obstruction in patients with severe gastrointestinal narrowing.

Major interactions.

• Increased effect: fluconazole, voriconazole, co-trimoxazole, clarithromycin, fluoroquinolones, alcohol.
• Reduced effect: rifampicin, corticosteroids, thiazides.
• Beta-blockers mask hypoglycaemia symptoms.

Special groups.

• Pregnancy: switch to insulin.
• Breastfeeding: avoid; infant hypoglycaemia risk.
• Children: not licensed.
• Older adults: a reasonable sulphonylurea choice at low doses.
• Kidney and liver impairment: start 2.5 mg when eGFR is under 60; inactive metabolites make it the safer sulphonylurea in renal disease; avoid in severe hepatic impairment.
• East Africa: same practical points on G6PD deficiency, rifampicin, co-trimoxazole and fluconazole that apply to all sulphonylureas.

Administration. Take IR 30 minutes before the meal for best effect. Swallow XL whole with breakfast; the empty tablet shell may appear in stool. Omit the dose when the meal is skipped.

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

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• Capillary glucose during titration, in kidney disease and in older adults.
• eGFR at least annually.

Dose reduction and stopping. Reduce after hypoglycaemia or with declining intake; stop with jaundice, severe rash or blood dyscrasia.

Referral and escalation. Admit severe hypoglycaemia for intravenous glucose 10% and observation; use octreotide 50 to 100 micrograms subcutaneously every 6 to 12 hours if hypoglycaemia recurs. Refer when targets are not met on maximum tolerated therapy.