Glimepiride

Glimepiride is an oral once-daily second-generation sulphonylurea. It lowers HbA1c by about 1 to 1.5%, has an intermediate hypoglycaemia risk between gliclazide and glibenclamide, and partly depends on renal clearance of an active metabolite.

Classification. Sulphonylurea, insulin secretagogue. Tablets of 1, 2, 3 and 4 mg; also in fixed-dose combinations with metformin and pioglitazone.

Mechanism. Binds SUR1 on beta-cell ATP-sensitive potassium channels, causing depolarisation, calcium influx and insulin release.

Pharmacodynamics. Lowers fasting and post-prandial glucose within days. Glucose-independent insulin release causes hypoglycaemia when intake falls.

Pharmacokinetics. Complete oral absorption; peak 2 to 3 hours; over 99% protein bound. Metabolised by CYP2C9 to M1 (about one third the activity of parent) and inactive M2. About 60% of metabolites appear in urine and 40% in faeces. Half-life 5 to 9 hours, with an effect lasting 24 hours. CYP2C9 poor metabolisers have higher exposure.

Type 2 diabetes, adults.

• Start 1 mg orally once daily with breakfast or the first main meal.
• Increase by 1 mg every 1 to 2 weeks (1, 2, 3, 4 mg, then 6 mg).
• Usual maintenance 1 to 4 mg once daily.
• Maximum 6 mg daily in most labels; 8 mg daily in some markets. No loading dose; continue long term while effective.

Combination use. Combines with metformin, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors and basal insulin. Reduce the glimepiride dose when adding agents that raise hypoglycaemia risk.

Adjustments.

• Kidney: start 1 mg and titrate slowly when eGFR is under 60 mL/min/1.73 m2; M1 accumulates. Avoid when eGFR is under 30 where an alternative exists.
• Liver: start 1 mg; avoid in severe hepatic impairment.
• Older adults and frail patients: start 1 mg; titrate no faster than every 2 weeks.
• Weight: no weight-based dosing.

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

Adverse effects. Hypoglycaemia (prolonged in renal impairment); weight gain of about 2 kg; nausea, abdominal pain; rash, photosensitivity; rare cholestatic jaundice, hepatitis, thrombocytopenia, agranulocytosis and haemolytic anaemia, especially in G6PD deficiency; hyponatraemia.

Major interactions.

• Increased effect: fluconazole and other CYP2C9 inhibitors, co-trimoxazole, clarithromycin, fluoroquinolones, ACE inhibitors, alcohol.
• Reduced effect: rifampicin, carbamazepine, phenytoin, corticosteroids, thiazides.
• Colesevelam reduces absorption; give glimepiride at least 4 hours before it.
• Beta-blockers mask adrenergic warning symptoms.

Special groups.

• Pregnancy: switch to insulin before conception or when pregnancy is confirmed.
• Breastfeeding: avoid; infant hypoglycaemia risk.
• Children: not advised; no safety advantage over metformin and more weight gain.
• Older adults: higher hypoglycaemia risk than gliclazide; prefer gliclazide or a non-secretagogue.
• Kidney and liver impairment: start 1 mg when eGFR is under 60 because the active metabolite accumulates; avoid in severe renal or hepatic impairment.
• East Africa: G6PD deficiency, rifampicin during TB treatment, and co-trimoxazole or fluconazole in HIV care all change glimepiride effect or safety.

Administration. Swallow whole with breakfast or the first main meal. Skip the dose when the meal is skipped. During Ramadan, move the dose to the sunset meal and consider reducing it.

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

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• Capillary glucose during titration, in older adults and in drivers.
• eGFR at least annually; more often when eGFR is under 60.

Dose reduction and stopping. Reduce after any hypoglycaemia or when eGFR falls; stop when eGFR falls under 30 if an alternative exists, and with jaundice, severe rash or blood dyscrasia.

Referral and escalation. Admit severe or recurrent hypoglycaemia for intravenous glucose 10%, observation for at least 24 hours, and octreotide 50 to 100 micrograms subcutaneously every 6 to 12 hours if hypoglycaemia recurs.