Gliclazide

Gliclazide is an oral second-generation sulphonylurea that stimulates insulin release independent of glucose level. It lowers HbA1c by about 1 to 1.5%, acts quickly, is inexpensive and has the lowest hypoglycaemia risk among commonly used sulphonylureas, but causes weight gain and loses effect over years as beta-cell function declines.

Classification. Sulphonylurea, insulin secretagogue. Available as 80 mg IR tablets and 30 mg and 60 mg modified-release (MR) tablets. A 30 mg MR dose is roughly equivalent to 80 mg IR.

Mechanism. Binds the SUR1 subunit of the ATP-sensitive potassium channel on pancreatic beta cells, closing the channel. Membrane depolarisation opens voltage-gated calcium channels and triggers insulin exocytosis.

Pharmacodynamics. Restores early-phase insulin secretion and lowers fasting and post-prandial glucose. Because release is not glucose dependent, hypoglycaemia occurs when intake falls or activity rises.

Pharmacokinetics. Well absorbed; about 95% protein bound. Extensively metabolised in the liver, largely by CYP2C9 and CYP2C19, to inactive metabolites; under 1% excreted unchanged in urine. Half-life 10 to 12 hours (IR) and about 16 hours (MR), allowing once-daily MR dosing.

Type 2 diabetes, adults (IR).

• Start 40 to 80 mg orally once daily with breakfast.
• Titrate every 1 to 2 weeks by 40 to 80 mg to glucose targets.
• Doses over 160 mg daily are given in two divided doses with breakfast and evening meal.
• Maximum 320 mg daily. No loading dose; continue long term while effective.

Type 2 diabetes, adults (MR).

• Start 30 mg orally once daily with breakfast.
• Increase in 30 mg steps every 4 weeks, or after 2 weeks when glucose has not fallen.
• Maximum 120 mg once daily.

HNF1A and HNF4A monogenic diabetes.

• These forms are highly sensitive to sulphonylureas. Start low, around 20 to 40 mg IR daily, and titrate slowly to avoid hypoglycaemia. Usually directed by a diabetes specialist.

Combination use. Adds well to metformin, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors and basal insulin. When adding a DPP-4 inhibitor, GLP-1 receptor agonist or insulin, reduce the gliclazide dose by about half if HbA1c is near target.

Adjustments.

• Kidney: mild to moderate impairment, use the usual regimen with closer glucose checks. Avoid when eGFR is under 30 mL/min/1.73 m2 unless no alternative exists; then use the lowest dose with intensive monitoring.
• Liver: avoid in severe hepatic impairment.
• Older adults: start at 30 mg MR or 40 mg IR and titrate slowly.
• Weight: no weight-based dosing.

Contraindications. Type 1 diabetes; diabetic ketoacidosis; severe renal or hepatic impairment; hypersensitivity to sulphonylureas or sulphonamides; co-administration with miconazole by any route including oral gel; pregnancy and breastfeeding.

Hypoglycaemia. The main risk. Predisposing factors are missed meals, alcohol, older age, renal or hepatic impairment, interacting drugs and combination with insulin. Sulphonylurea hypoglycaemia can recur for 24 hours or more after correction.

Other adverse effects. Weight gain of about 2 kg; nausea, dyspepsia and altered bowel habit; rash, pruritus and photosensitivity; rare hepatitis, cholestatic jaundice, blood dyscrasias and haemolytic anaemia in G6PD deficiency.

Major interactions.

• Increased hypoglycaemia: miconazole (contraindicated), fluconazole, clarithromycin, co-trimoxazole and other sulphonamides, fluoroquinolones, ACE inhibitors, alcohol and high-dose salicylates.
• Masked warning symptoms: non-selective and selective beta-blockers.
• Reduced effect: rifampicin and other enzyme inducers, corticosteroids, thiazides, danazol and chlorpromazine.
• Warfarin anticoagulant effect may increase; check INR when starting.

Special groups.

• Pregnancy: switch to insulin, with or without metformin, before conception or when pregnancy is confirmed.
• Breastfeeding: avoid because of the risk of infant hypoglycaemia.
• Children: not licensed except under specialist direction in monogenic diabetes.
• Older adults: shortest-acting choices and modest targets; reassess need when HbA1c falls under 7% (53 mmol/mol).
• Kidney and liver impairment: usual regimen with closer glucose checks in mild to moderate renal impairment; avoid when eGFR is under 30 or in severe hepatic impairment.
• East Africa: G6PD deficiency is common in parts of the region, so watch for haemolysis. Rifampicin during TB treatment lowers gliclazide levels, and glucose can fall sharply when rifampicin stops. Co-trimoxazole prophylaxis and fluconazole in HIV care raise hypoglycaemia risk.

Administration. Take with breakfast. Swallow MR tablets whole; the 60 mg MR tablet can be halved. Do not take a dose when a meal is skipped.

Ramadan and fasting. Move the main or only dose to the sunset meal (iftar). With twice-daily IR, give the usual morning dose at iftar and halve the pre-dawn (suhoor) dose. Advise stopping the fast if glucose falls under 3.9 mmol/L.

Driving. Patients check capillary glucose before driving and at intervals on long journeys, and do not drive when glucose is under 5 mmol/L.

Baseline. HbA1c, eGFR, liver enzymes, and G6PD status where deficiency is common and testing is available.

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• Capillary glucose monitoring when hypoglycaemia risk is high, during dose changes, or for drivers.
• eGFR and liver enzymes at least annually.

Dose reduction and stopping. Reduce or stop after any hypoglycaemia without a clear cause, when eGFR falls under 30, when intake is poor, or when HbA1c is well under target in older adults. Stop if jaundice, a blood dyscrasia or a severe rash develops.

Referral and escalation. Admit severe or recurrent sulphonylurea hypoglycaemia for intravenous glucose 10% and at least 24 hours of observation; give octreotide 50 to 100 micrograms subcutaneously every 6 to 12 hours for recurrent hypoglycaemia. Refer when HbA1c remains over target on maximum dose.