Nateglinide

Nateglinide is an oral very short-acting meglitinide taken before meals to lower post-prandial glucose. It lowers HbA1c by about 0.5 to 1%, is weaker than repaglinide, and is used mainly with metformin when post-meal hyperglycaemia dominates. Availability is limited in many markets.

Classification. Meglitinide (glinide), D-phenylalanine derivative. Tablets 60 mg and 120 mg.

Mechanism. Binds SUR1 and closes beta-cell ATP-sensitive potassium channels, with faster association and dissociation than repaglinide, producing a brief insulin pulse.

Pharmacodynamics. Restores early-phase insulin release; insulin returns to baseline within 4 hours, so between-meal hypoglycaemia is uncommon.

Pharmacokinetics. Peak within 1 hour; bioavailability about 73%; 98% protein bound. Metabolised by CYP2C9 (about 70%) and CYP3A4 (about 30%); metabolites, one with weak activity, are excreted mainly in urine. Half-life about 1.5 hours.

Type 2 diabetes, adults.

• Usual dose 120 mg orally three times daily, 1 to 30 minutes before main meals.
• Use 60 mg three times daily when HbA1c is near target.
• Maximum 180 mg three times daily in labels that permit it; others cap at 120 mg three times daily. No loading dose.
• Skip the dose when the meal is skipped.

Combination use. Mainly with metformin; may be used with pioglitazone. Do not combine with sulphonylureas or repaglinide.

Adjustments.

• Kidney: no adjustment in mild to moderate impairment. In severe impairment and dialysis, start 60 mg with meals and monitor because a metabolite accumulates.
• Liver: no adjustment in mild impairment; avoid in moderate to severe impairment.
• Older adults: start 60 mg three times daily.
• Weight: no weight-based dosing.

Contraindications. Type 1 diabetes; diabetic ketoacidosis; severe hepatic impairment; pregnancy and breastfeeding.

Adverse effects. Mild hypoglycaemia; small weight gain; upper respiratory infection symptoms, dizziness, arthralgia; rare raised liver enzymes and hypersensitivity.

Major interactions.

• Fluconazole and other CYP2C9 inhibitors raise exposure.
• Rifampicin and other inducers lower exposure.
• Gemfibrozil has a smaller effect than with repaglinide; monitor glucose.
• Beta-blockers mask hypoglycaemia symptoms.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid.
• Children: not licensed.
• Older adults: low hypoglycaemia risk; useful with irregular meals.
• East Africa: often unavailable or costly; repaglinide or gliclazide are usual alternatives. Fluconazole for cryptococcal disease and rifampicin for TB alter levels.

Administration. Take 1 to 30 minutes before each main meal; giving it after the meal reduces effect.

Baseline. HbA1c, eGFR, liver enzymes.

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• Post-prandial capillary glucose during titration.

Dose reduction and stopping. Reduce after hypoglycaemia; stop when HbA1c reduction is under 0.5% after 3 to 6 months, or with liver injury.

Referral and escalation. Admit severe hypoglycaemia, especially with renal failure or interacting drugs. Refer when post-prandial glucose stays high despite combination therapy.