Meglitinides

Meglitinides (repaglinide and nateglinide) are short acting oral insulin secretagogues taken before meals to reduce postprandial glucose. They carry a lower risk of prolonged hypoglycaemia than sulphonylureas, but require dosing with each meal.

Mechanism. They bind a separate site on the SUR1 subunit of the ATP-sensitive potassium channel, closing it and triggering insulin release. The binding is rapid and brief, so insulin secretion is short lived.

Pharmacokinetics. Onset within 15 to 30 minutes, half-life about 1 hour, duration 3 to 4 hours. Repaglinide is metabolised by CYP2C8 and CYP3A4 and excreted in bile, with low renal dependence. Nateglinide is metabolised by CYP2C9 and CYP3A4. Reduces HbA1c by 0.5 to 1.5% (repaglinide) and 0.5 to 1% (nateglinide).

Repaglinide. 0.5 mg before each meal (1 to 2 mg if HbA1c is over 8%), titrated at 1 to 2 week intervals to a maximum of 4 mg for each dose and 16 mg daily.

Nateglinide. 60 to 120 mg before each meal, maximum 360 mg daily. Weaker than repaglinide.

Versus sulphonylureas. Shorter action, less late hypoglycaemia and a better fit to irregular meal patterns. Both classes act on the same target, so they are not given together.

• Dosing rule: take 0 to 30 minutes before the meal and omit the dose when the meal is skipped.
• Postprandial hyperglycaemia: useful where HbA1c is near target but post-meal glucose is high.
• Irregular meals or Ramadan fasting: the dosing is matched to the meal.
• Kidney impairment: repaglinide is an alternative when sulphonylureas are unsuitable; start at 0.5 mg.
• Combinations: with metformin, pioglitazone or basal insulin; not with a sulphonylurea.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: not licensed. Older adults: lower hypoglycaemia risk, but frequent dosing may reduce adherence. Kidney impairment: acceptable with caution. Liver impairment: avoid in severe disease and reduce doses in mild disease.

Adverse effects. Hypoglycaemia (lower than sulphonylureas), weight gain, nausea and abdominal pain.

Contraindications. Type 1 diabetes, ketoacidosis, pregnancy and breastfeeding, and gemfibrozil co-prescription with repaglinide.

Interactions. Gemfibrozil raises repaglinide exposure about 8-fold through CYP2C8 inhibition, and is contraindicated. Clopidogrel, ciclosporin, clarithromycin and ketoconazole also raise levels. Rifampicin lowers levels.

Monitoring. Postprandial and fasting glucose, HbA1c every 3 months, liver function in hepatic disease.

Referral and escalation. Failure to reach target on two to three agents, recurrent hypoglycaemia, or the need for insulin.