Premixed Insulin Preparations

Premixed insulins are fixed ratio mixtures of a rapid or short acting component with an intermediate acting protamine component in one vial or pen. They cover mealtime and basal needs in two injections each day for patients with stable meals.

Mechanism. Receptor activity matches human insulin. The soluble or rapid component acts on postprandial glucose, and the protamine component provides basal cover.

Pharmacokinetics. Two peaks appear after each injection. Human mixes act over up to 18 hours and are given 30 minutes before meals. Analogue mixes start faster and are given immediately before, or just after, the meal. They must be resuspended thoroughly before each injection.

Human premixes. Soluble to isophane at 30 to 70 (most common) and 50 to 50.

Analogue premixes. Biphasic aspart 30 to 70 and 50 to 50, biphasic lispro 25 to 75 and 50 to 50. Insulin degludec with aspart (70 to 30) is a co-formulation without protamine, having a long basal component and no resuspension need.

Limitations. The ratio is fixed, so mealtime and basal doses cannot be separated. They suit patients with regular meals and are less suitable for type 1 diabetes, variable intake or frequent exercise.

• Type 2 diabetes starting on premix: 0.2 to 0.3 units/kg daily, in two divided doses with about two-thirds before breakfast and one-third before the evening meal, or 10 units twice daily, then titrated by 2 units every 3 days, adjusting the morning dose to the pre-evening glucose and the evening dose to the fasting glucose.
• Switching from basal insulin: the total dose is split between the two meals, then titrated.
• Moving from twice daily to basal bolus: when postprandial or between meal control is poor, or when the lunchtime glucose is unpredictable.
• Ramadan: the usual morning dose is taken at iftar (full dose) and the evening dose is taken at suhoor, reduced by about 25 to 50%, with glucose checks during fasting. This varies by regimen and should be individualised.

Special groups. Pregnancy: used in gestational and type 2 diabetes when needed, though basal bolus allows tighter control. Breastfeeding: compatible. Children: used rarely. Older adults: twice daily premix suits patients unable to manage basal bolus. Kidney and liver impairment: reduce doses by 25 to 50%.

Adverse effects. Hypoglycaemia in the late morning, late afternoon and overnight where meals are delayed or missed, weight gain, lipohypertrophy.

Key errors. Failing to resuspend the pen (variable ratio delivered), skipping a meal and still taking the premix, using premix in a patient with ketosis-prone type 1 diabetes, and using human premix as an analogue (timing error).

Monitoring. Fasting and pre-evening meal glucose during titration, with bedtime and 3 a.m. glucose if nocturnal hypoglycaemia is suspected. HbA1c every 3 months.

Referral and escalation. Recurrent hypoglycaemia, total daily dose over 1 unit/kg without control, or conversion to basal bolus.