Intermediate Acting Insulin

Intermediate acting insulin is isophane insulin (neutral protamine Hagedorn, NPH), a cloudy suspension of human insulin crystals bound to protamine and zinc. Protamine delays release, giving a peaked profile that is useful as twice-daily basal cover and for steroid-induced hyperglycaemia.

Mechanism. Same receptor activity as endogenous insulin. Protamine proteolysis slows absorption.

Pharmacokinetics. Onset 1 to 2 hours, peak 4 to 10 hours, duration 10 to 18 hours. Absorption varies between injections by 20 to 30% and is dose-dependent, with larger doses acting longer. The suspension must be resuspended (roll gently and invert about 10 times) before each dose, or dose delivery is erratic.

Preparations. Human isophane insulin (U100) is the only widely used form. Protamine suspensions of lispro and aspart exist only in premixed products.

Versus long acting analogues. NPH is cheaper and more widely available, but its peak causes nocturnal hypoglycaemia and its duration is too short to cover 24 hours reliably on a single dose in many patients. Basal analogues reduce nocturnal hypoglycaemia by about 20 to 30% in type 2 diabetes and more in type 1.

Mixing. May be mixed in the same syringe with soluble insulin (soluble drawn up first) or rapid analogues, and given at once. It must not be given intravenously.

• Type 2 diabetes basal: start 10 units or 0.1 to 0.2 units/kg at bedtime, titrate by 2 units every 3 days to a fasting glucose of 4.4 to 7.2 mmol/L (80 to 130 mg/dL).
• Twice-daily regimen: about two-thirds of the total dose before breakfast and one-third before the evening meal, usually with soluble or rapid insulin.
• Steroid-induced hyperglycaemia: give NPH in the morning with the steroid, 0.1 units/kg for each 10 mg of prednisolone (or equivalent), to a maximum of 0.4 units/kg at 40 mg or more. Reduce in step with steroid tapering.
• Pregnancy: isophane has long experience of use and is a usual basal choice, given at bedtime and often twice daily.
• Type 1 diabetes: twice daily with mealtime insulin when analogues are unavailable.

Special groups. Pregnancy and breastfeeding: acceptable. Children: used twice daily with soluble insulin. Older adults: prefer bedtime dosing with a conservative start to limit nocturnal hypoglycaemia. Kidney impairment: reduce dose by 25 to 50%. Liver impairment: reduce dose. Regional: in settings without cold storage, in-use vials last about 28 days at temperatures under 30 degrees C.

Adverse effects. Nocturnal hypoglycaemia at 4 to 10 hours (3 to 4 a.m. for a bedtime dose), weight gain, lipohypertrophy and variable control.

Key errors. Not resuspending the vial, drawing cloudy before clear insulin when mixing, giving an evening dose after a late meal with no check, and increasing the dose in response to a high morning glucose without excluding a nocturnal low followed by rebound.

Monitoring. Fasting glucose daily during titration; glucose at 3 a.m. when fasting values are unexpectedly high or morning symptoms occur; HbA1c every 3 months.

Referral and escalation. Recurrent nocturnal hypoglycaemia, or fasting hyperglycaemia not responding to dose over 0.5 units/kg.