NPH Insulin

NPH insulin (isophane insulin) is intermediate-acting human insulin in a cloudy protamine suspension, given subcutaneously once or twice daily as basal insulin or as part of a premixed insulin. It is the cheapest and most widely available basal insulin in public facilities. Its action peaks 4 to 8 hours after injection, so nocturnal hypoglycaemia and variable absorption are its main drawbacks compared with long-acting analogues.

Classification. Intermediate-acting human insulin; neutral protamine Hagedorn suspension. Vials and pens of 100 units/mL (U100). Also supplied in premixed combinations with regular insulin.

Mechanism. Binds the insulin receptor, increasing glucose uptake in muscle and fat, suppressing hepatic glucose output and ketogenesis, and driving potassium into cells. Protamine delays absorption from the injection site.

Pharmacodynamics. Subcutaneous onset 1 to 2 hours, peak 4 to 8 hours, duration 12 to 18 hours (up to 24 hours with larger doses).

Pharmacokinetics. Absorption is slow and variable from the subcutaneous depot, rising with exercise, heat and abdominal injection, and falling when the suspension is not mixed. Cleared by the liver and kidney.

Type 2 diabetes, adults (basal insulin).

• Start 10 units, or 0.1 to 0.2 unit/kg, subcutaneously once daily at bedtime (or twice daily in some patients).
• Titrate by 2 units every 3 days (4 units if fasting glucose is over 10 mmol/L) to a fasting glucose of 4 to 7 mmol/L (about 70 to 130 mg/dL). Reduce the dose by 10 to 20% after any hypoglycaemia.
• No fixed maximum. A total basal dose over 0.5 unit/kg suggests over-basalisation; add prandial insulin or another agent rather than raising basal insulin further.

Type 1 diabetes, adults.

• Total daily insulin about 0.4 to 1 unit/kg, commonly 0.5 unit/kg. As basal insulin in a basal-bolus regimen give about 40 to 50% of the total dose as NPH, divided between before breakfast and bedtime, with regular or rapid-acting insulin before meals.
• Conventional twice-daily regimen where basal-bolus is not possible: about two thirds of the total daily dose before breakfast and one third before the evening meal, each dose being two thirds NPH and one third regular insulin.
• Titrate by 1 to 2 units, or 10 to 15%, every 3 days.

Steroid-induced hyperglycaemia.

• NPH insulin subcutaneously once daily in the morning at the same time as the oral corticosteroid: 0.1 unit/kg for each 10 mg of prednisolone, up to 0.4 unit/kg at 40 mg or more. Adjust daily to glucose and reduce as the steroid dose falls.

Gestational diabetes and pregnancy. Used when metformin is inadequate; usually given at bedtime or twice daily, with prandial insulin as needed. Needs fall in the first trimester and rise from the second trimester through the third.

Children and adolescents with type 1 diabetes.

• Total daily insulin 0.7 to 1 unit/kg before puberty and up to 1.2 unit/kg in puberty, with NPH as part of a split regimen; directed by a paediatric diabetes team.

Adjustments.

• Kidney: reduce dose by about 25% when eGFR is 10 to 50 and about 50% when under 10, adjusted to glucose.
• Liver: reduce dose in cirrhosis and acute liver failure.
• Older adults: use less strict targets and lower starting doses.
• Weight: dose by weight in children.

Contraindications. Hypoglycaemia; hypersensitivity to insulin or protamine (rare, more likely after exposure to protamine-containing insulin or fish-derived protamine products).

Hypoglycaemia. The main risk, most often at night or between meals when the dose peaks. Treat glucose under 4 mmol/L (70 mg/dL) with 15 to 20 g fast oral glucose and recheck at 15 minutes. For severe hypoglycaemia give intravenous glucose 10% 150 to 200 mL over 15 minutes, or glucagon 1 mg intramuscularly or subcutaneously (0.5 mg for children under 25 kg).

Other serious adverse effects.

• Weight gain; lipohypertrophy at repeated injection sites with erratic absorption; rotate sites.
• Rare insulin allergy and injection site reactions; fluid retention with pioglitazone.
• Not for intravenous use or for ketoacidosis.

Common prescribing errors.

• Not resuspending the vial or pen before use, which gives a weak first dose and an excess last dose.
• Using a syringe that does not match the vial concentration, or confusing units with millilitres.
• Giving NPH insulin intravenously, or confusing it with regular insulin.
• Giving the premixed form where a basal-only dose is intended.

Major interactions.

• Increased hypoglycaemia: sulphonylureas, ACE inhibitors, fibrates, fluoxetine, monoamine oxidase inhibitors, salicylates, alcohol.
• Reduced effect: corticosteroids, thiazides, atypical antipsychotics, oestrogen-containing contraceptives, protease inhibitors, thyroid hormones.
• Beta-blockers mask hypoglycaemia symptoms.
• Pioglitazone and insulin together: fluid retention and heart failure.

Special groups.

• Pregnancy: compatible, with long experience; needs rise from the second trimester and fall sharply after delivery.
• Breastfeeding: compatible; needs fall in lactation.
• Children: 0.7 to 1 unit/kg/day before puberty and up to 1.2 unit/kg/day in puberty, divided across basal and meal doses.
• Older adults: avoid nocturnal hypoglycaemia; relax targets.
• Kidney impairment: reduce doses; prolonged action.
• Liver impairment: reduce doses.
• East Africa: usually the basal insulin available in public facilities and affordable for patients. Unopened vials keep in a fridge (2 to 8 degrees Celsius); an in-use vial or pen keeps at room temperature up to 25 degrees Celsius for 28 days; protect from direct sunlight and never freeze. Check the syringe markings against the vial concentration, since U40 and U100 supplies can coexist.

Formulation and preparation. Cloudy white suspension. Roll the vial or pen gently between the palms 10 times and tip it up and down until evenly cloudy; do not shake. Use U100 syringes with U100 vials. NPH insulin can be mixed with regular or rapid-acting insulin in the same syringe, drawing the clear insulin first, and the mix is given immediately.

Subcutaneous administration. Inject into the thigh or abdomen at bedtime and the abdomen or upper arm before breakfast; rotate sites. Never give intravenously.

Baseline. Capillary glucose, HbA1c, eGFR, hypoglycaemia history.

Monitoring.

• Fasting and bedtime capillary glucose during titration; occasional 3 a.m. glucose when nocturnal hypoglycaemia is suspected.
• HbA1c every 3 months.
• eGFR at least annually.

Dose reduction and stopping. Reduce the dose by 10 to 20% after any hypoglycaemia without a clear cause. Consider changing to a long-acting analogue when nocturnal hypoglycaemia recurs and the analogue is available.

Referral and escalation. Admit severe hypoglycaemia (observe at least 24 hours after large doses because of the long tail), ketoacidosis or glucose over 25 mmol/L (450 mg/dL) with illness.