Insulin Lispro

Insulin lispro is a rapid-acting human insulin analogue given subcutaneously 0 to 15 minutes before meals, or by infusion pump. Its faster onset and shorter duration than regular human insulin give better post-meal control and less late hypoglycaemia. It lowers HbA1c similarly to regular insulin in most patients, and is preferred in pumps and for flexible meal timing.

Classification. Rapid-acting insulin analogue; proline and lysine are reversed at positions B28 and B29 of the human insulin chain, reducing hexamer formation. U100 and U200 pens and vials; a faster-acting formulation with added excipients and biosimilar versions exist.

Mechanism. Binds the insulin receptor with the same affinity and effects as human insulin, increasing glucose uptake, suppressing hepatic glucose output and ketogenesis, and driving potassium into cells.

Pharmacodynamics. Subcutaneous onset 10 to 15 minutes, peak 1 to 2 hours, duration 3 to 5 hours. The effect of the faster formulation starts a few minutes earlier.

Pharmacokinetics. Absorbed faster than regular insulin because it dissociates rapidly from hexamers. Cleared by the liver and kidney. Subcutaneous half-life about 1 hour; intravenous half-life about 20 to 30 minutes.

Type 1 diabetes, adults (basal-bolus).

• Total daily insulin about 0.4 to 1 unit/kg, commonly 0.5 unit/kg; about half as basal insulin and half as meal doses.
• Insulin lispro 0.1 unit/kg subcutaneously 0 to 15 minutes before each main meal, adjusted to glucose; may be given straight after the meal in children and unpredictable eaters.
• Insulin-to-carbohydrate ratio often 1 unit to 10 to 15 g carbohydrate; correction dose estimated from the rule of 1800 divided by the total daily dose in units, giving the mg/dL fall for 1 unit (for glucose in mmol/L, 100 divided by the total daily dose).
• Titrate meal doses by 1 to 2 units, or 10 to 15%, every 3 days. No fixed maximum; total needs over 2 units/kg/day suggest insulin resistance or error.

Type 2 diabetes, adults.

• Add prandial insulin to basal insulin when HbA1c stays over target: start 4 units, or 10% of the basal dose, subcutaneously with the largest meal; add further meal doses as needed.
• Titrate by 1 to 2 units, or 10 to 15%, every 3 days. Reduce basal insulin or sulphonylureas if hypoglycaemia occurs.

Children and adolescents with type 1 diabetes (licensed from 1 year in many markets).

• Total daily insulin 0.7 to 1 unit/kg before puberty and up to 1.2 unit/kg in puberty, divided as basal and meal doses; directed by a paediatric diabetes team.

Continuous subcutaneous insulin infusion (pump).

• Start at about 75 to 80% of the previous total daily insulin dose, about half as the basal rate and half as meal boluses; adjust to glucose.

Diabetic ketoacidosis.

• Intravenous: same fixed-rate infusion as regular insulin (0.1 unit/kg/hour after potassium is 3.3 mmol/L or more and fluids are running; reduce to 0.02 to 0.05 unit/kg/hour with dextrose when glucose is 14 mmol/L).
• Mild to moderate uncomplicated ketoacidosis with hourly monitoring: 0.2 unit/kg subcutaneously, then 0.1 unit/kg subcutaneously every hour until glucose is 14 mmol/L, then 0.05 unit/kg every hour.

Gestational diabetes and pregnancy. Compatible; used for post-meal control. Needs fall in the first trimester and rise from the second trimester through the third.

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 lispro or an excipient (rare).

Hypoglycaemia. The main risk, most often 2 to 4 hours after a meal dose. 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.

• Hypokalaemia with intravenous insulin.
• Pump failure leading to ketoacidosis within hours because only rapid-acting insulin is in the body.
• Lipohypertrophy at repeated injection sites; rotate sites.
• Weight gain; rare insulin allergy and injection site reactions; fluid retention with pioglitazone.

Common prescribing errors.

• Drawing U200 insulin out of a pen with a syringe: the pen delivers the intended units, and the insulin must never be transferred to a syringe.
• Giving a meal dose when the patient is not about to eat.
• Using a syringe that does not match the vial concentration, or confusing units with millilitres.
• Giving the rapid-acting dose as basal insulin or the basal dose as the mealtime dose.

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.
• SGLT2 inhibitors with large insulin dose cuts: ketoacidosis.

Special groups.

• Pregnancy: compatible; 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 as basal and meal doses.
• Older adults: avoid hypoglycaemia; relax targets.
• Kidney impairment: reduce doses; prolonged action.
• Liver impairment: reduce doses.
• East Africa: costlier than human regular insulin, so supply in public facilities is limited. Unopened vials and pens keep in a fridge (2 to 8 degrees Celsius); an in-use vial or pen keeps at room temperature up to 30 degrees Celsius for 28 days; protect from direct sunlight and never freeze. Check the syringe markings against the vial concentration.

Formulation and preparation. Clear, colourless solution; do not use if cloudy or discoloured. Use pens or U100 syringes with U100 vials. Insulin lispro can be mixed with NPH insulin in the same syringe, drawing lispro first, and the mix is given immediately.

Subcutaneous administration. Inject into the abdomen, thigh or upper arm 0 to 15 minutes before the meal; rotate sites.

Intravenous infusion. Dilute to 0.1 to 1 unit/mL in 0.9% sodium chloride or 5% dextrose; flush the line with 20 to 50 mL before use because insulin binds to the plastic. Use only in a monitored setting.

Baseline. Capillary glucose, HbA1c, eGFR, hypoglycaemia history; potassium, bicarbonate and ketones in acute illness.

Monitoring.

• Capillary glucose before meals, at bedtime and when unwell; continuous glucose monitoring where available; HbA1c every 3 months.
• Pump users check glucose at least every 4 hours and ketones if glucose over 14 mmol/L (250 mg/dL) with illness.
• Intravenous infusion: glucose hourly and potassium every 2 to 4 hours.

Dose reduction and stopping. Reduce the dose by 10 to 20% after any hypoglycaemia without a clear cause. Stop the meal dose if the meal is skipped.

Referral and escalation. Admit severe hypoglycaemia, ketoacidosis or glucose over 25 mmol/L (450 mg/dL) with illness. Involve critical care for pH under 7.0, serum potassium under 3.3 mmol/L at presentation, reduced consciousness or shock.