Insulin Degludec

Insulin degludec is an ultra-long-acting human insulin analogue given subcutaneously once daily as basal insulin, with flexible timing. Its half-life is about 25 hours and its action lasts over 42 hours, so day-to-day variability is lower and nocturnal hypoglycaemia is less frequent than with insulin glargine. A cardiovascular outcome study showed safety compared with insulin glargine. The cost is higher.

Classification. Ultra-long-acting insulin analogue; threonine at B30 is removed and a fatty diacid is attached at B29 through a glutamic acid link. U100 and U200 pens; a fixed-dose combination with liraglutide and a co-formulation with insulin aspart exist.

Mechanism. Binds the insulin receptor with the same effects as human insulin. In the pen it forms dihexamers, and after injection it forms soluble multihexamers that release monomers slowly.

Pharmacodynamics. Onset 1 to 2 hours; flat profile, duration over 42 hours; steady state after 3 to 4 days of dosing.

Pharmacokinetics. Bioavailability about 50 to 60%; albumin binding over 99%; half-life about 25 hours independent of dose. Cleared by the liver and kidney, with metabolism like human insulin.

Type 2 diabetes, adults.

• Start 10 units, or 0.1 to 0.2 unit/kg, subcutaneously once daily at any time of day.
• Titrate by 2 units every 3 to 4 days 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; about 40 to 50% as insulin degludec once daily, with rapid-acting insulin before meals.
• Titrate by 1 to 2 units, or 10 to 15%, every 3 to 4 days.

Switching. From another basal insulin: unit for unit; consider a 20% reduction when the previous basal insulin was given twice daily or when hypoglycaemia risk is high. Adjust over the next week.

Flexible dosing. Doses can be taken at different times each day, provided at least 8 hours separate them and the interval does not exceed 40 hours. Keep the usual time on other days.

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

• Basal dose about 30 to 50% of the total daily insulin of 0.7 to 1 unit/kg before puberty and up to 1.2 unit/kg in puberty; 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: start 10 units or less; use less strict targets.
• Weight: dose by weight in children.

Contraindications. Hypoglycaemia; hypersensitivity to insulin degludec or an excipient (rare).

Hypoglycaemia. The main risk, with a long tail after large doses. 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). Observe for at least 24 hours after large doses.

Other serious adverse effects.

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

Common prescribing errors.

• Confusing U100 and U200 pens: the pen dial shows the dose in units for either strength, and the insulin must never be transferred to a syringe.
• Titrating more often than every 3 to 4 days, before steady state, which causes dose stacking and hypoglycaemia.
• Mixing insulin degludec with other insulins, or confusing the basal pen with the rapid-acting pen.
• Using a syringe that does not match the vial concentration, or confusing units with millilitres.

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.
• GLP-1 receptor agonists and SGLT2 inhibitors: lower the insulin dose when starting.

Special groups.

• Pregnancy: limited data; use only if the benefit is clear, and prefer NPH insulin or insulin detemir.
• Breastfeeding: compatible; needs fall in lactation.
• Children: from 1 year in many markets.
• Older adults: low nocturnal hypoglycaemia risk and flexible timing suit those relying on carers.
• Kidney impairment: reduce doses; prolonged action.
• Liver impairment: reduce doses.
• East Africa: a costlier choice, used where hypoglycaemia is recurrent or dosing times are unpredictable (for example, shift work and fasting). Unopened pens keep in a fridge (2 to 8 degrees Celsius); an in-use pen keeps at room temperature up to 30 degrees Celsius for 56 days; protect from direct sunlight and never freeze.

Formulation and preparation. Clear, colourless solution; do not use if cloudy or discoloured. Do not mix with other insulins. Use only the pen provided; never draw the insulin into a syringe.

Subcutaneous administration. Inject into the abdomen, thigh or upper arm once daily; rotate sites. Never give intravenously.

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

Monitoring.

• Fasting capillary glucose daily during titration, with changes made no more often than every 3 to 4 days.
• 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, and when starting a GLP-1 receptor agonist or an SGLT2 inhibitor.

Referral and escalation. Admit severe hypoglycaemia, ketoacidosis or glucose over 25 mmol/L (450 mg/dL) with illness.