Ultra Long Acting Insulin Analogues

Ultra long acting insulin analogues (insulin degludec, and insulin glargine U300) give a flat basal profile lasting 36 hours or more, with low day to day variability and allowance for flexible dose timing.

Mechanism. Receptor activity matches human insulin. Degludec forms soluble multi-hexamer chains after injection, releasing monomers slowly. Glargine U300 is a concentrated form, with a smaller depot surface area and slower release.

Pharmacokinetics. Degludec: half-life about 25 hours, duration over 42 hours, steady state in 3 to 4 days. Glargine U300: duration up to 36 hours, steady state in 3 to 4 days. Neither should be titrated before steady state.

Degludec. Available as U100 and U200. Doses may be taken at a flexible time, with at least 8 hours between doses.

Glargine U300. Doses may be taken up to 3 hours either side of the usual time. Units are not interchangeable beyond conversion: switching from glargine U100 uses a unit for unit start, with an increase of 10 to 18% often needed afterwards.

Versus glargine U100. Less nocturnal and overall hypoglycaemia in type 2 diabetes, with similar HbA1c. Cost and limited supply restrict use in many settings.

Fixed combinations. Degludec with liraglutide, and glargine with lixisenatide, combine basal insulin with a GLP-1 receptor agonist, and are titrated by the insulin component.

• Type 2 diabetes: start 10 units daily or 0.1 to 0.2 units/kg, titrate every 3 to 4 days by 2 units to a fasting glucose of 4.4 to 7.2 mmol/L (80 to 130 mg/dL).
• Type 1 diabetes: about 40 to 50% of the total daily dose, with rapid mealtime insulin.
• Switch from other basal insulin: degludec unit for unit, reduced by 20% if previously on twice daily basal insulin. Glargine U300 unit for unit from U100, with a 20% reduction when changing from twice daily basal.
• Best candidates: recurrent nocturnal hypoglycaemia, irregular dosing schedules (shift workers, carers, missed doses), hypoglycaemia unawareness, older adults living alone.
• Ramadan: the flat profile allows dose timing at iftar or suhoor without large dose changes.

Special groups. Pregnancy: degludec has limited data and may be used when benefit outweighs risk. Breastfeeding: likely compatible. Children: degludec is used from 1 year in many settings. Older adults: preferred where available. Kidney and liver impairment: reduce doses by 25 to 50%, and titrate more slowly.

Adverse effects. Hypoglycaemia (lower rate than other basal insulins), weight gain, lipohypertrophy, and injection site reactions.

Key errors. Titrating before steady state, which leads to overdose and prolonged hypoglycaemia for 2 or more days, and confusing the U200 degludec pen with U100. The pen dial shows the dose in units and must not be recalculated.

Monitoring. Fasting glucose daily, titration every 3 to 4 days only, HbA1c every 3 months.

Referral and escalation. Prolonged hypoglycaemia after overdose, unexplained fasting hyperglycaemia on over 0.5 units/kg, or recurrent severe hypoglycaemia.