Rapid Acting Insulin Analogues

Rapid acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine, and the faster formulations of aspart and lispro) are amino acid modified insulins that resist hexamer formation and dissociate quickly into active monomers after subcutaneous injection. They are used for mealtime and correction doses.

Mechanism. Receptor activity matches human insulin. The modifications change only absorption: lispro reverses proline and lysine at B28 and B29, aspart substitutes aspartic acid at B28, and glulisine replaces B3 asparagine with lysine and B29 lysine with glutamic acid.

Pharmacokinetics. Onset 10 to 20 minutes, peak 1 to 3 hours, duration 3 to 5 hours. Faster aspart and ultra rapid lispro start about 5 to 10 minutes sooner. Lispro, aspart and glulisine can be given intravenously in monitored settings.

Agents. Lispro (U100 and U200), aspart, glulisine, faster aspart and ultra rapid lispro. Efficacy is equivalent between them at unit-for-unit doses.

Differences. Glulisine has less pregnancy data than lispro and aspart. Faster aspart can be given at the start of the meal or up to 20 minutes after it. Ultra rapid lispro lowers early postprandial glucose slightly more. Pumps may use lispro, aspart or glulisine; only rapid analogues are used in pump reservoirs.

Versus soluble human insulin. Less postprandial excursion, less late hypoglycaemia, no need for a mid-meal snack, and an injection timed 0 to 15 minutes before eating (rather than 30 minutes).

• Mealtime dose: inject 0 to 15 minutes before eating. If intake is unpredictable (young children, gastroparesis, nausea), inject straight after the meal and dose to what was eaten.
• Type 1 diabetes: carbohydrate ratio approximately 500 divided by the total daily dose in g/unit; correction factor approximately 100 divided by the total daily dose in mmol/L (1800 divided by it in mg/dL). Typical ranges are 1 unit to 8 to 15 g of carbohydrate, and 1 unit lowering glucose by 1.5 to 3 mmol/L (27 to 54 mg/dL).
• Type 2 diabetes: when basal insulin alone fails, add 4 units or 10% of the basal dose before the largest meal and titrate by 1 to 2 units (or 10 to 15%) every 3 days.
• Insulin pump: only rapid analogues; a pump interruption of 4 to 6 hours can cause ketoacidosis, so a pen backup and a ketone check at glucose over 14 mmol/L (250 mg/dL) are essential.
• Correction doses: repeat no more often than every 3 to 4 hours to avoid stacking.

Special groups. Pregnancy: lispro and aspart are used throughout. Breastfeeding: compatible. Children: all are used from early childhood; dose after the meal when intake is erratic. Older adults: simplified once-daily or fixed mealtime doses. Kidney impairment: lower doses and more frequent checks. Liver impairment: lower doses.

Hypoglycaemia. Peaks 1 to 3 hours after injection. Missed meals, exercise within 3 hours, alcohol and stacked corrections are the usual causes. Delayed gastric emptying causes a mismatch, with early hypoglycaemia and late hyperglycaemia.

Other adverse effects. Lipohypertrophy (rotate sites), weight gain, local reactions, rare systemic allergy and, with intravenous use, hypokalaemia.

Monitoring. Glucose before meals, 2 hours after meals when adjusting ratios, bedtime and, when possible, continuous glucose monitoring. HbA1c every 3 months.

Referral and escalation. Recurrent nocturnal or unexplained hypoglycaemia, pump malfunction, recurrent ketoacidosis, or marked lipohypertrophy affecting absorption.