PharmacologyTier 1Medical Sciences concept

Insulin preparations - duration/onset of action comparison

Core concept

All insulins are the same hormone - the formulation controls the absorption rate from the subcutaneous depot, and that is the entire pharmacology
Native insulin self-associates into hexamers at pharmacological concentration; only monomers and dimers are absorbed
- Rapid-acting analogues destabilise the hexamer (amino acid substitutions) -> faster dissociation -> faster onset
- Long-acting analogues are engineered to slow release from the depot
  - Glargine - formulated at pH 4, precipitates as a microprecipitate at neutral subcutaneous pH, then slowly redissolves; this, not altered receptor binding or degradation, is the mechanism
  - Detemir and degludec - fatty acid acylation -> albumin binding (detemir) and multihexamer chains (degludec)
NPH (isophane) - protamine-complexed crystalline suspension; must be resuspended, and it has a genuine peak

Preparation	Onset	Peak	Duration
Ultra-rapid (Fiasp, faster aspart)	2-5 min	0.5-1.5 h	3-5 h
Rapid analogue - aspart, lispro, glulisine	10-20 min	1-2 h	3-5 h
Regular/neutral (Actrapid, Humulin R)	30 min	2-4 h	6-8 h
NPH/isophane (Protaphane, Humulin NPH)	1-2 h	4-8 h - a real peak	12-18 h
Glargine U100	2-4 h	Peakless	~24 h
Glargine U300, degludec	2-6 h	Peakless	>24 h (degludec ~42 h)
Detemir	1-2 h	Minimal	12-20 h
Premixed 30/70	30 min	Dual	12-18 h

Rapid analogue -> inject with the meal. Regular insulin -> inject 30 minutes before it (a common ward error)
NPH peaks overnight -> nocturnal hypoglycaemia; glargine and degludec do not, which is their main clinical advantage
Degludec's ~42 h half-life gives day-to-day flexibility and the lowest nocturnal hypoglycaemia rate
Absorption is faster from abdomen > arm > thigh > buttock, and accelerated by exercise, heat and massage
- Lipohypertrophy from repeated injection into one site causes erratic absorption - rotate sites, and examine them
IV insulin has a half-life of ~5 minutes - the infusion is the only thing keeping the level up
- Stopping an IV insulin infusion in DKA without overlapping subcutaneous long-acting insulin -> rebound ketosis; overlap by 1-2 hours

Basal-bolus for type 1 diabetes: long-acting once daily plus rapid analogue with each meal (50% basal, 50% bolus as a starting split)
Premixed twice daily suits fixed meal patterns and poor dexterity, at the cost of flexibility and more hypoglycaemia
Type 1 diabetes must never have basal insulin withheld, including when fasting or nil by mouth - omission causes DKA
Sick day rules: continue basal, monitor ketones, increase not decrease insulin with intercurrent illness
Renal impairment reduces insulin clearance -> falling insulin requirements are a sign of declining eGFR (or of coeliac disease, or Addison, in type 1)
U-500 and concentrated insulins - prescribe in units, never mL; a recurrent serious error
Insulin is a high-risk medicine - never abbreviate "units" to "U"

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