INTRODUCTION

Insulin may be prescribed to either provide glycaemic control in the postprandial or fasting state or both

• Intermediate- or long-acting insulin is used to provide basal cover in the fasting (pre-meal) state by predominantly suppressing gluconeogenesis. Monitoring fasting glucose therefore best assesses the efficacy of the dose prescribed (Aim 4.0-7.0 mmol/l, but may need to be individualised e.g. pregnancy, hypoglycaemic risk).
• Ultrafast- or fast-acting insulin is used as boluses with meals to facilitate glucose uptake by cells after meals. Monitoring pre- and postprandial glucose best assesses the efficacy of the dose prescribed (postprandial glucose should ideally be <8mmol/l or not be more than 2mmol/l above the preprandial value if pre-prandial glucose is not in target range). Patients may be taught how to adjust bolus insulin to correct for high pre-prandial glucose or the amount of carbohydrates to be consumed. Note: Although bolus insulin may be used to correct for high pre-prandial or fasting glucose, adjustment of the basal insulin is required if a pattern of high fasting glucose persists.

INSULINS

Ultrafast-acting insulins:

These synthetic analogues have a more rapid onset of peak action as well as a shorter duration of action.

Advantages:

• Given at the time of a meal and therefore does not require patients to plan dosing prior to meals
• Shorter duration allows greater flexibility of the time between meals as the effects of two consequent doses are unlikely to overlap
• Lower risk of delayed postprandial hypoglycemia

Disadvantages:

• Cost
• Does not provide any basal cover after meals. If the basal insulin dose is missed or inadequate, there is a risk of significant hyperglycaemia or ketoacidosis.

Fast-acting (regular) insulins:

Biosynthetic (using recombinant DNA) soluble human insulin.
Universally coded with yellow labeling to ensure easy recognition by patients.
Onset of peak action slower than ultrafast analogues. Doses should therefore be given 30-45 minutes before meals.
Duration of action up to 8 hours with significant risk of postprandial hypoglycaemia. Patients should be advised to take a snack 2 hours after a meal.

Advantages:

• Cheap
• Provides some basal cover in the postprandial state

Disadvantages:

• Inconvenience of planning doses before meals
• Risk for postprandial hypoglycaemia
• Inflexibility of the timing of meals as effects of doses may overlap if meals occur too close together

Intermediate-acting insulin:

Universally coded with green labeling to ensure easy recognition by patients.
Duration of action is variable depending on dose but usually <24 hours. Therefore doses should be given before bed to ensure adequate basal cover during the night and to counteract the dawn phenomenon.
When single bedtime dose intermediate acting insulin is used as basal cover, basal effects are usually worn off by the early evening, which puts the patient at risk of breakthrough hyperglycaemia or even ketoacidosis especially if ultrafast-acting insulin is used (which provides little additional basal cover).
Significant peak effect is observed after about 4 hours after administration. Patients should be advised to take a snack before bedtime to avoid nocturnal hypoglycaemia.
Problems with peak-effect or duration of action may be remedied by splitting the basal insulin dose into a morning and an evening dose (usual ratio 2:1), which comes at the expense of an additional injection. Splitting of the basal dose and peak effect may also be advantageously used in patients for whom administration of a lunch bolus dose (e.g. school going children) is problematic as the peak action of the morning intermediate acting insulin coincides more-or-less with lunch.
Suspension requires mixing prior to administration.

Advantages:

• Cheap
• Can be mixed with ultrafast-acting insulins

Disadvantages:

• Risk of nocturnal hypoglycaemia
• Does not provide full 24-hour basal cover

Long-acting insulin

Analogue insulins designed to have a smooth onset and duration of action by forming a subcutaneous depot.

Advantages:

• Minimal peak effect
• Longer duration of action

Disadvantages

• Cost
• Cannot be mixed with ultrafast-acting insulin (except degludec) due to differences in pH solubility
• Prolonged risk of hypoglycaemia.

DOSING

Total daily dose (TDD) should be determined using weight
Higher doses may be considered in the following situations:

• Evidence of difficult control (3 or more oral agents, HbA1c>8% or fasting glucose >11mmol/l)
• BMI>35kg/m2
• Use of corticosteroids

Lower doses may be considered if:

• Renal failure
• >70 years
• Hypoglycaemic unawareness
• Recurrent hypoglycaemia

Regimens:

Basal only

• Only for use in type 2 diabetes
• Start at 0.1-0.2U/kg intermediate- or long-acting insulin
• Titrate dose upwards until fasting glucose in the desired target (provided that nocturnal hypoglycaemia does not occur). Patient may be taught to self titrate up to the desired glucoses provided that the practitioner is satisfied that the patient is able to recognise and treat nocturnal hypoglycaemia. Note: As prandial blood glucose is not targeted, monitoring should be restricted to fasting glucose only.

Basal & stepwise bolus insulin

• Initiate basal only as above.
• Should HbA1c remain above target with adequately controlled fasting glucose, prandial glucose excursions should be targeted by adding a dose 4-6U ultrafast- or fast-acting insulin to the biggest meal (usually breakfast).
• Pre- and postprandial glucose of the targeted meal should be measured. Ultrafast- or fast-acting dose should be adjusted to achieve satisfactory postprandial targets.
• Should HbA1c remain above target despite fasting and targeted postprandial glucose in target, a second meal may be targeted in a similar fashion (stepwise approach).

Basal bolus

• Suitable for use in type I diabetics (who require whole day insulin cover)
• After determining the TDD, the basal dose should be calculated at 50% of the TDD if long-acting insulin is used and 30-40% of TDD if intermediate-acting insulin is used. The remainder of the TDD should be given as 3 equal boluses ultrafast- or fast-acting insulin with meals.
• Monitoring should include pre-meal and 2 hour postprandial glucose.
• Fasting glucose in the accepted range should be maintained by adjusting basal insulin whilst postprandial glucose is managed by adjustments in bolus insulin as set out above.

Biphasic regimen/ Premixed insulin

• Suitable for use in type I diabetics (who require whole day insulin cover)
• Insulin pre-mixed at various ratios basal to bolus insulin (1:4, 1:3 or 1:2).
• The mixes can either be:
  1. protamine insulin + short acting human insulin (e.g. actraphane)
  2. degludec (a long acting analogue) + aspart (short acting analogue) i.e. Ryzodec.
  3. protamine insulin + short acting analogue(e.g. novomix, humalog mix)
• Starting dose of 2/3 TDD with breakfast and 1/3 TDD with supper.
• Usually one can initiate with a premixed insulin with a basal:bolus ratio of 1:3. Then adjust ratio depending on whether patient requires more short-acting or intermediate-acting insulin cover

Advantage:

• Full insulin dose with only 2 injections

Disadvantage:

• Fixed ratios does not allow individualised fine-tuning of basal vs. bolus insulin requirements. Conflicts between these two components may lead to hypo- or hyperglycaemia.
• Does not allow for correction for meal size or pre-prandial glucose.
• Lunch is not covered by bolus insulin leading to glucose excursions.
• Mealtimes should be fixed (exception Ryzodec®)

Monitoring and adjustment:

• Adequacy of bolus component determined by glucose after breakfast and supper.
• Adequacy of basal component determined by fasting morning and pre-dinner glucose
• Adjustments should be made as targets attained (either fasting or postprandial).
• Care should be taken not to adjust doses for basal effect and in so doing cause a postprandial hypoglycaemia or vice versa. The risk of hypoglycaemia should always take priority at the expense of hyperglycaemia.

INSULIN ADMINISTRATION

• Patients should be instructed on the recognition and management of hypoglycaemia when started on insulin. A glucagon hypokit should be provided (*see glucagon)
• Unused insulin should be stored in a fridge. Insulin pens or vials that are in use should ideally be stored at room temperature as cold temperatures retard the action of insulin and worsens pain of injection.
• Insulin pens are preferred to vials in patients not mixing insulin themselves, especially if vision or hand function is poor.
• Needles with a length of 6mm or less should be used to avoid intramuscular administration.
• Thighs are the preferred injection site for long or intermediate acting insulin, whilst fast- and ultrafast-acting should ideally be injected in the abdomen. Other sites (deltoid, arms or buttocks) are best avoided. Injection sites should be rotated on a continuous basis to avoid lipohypertrophy. Injection sites should be evaluated for lipohypertrophy at every visit.
• Patients should be instructed on the safe medical disposal of used insulin needles and syringes. If patients do not have access to medical waste disposal, used needles should be stored in a suitable container (e.g. empty plastic bottle) and taken to the health care facility for safe disposal.
• Cloudy insulin should be tipped and rolled 10 times before administration.
• Insulin pens should be primed by ejecting 1-2 U into the air before each injection to ensure that air is dispersed as well as confirm patency of the needle.
• Pen needles need to remain subcutaneously 10 seconds with the injection button compressed to allow complete delivery of the insulin dose. Injection sites should not be rubbed or massaged.