Types of insulin

Insulins are classified according to their duration of action:^[1]

Short-acting insulins

• Rapid-acting insulin analogues, eg insulin aspart, lispro and glulisine: These are genetically engineered analogues of human insulin. They aim to work like the insulin normally produced with a meal. Given subcutaneously, they have an onset of action of approximately 15 minutes, peak at 1 hour and last 3-4 hours. They can be injected shortly before, during or immediately after meals.
• Soluble insulins: These are the conventional short-acting insulins. Used subcutaneously, they have an onset of action of 30 minutes, peak at 2-3 hours and last 8 hours. They should be injected 30 minutes before meals. Short-acting insulins may also be given intravenously by pump (in hospital care). If used intravenously, the half-life is very short (a few minutes) and the insulin disappears by 30 minutes.

Intermediate-acting insulins

These have an onset of action of 2-4 hours, peak at 6-7 hours and last 20 hours. The standard intermediate-acting insulin is isophane insulin - also known as neutral protamine Hagedorn (NPH).

Long-acting insulin analogues (insulin detemir and insulin glargine)

These are also genetically modified analogues. They have an onset of action at 1-3 hours, then plateau and last for 20-24 hours. They are used once- or twice-daily, and achieve a steady-state to produce a constant level of insulin. This is physiologically similar to normal endogenous basal insulin secretion.

Biphasic insulins

These are a mix of rapid- or short-acting insulin with intermediate-acting insulins, available in mixes of different proportions.

Insulin regimens^[1][4]

Once-daily regimen

• Long- or intermediate-acting insulin is given at bedtime.
• It is suitable only for patients with type 2 diabetes and may be used in combination with oral hypoglycaemic agents.^[5]
• This regimen may be used when starting insulin in type 2 diabetes and when there is dependence on others to give injections.

Twice-daily regimen

• A biphasic insulin is injected twice a day (pre-breakfast and pre-evening meal).
• This assumes that the patient eats three meals per day.
• The peak action varies directly with the proportion of soluble insulin in the combination.
• It may be difficult to achieve optimal glycaemic control, and the regimen can be complicated by hypoglycaemic episodes.
• The peak and trough of the evening dose of longer-acting insulin can lead to the combination of nocturnal hypoglycaemia and then fasting hyperglycaemia in the morning.

The overlap of short-acting and long-acting insulin between meals means that additional snacks are often required to avoid hypoglycaemia. Using faster-acting insulin analogues instead of soluble insulin in the premixed combination can reduce this problem.

Basal-bolus regimen

• Intermediate- or long-acting insulin is given at bedtime to cover overnight insulin requirements.
• It is combined with rapid- or short-acting insulin injections to cover mealtimes. This offers greater flexibility and is the most commonly adopted method when intensified insulin therapy is used to provide optimal glycaemic control.

There may be hypoglycaemic episodes between meals and at night; again, use of fast-acting analogues instead of soluble insulin may reduce this problem.^[6]

Continuous subcutaneous insulin infusion, or insulin pump therapy^[7][8]

• Continuous subcutaneous insulin infusion (CSII) - insulin pump therapy - is where an adjustable basal infusion rate of insulin is given via an indwelling catheter, supplied from a syringe reservoir worn underneath the patient's clothing.
• The patient can then activate pre-meal boluses.
• Pumps can be disconnected for short periods (up to 1 hour) for activities such as swimming.
• They can be pre-programmed; for example, to compensate for nocturnal and early morning glucose fluctuations.
• The rate of insulin absorption from pumps is more predictable than with multiple subcutaneous injections.
• CSII is particularly useful for patients with recurrent hypoglycaemia, unpredictable lives, delayed meals or pre-breakfast hyperglycaemia.^[9]

The insulin used in pumps may be soluble or a fast-acting analogue. Note that there have been 2 anecdotal case reports of insulin lispro precipitating in pumps: if users have unpredictable glucose fluctuations, they should consider changing to aspart or soluble insulin.^[10]

New insulin therapies and their use

New insulin therapies refers to the insulin analogues and pumps.

Rapid-acting human insulin analogues

With their faster onset and shorter duration of action, the rapid-acting analogues are useful for:^[4]

• Those who wish to inject shortly before or immediately after meals (helpful for unpredictable meals or young children)
• Those prone to hypoglycaemia between meals
• Those prone to nocturnal hypoglycaemia
• To avoid the need for snacks between meals

When rapid-acting analogues are used as the mealtime bolus, the National Institute for Clinical Excellence (NICE) suggests that the basal insulin should be a long-acting analogue (rather than NPH insulin).

Long-acting human insulin analogues

These are insulin detemir (Levemir®) and insulin glargine (Lantus®). Insulin detemir is given once- or twice-daily, and insulin glargine is given once-daily, which may increase convenience for some patients.

Which regimen for which patient?

Type 1 diabetes

The options are:^[4]

• Twice-daily biphasic insulin
• Basal-bolus regimen - this gives greater flexibility and can improve glycaemic control, but requires more injections
• Insulin pump - see NICE guidance above

Type 2 diabetes

In type 2 diabetes, there is a gradual decline in beta cell function, so that treatment will need regular adjustment.^[12] When oral agents are insufficient options are:

• Basal insulin - this is often a suitable first step, using once- or twice-daily intermediate- or long-acting insulin
• Twice-daily biphasic insulin
• Basal-bolus regimen

Oral hypoglycaemic agents are often used in combination with insulin:

• Metformin is usually continued.
• Sulphonylureas are often continued with a basal insulin regimen; however, if a bolus regimen is used, they should be gradually stopped.

Pregnancy

Good glycaemic control is especially important both pre-conception and antenatally, to reduce fetal abnormalities and obstetric complications. Insulin must be continued for patients with type 1 diabetes and is often required in type 2 and gestational diabetes. Specialist guidance is recommended. Insulin pumps may have a role.^[11]

Insulin does not cross the placenta. Conventional insulins are well-established as safe in pregnancy; human insulins are preferred because of the possibility of antibody development.

The safety of insulin analogues in pregnancy is uncertain. There have been successful clinical trials of insulin lispro and insulin aspart in pregnancy.^[13] There is little data on the long-acting insulins, although no harmful effects have been found with insulin glargine. Further information is available from the National Teratology Information Service.^[14]

Insulin dose estimation and adjustment

Type 1 diabetes

Patients with newly-diagnosed type 1 diabetes often have insulin started in hospital (if patient is ill, dehydrated, ketotic or has high glucose levels). If insulin is initiated in the community, this will usually be done in conjunction with a specialist team or a diabetes specialist nurse. Starting doses are estimated on an individual basis, though local teams usually have their own guidelines. The dose is always started low and titrated up gradually on the basis of blood glucose measurements.

Type 2 diabetes

Insulin is often started in the community, again with the the support of the local specialist team. Some local guidelines on starting regimens and doses are available.^[15] After starting insulin, dose adjustment information will be useful for patients and their doctors,^[15][16] and 'sick day' guidance is also required.^[17]

Risks and disadvantages of new insulin therapies

Long-term safety is uncertain, in terms of adverse drug effects and risk of hypoglycaemic episodes. In particular, there are concerns about:

• Insulin analogues may have mitogenic potential, due to the alteration in DNA sequence.^[18][19]
• Some trials have found an increase in progression of retinopathy with insulin glargine^[20] and lispro;^[19] however, other trials have not confirmed this result, and the increase could also be caused by a rapid reduction in blood glucose.^[19]
• Glulisine and glargine are still under safety monitoring ("black triangle" drugs).

Insulin pumps can become disconnected or blocked, with the risk of ketoacidosis if unnoticed. They require specialised staff and patient training, and ongoing support.

Cost implications: insulin analogues and pumps are more expensive.

What is the evidence for new insulin therapies?

Overall, there is a lack of clear evidence regarding benefits and harms of the newer insulin therapies. As a summary, the evidence so far suggests that:

• Rapid-acting insulin analogues may improve postprandial hyperglycaemia and reduce hypoglycaemia.^[6][21][22]
• Long-acting insulin analogues may reduce nocturnal hypoglycaemia and weight gain,^[6] but some studies found them no better than conventional NPH insulin.^[20][23]
• Insulin pumps improve HbA1c values slightly overall,^[8] but seem to be of greater benefit to some patients, particularly those who previously had poorer glycaemic control.^[24]
• The newer treatments seem to be safe so far.^{[6][8][25][21][26]}

In practice, treatment should be tailored to the individual, taking into account lifestyle, preferences and personal patterns of glycaemic control.^[1][4] Whatever the regimen, patient education and involvement is crucial in achieving good results.^[4]

Future possibilities

Continuous glucose monitoring is now possible using a transcutaneous sensor. This could assist patients in achieving tight glycaemic control, and has the potential to develop into an 'artificial pancreas', if combined with an 'intelligent' insulin pump.^[27] peri

Insulin management around surgery

It is usually best to admit patients 2-3 days before elective surgery, particularly if outpatient adjustments are difficult. There are different recommended routines but it is important that ward staff and those responsible for postoperative care have clear instructions. Complicated regimens can cause confusion amongst staff. Ensure good pre-operative control, usually with short-acting insulin (or a mixture of short- and intermediate-acting insulin), twice-daily. Extra short-acting insulin can be added if necessary:

• Monitor blood glucose throughout the day.
• On day of surgery starve from midnight and do not give first dose of insulin.
• Operation as early as possible (ie put the diabetic patient first on the list).
• Check glucose and electrolytes early on the day of surgery (defer if glucose >13 mmol/l or if significant electrolyte disturbance).
• Start IV infusions of dextrose (500 mls 10% dextrose plus 10 units soluble insulin plus 10 mmol KCl at 125 mls per hour). Check blood glucose and electrolytes at end of operation or at 1-2 hour intervals.
• Monitor blood glucose during surgery at least every 30 minutes. Continue this as long as blood glucose is between 5-10 mmol/l. Reduce insulin to 5 units if less than 5 mmol/l and increase to 15 units if blood glucose 10-20 mmol/l (new infusion needed of course).
• After surgery check glucose every 2 hours and electrolytes every 6-12 hours adjusting infusions as necessary.
• Continue infusions but, when eating normally, restart subcutaneous insulin (as before surgery).

Historical

Inhaled insulin

In January 2008, Pfizer ceased production of its inhaled insulin product Exubera®. It was considered as rapid-acting; its peak action is 30-90 minutes.^[28] It probably also had some prolonged action.^[29] It was apparently discontinued because it was expensive and uptake by patients and physicians was low.