Insulin regimens

The appropriate insulin regimen for each patient with diabetes will depend on their type of diabetes and their individual needs and circumstances. Insulin regimens which attempt to improve glycaemic control will require more active involvement of the patient, both with the number of injections and with the need for close self-monitoring of blood glucose. See the separate Diabetes Education and Self-management Programmes article.

Insulin regimens should be tailored to the individual, taking into account the patient's type of diabetes, previous control, age, dexterity, eyesight, and personal and cultural preferences.

Insulin is usually injected into the upper arms, thighs, buttocks or abdomen. The absorption may be increased if the limb is used in strenuous exercise after the injection. Lipodystrophy can be minimised by using different injection sites in rotation. Local allergic reactions may occur but are rare¹ .

Effective patient education for people using insulin treatment is essential, including 'sick day' guidance. See also the separate Diabetes and Intercurrent Illness article. Insulin Passports and patient information booklets should be offered to patients receiving insulin .

Types of insulin¹

Insulins are classified according to their duration of action² .

Short-acting insulins

• Short-acting (soluble) insulin is usually injected 15-30 minutes before meals. Soluble insulin is also the most appropriate form of insulin for use in diabetic emergencies - eg, diabetic ketoacidosis and at the time of surgery.

• When injected subcutaneously, soluble insulin has a rapid onset of action (30-60 minutes), a peak action between two and four hours, and a duration of action of up to eight hours.

• When injected intravenously, soluble insulin has a very short half-life of only about five minutes and its effect disappears within 30 minutes.

• The rapid-acting human insulin analogues (insulin aspart, insulin glulisine and insulin lispro) have a faster onset and shorter duration of action than soluble insulin. Subcutaneous injection of insulin analogues can be injected shortly before or even after a meal. They can also help those susceptible to hypoglycaemia before lunch and those who eat late in the evening and are prone to nocturnal hypoglycaemia.

• Rapid-acting human insulin analogues can also be administered by subcutaneous infusion.

• Insulin aspart and insulin lispro can be administered intravenously and can be used as alternatives to soluble insulin for diabetic emergencies and at the time of surgery.

Intermediate-acting and long-acting insulins

• Subcutaneous injections of intermediate-acting and long-acting insulins have an onset of action of approximately 1-2 hours, a maximal effect at 4-12 hours and a duration of 16-42 hours. Some are given twice daily in conjunction with short-acting (soluble) insulin; others are given once daily, particularly in elderly patients.

• Soluble insulin can be mixed with intermediate-acting and long-acting insulins (except insulin detemir, insulin glargine and insulin degludec) in the syringe but there may be some reduction of the initial effect of the soluble insulin, especially when mixed with protamine zinc insulin.

• Isophane insulin is a suspension of insulin with protamine and is particularly useful for initiation of twice-daily insulin regimens. Patients usually mix isophane with soluble insulin but ready-mixed preparations may be appropriate (biphasic isophane insulin, biphasic insulin aspart or biphasic insulin lispro).

• Insulin zinc suspension has a more prolonged duration of action. Protamine zinc insulin is usually given once daily with short-acting (soluble) insulin. However, it binds with the soluble insulin when mixed in the same syringe and is now rarely used.

• Insulin glargine and insulin detemir are both long-acting human insulin analogues with a prolonged duration of action. Insulin glargine is given once daily and insulin detemir is given once or twice daily.

• Insulin degludec is a long-acting human insulin analogue for once daily subcutaneous administration.

Insulin regimens

Once-daily insulin regimen

• Long-acting 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.

• This insulin regimen may be used when starting insulin in type 2 diabetes and when there is dependence on others to give injections.

Twice-daily insulin 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 insulin 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 pre-mixed combination can reduce this problem.

Basal-bolus regimen

• Intermediate-acting or long-acting insulin is given at bedtime to cover overnight insulin requirements.

• It is combined with rapid-acting 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 problem³ .

Continuous subcutaneous insulin infusion (CSII) therapy, or insulin pump therapy

In CSII therapy, 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 one 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 therapy provides some advantages over multiple daily injections (MDIs) in type 1 diabetes, both for children and adults⁴ . CSII therapy is particularly useful for patients with recurrent hypoglycaemia, unpredictable lives, delayed meals or pre-breakfast hyperglycaemia⁵ .

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

National Institute for Health and Care Excellence (NICE) guidance for CSII therapy⁵

CSII therapy is recommended as a treatment option for adults and for children aged 12 years and older with type 1 diabetes mellitus provided that:

• Attempts to achieve target HbA1c levels with MDIs result in the person experiencing repeated and unpredictable occurrence of hypoglycaemia that results in persistent anxiety about recurrence and is associated with a significant adverse effect on quality of life; or

• HbA1c levels have remained high (8.5% or above) on MDI therapy despite a high level of care.

CSII therapy is recommended as a treatment option for children younger than 12 years with type 1 diabetes mellitus provided that MDI therapy is considered to be impractical or inappropriate. Children on CSII therapy would be expected to undergo a trial of MDI therapy between the ages of 12 and 18 years.

CSII therapy is not recommended for the treatment of people with type 2 diabetes mellitus.

Adults with type 1 diabetes

NICE recommends⁶ :

Offer MDI basal-bolus insulin regimens, rather than twice-daily mixed insulin regimens, as the insulin injection regimen of choice for all adults with type 1 diabetes.

Long-acting insulin
Offer twice-daily insulin detemir as basal insulin therapy for adults with type 1 diabetes.

Consider, as an alternative basal insulin therapy for adults with type 1 diabetes:

• An existing insulin regimen being used by the person that is achieving their agreed targets

• Once-daily insulin glargine or insulin detemir if twice-daily basal insulin injection is not acceptable to the person, or once-daily insulin glargine if insulin detemir is not tolerated.

Consider other basal insulin regimens for adults with type 1 diabetes only if the above regimens do not deliver agreed targets.

Rapid-acting insulin
Offer rapid-acting insulin analogues injected before meals, rather than rapid-acting soluble human or animal insulins, for mealtime insulin replacement for adults with type 1 diabetes. Do not advise routine use of rapid-acting insulin analogues after meals for adults with type 1 diabetes.

Mixed insulin
Consider a twice-daily human mixed insulin regimen for adults with type 1 diabetes if an MDI basal-bolus insulin regimen is not possible and a twice-daily mixed insulin regimen is chosen. Consider a trial of a twice-daily analogue mixed insulin regimen if an adult using a twice-daily human mixed insulin regimen has hypoglycaemia that affects their quality of life.

Optimising insulin therapy
Consider adding metformin to insulin therapy if an adult with type 1 diabetes and a BMI of 25 kg/m² (23 kg/m² for people from South Asian and related minority ethnic groups) or above wants to improve their blood glucose control while minimising their effective insulin dose.

Children and young people with diabetes

NICE recommends⁷ :

While the insulin regimen should be individualised for each patient, there are three basic types of insulin regimen:

• MDI basal-bolus insulin regimens: injections of short-acting insulin or rapid-acting insulin analogue before meals, together with one or more separate daily injections of intermediate-acting insulin or long-acting insulin analogue.

• CSII therapy: a programmable pump and insulin storage device that gives a regular or continuous amount of insulin (usually a rapid-acting insulin analogue or short-acting insulin) by a subcutaneous needle or cannula.

• One, two or three insulin injections per day: these are usually injections of short-acting insulin or rapid-acting insulin analogue mixed with intermediate-acting insulin.

Offer children and young people with type 1 diabetes MDI basal-bolus insulin regimens from diagnosis. If an MDI regimen is not appropriate for a child or young person with type 1 diabetes, consider CSII therapy as recommended in CSII therapy for the treatment of diabetes mellitus.

Offer children and young people with type 1 diabetes a choice of insulin delivery systems that takes account of their insulin requirements and personal preferences.

Adults with type 2 diabetes

NICE recommends⁸ :

When starting insulin therapy in adults with type 2 diabetes, continue to offer metformin for people without contra-indications or intolerance. Review the continued need for other blood glucose-lowering therapies.

Intermediate-acting insulins are also referred to as isophane or neutral protamine Hagedorn (NPH) insulins. Offer NPH insulin injected once or twice daily according to need. Consider starting both NPH and short-acting insulin (particularly if the person's HbA1c is 75 mmol/mol (9.0%) or higher), administered either separately or as a pre-mixed (biphasic) human insulin preparation.

Consider, as an alternative to NPH insulin, using insulin detemir or insulin glargine if the person needs assistance from a carer or healthcare professional to inject insulin, and use of insulin detemir or insulin glargine would reduce the frequency of injections from twice to once daily, or the person's lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes, or the person would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs.

Consider pre-mixed (biphasic) preparations that include short-acting insulin analogues, rather than pre-mixed (biphasic) preparations that include short-acting human insulin preparations, if a person prefers injecting insulin immediately before a meal or hypoglycaemia is a problem or blood glucose levels rise markedly after meals.

Consider switching to insulin detemir or insulin glargine from NPH insulin in adults with type 2 diabetes:

• Who do not reach their target HbA1c because of significant hypoglycaemia; or

• Who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached; or

• Who cannot use the device needed to inject NPH insulin but who could administer their own insulin safely and accurately if a switch to one of the long-acting insulin analogues was made; or

• Who need help from a carer or healthcare professional to administer insulin injections and for whom switching to one of the long-acting insulin analogues would reduce the number of daily injections.

Monitor adults with type 2 diabetes who are on a basal insulin regimen (NPH insulin, insulin detemir or insulin glargine for the need for short-acting insulin before meals (or a pre-mixed (biphasic) insulin preparation).

Monitor adults with type 2 diabetes who are on pre-mixed (biphasic) insulin for the need for a further injection of short-acting insulin before meals or for a change to a basal bolus regimen with NPH insulin or insulin detemir or insulin glargine, if blood glucose control remains inadequate.

Treatment with combinations of medicines including sodium-glucose co-transporter type 2 (SGLT-2) inhibitors may be appropriate for some people with type 2 diabetes.

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.

See the separate Diabetes in Pregnancy article.

Insulin management around surgery

See the separate Precautions for Patients with Diabetes Undergoing Surgery article.

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 hypoglycaemia⁹ .

• Long-acting insulin analogues may reduce nocturnal hypoglycaemia and weight gain³ .

• A Cochrane review comparing insulin detemir with NPH insulin for people with type 1 diabetes showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia¹⁰ .

• A Cochrane review of (ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes found that¹¹ :

  • While the effects on HbA1c were comparable, treatment with insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Treatment with insulin detemir also reduced the incidence of serious hypoglycaemia.

  • However, serious hypoglycaemic events were rare and the absolute risk-reducing effect was low. It was concluded that results from the studies are only applicable to people in whom low blood glucose concentrations are targeted.

  • However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (eg, people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people).

• CSII therapy improves HbA1c values slightly overall but seems to be of greater benefit to some patients, particularly those who previously had poorer glycaemic control¹² .

• The newer treatments seem to be safe so far⁹ .

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