Insulin Regimens

The appropriate insulin regimen for each patient with diabetes will depend on their type of diabetes and their individual needs and circumstances.¹ Improved glycaemic control has been shown to reduce the risk of complications for both type 1 diabetes² and type 2 diabetes.³ 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. Insulin regimens should be tailored to the individual, taking into account the patient's type of diabetes, previous control, age, dexterity, eyesight, personal and cultural preferences.⁴

Types of insulin

Insulins are classified according to their duration of action:¹

Short-acting insulins

Rapid-acting insulin analogues (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.
Inhaled insulin - this new insulin is considered as rapid-acting; its peak action is 30-90 minutes. It probably also has some prolonged action.⁵ It should be taken 10 minutes before meals.

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 or 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 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 regimens¹^,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. 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 (CSII or insulin pump therapy)⁷^,⁸

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.

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.⁹

NICE guidelines for insulin pump therapy⁷

Insulin pump therapy is one option for people with type 1 diabetes provided that:

Multiple-dose insulin therapy has failed to achieve targets without causing disabling. hypoglycaemic episodes (having used insulin analogues where appropriate, and good diabetes care).
They are willing and able to use pump therapy effectively.
Pump therapy should be started and reviewed by a trained, specialist team.

In addition, the National Service Framework¹⁰ suggests that insulin pump therapy should be considered for those with a particular need for tight glycaemic control: pregnant women, women planning a pregnancy, and people with accelerated complications.

New insulin therapies and their use

"New insulin therapies" refers to the insulin analogues, inhaled insulin, 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, 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.

NICE guidance for insulin glargine¹¹

NICE has recommended that insulin glargine should be an option for patients with type 1 diabetes, and should be used when:⁴

Nocturnal hypoglycaemia is a problem on isophane (intermediate-acting) insulin
Morning hyperglycaemia on isophane insulin results in difficult daytime glucose control
Rapid-acting insulin analogues are used for meal-time blood glucose control

Insulin glargine is not recommended for routine use in patients with type 2 diabetes, but it may be considered for those who:

Require assistance with injecting their insulin, or
Would otherwise need twice daily insulin injections in combination with oral antidiabetic drugs, or
Whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemia

Inhaled insulin⁵^,¹²

Inhaled insulin (Exubera) is a hand-held device using a dry powder aerosol. Note that the dose is given in milligrams, not units, because the activity of inhaled insulin is different from injected insulin on a weight for weight basis. There is a lack of fine dose adjustment with the current preparation.

So far, inhaled insulin has been tested as a bolus regimen, in conjunction with basal injected insulin or oral hypoglycaemia agents. It seems to be effective, and is well tolerated, with good patient satisfaction and quality of life reported. The main side effect is mild cough, which improves with time.¹³

It is contra-indicated in smokers (current smokers or <6 style="color: rgb(0, 0, 0); font-weight: 400; vertical-align: super; font-size: 0.75em; ">5

NICE guidance for inhaled insulin¹³

Inhaled insulin should not be used routinely, but should be considered as an option when:

There is evidence of poor glycaemic control despite other interventions, AND
Insulin is required, but cannot be used due to either a phobia of injections (diagnosed by a specialist), or severe and persistent problems with injection sites

Treatment should be reviewed after 6 months, and continued only if there has been improvement.
Inhaled insulin treatment should be given by specialists, and patients should be monitored as part of continuing research.

Which regimen for which patient?

Type 1 diabetes⁴

The options are:

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 diabetes¹⁴

In type 2 diabetes, there is a gradual decline in beta cell function, so that treatment will need regular adjustment. 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:

Note that glitazones are contraindicated with insulin.¹⁵
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.

Pregnancy¹⁶

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.¹⁰

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 lispro¹⁷ and insulin apart in pregnancy. There is little data on the long-acting insulins, although no harmful effects have been found with insulin glargine. Inhaled insulin should not be used, because of concerns about its inducing insulin antibodies. Further information is available from the National Teratology Information Service.¹⁶

Insulin dose estimation and adjustment

For newly diagnosed type 1 diabetes, insulin is often started in hospital (if patient is ill, dehydrated, ketotic or high glucose levels). If insulin is initiated in the community, this will usually be done in conjunction with a specialist team or 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.
In 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.¹⁸
After starting insulin, dose adjustment information will be useful for patients and their doctors,¹⁸^,¹⁹ and "sick day" guidance is also required.²⁰^,²¹

Risks and disadvantages of new insulin therapies

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

Inhaled insulin:²²
- May affect lung function (it is a mitogen and growth factor in the lung, and some studies report effects on lung diffusing capacity).
- May increase the formation of insulin antibodies.
Insulin analogues may have mitogenic potential, due to the alteration in DNA sequence.²³^,²²
Some trials have found an increase in progression of retinopathy with insulin glargine²⁴ and lispro,²³however, other trials have not confirmed this result, and the increase could also be caused by a rapid reduction in blood glucose.²³
Glulisine, glargine and inhaled insulin 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, pumps and inhaled insulin 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. Most trials show either modest benefits, or no difference, with newer treatments compared to conventional insulin. Reviewers comment that many of the existing trials are too small, too short-term or poorly designed. Also, it seems likely that certain patients can benefit largely from a particular treatment, eg. insulin pumps, while others may not require it.⁸^,²⁵ The benefits for some patients may be submerged in the "averaged" results of trials.

As a summary, the evidence so far suggests that:

Rapid-acting insulin analogues may improve post-prandial hyperglycaemia and reduce hypoglycaemia.⁶^,²⁶^,²⁷
Long-acting insulin analogues may reduce nocturnal hypoglycaemia and weight gain,⁶ but some studies found them no better than conventional NPH insulin.²⁴^,²⁸
Inhaled insulin as a bolus seems effective, but with possibly more severe hypoglycaemic episodes,¹²and with worse HbA1c values than intensive injected regimens.²⁹
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.²⁵
The newer treatments seem to be safe so far.⁶^,⁸^,¹²^,²⁶^,³⁰

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.³¹

Document references

Mooradian AD, Bernbaum M, Albert SG; Narrative review: a rational approach to starting insulin therapy. Ann Intern Med. 2006 Jul 18;145(2):125-34. [abstract]
No authors listed; The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86. [abstract]
No authors listed; Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. [abstract]
NICE Clinical guideline; #CG15;Type 1 diabetes in children, young people and adults. July 2004.
Morton-Eggleston E, Barrett EJ; Inhaled insulin. BMJ. 2006 May 6;332(7549):1043-4.
Gough SC; A review of human and analogue insulin trials. Diabetes Res Clin Pract. 2007 Jul;77(1):1-15. Epub 2006 Nov 16. [abstract]
Diabetes (type 1) - insulin pump therapy, NICE Technology appraisal (2003)
Pickup J, Keen H; Continuous subcutaneous insulin infusion in type 1 diabetes. BMJ. 2001 May 26;322(7297):1262-3.
Wolpert HA, Faradji RN, Bonner-Weir S, et al; Metabolic decompensation in pump users due to lispro insulin precipitation. BMJ. 2002 May 25;324(7348):1253.
National Service Framework; Insulin Pump Service; Report of the Insulin Pump Working Group, March2007
Diabetes - type 2 (update), NICE Clinical Guideline (May 2008); Type 2 diabetes: the management of type 2 diabetes (update)
Royle P, Waugh N, McAuley L, et al; Inhaled insulin in diabetes mellitus. Cochrane Database Syst Rev. 2003;(3):CD003890. [abstract]
NICE Technology appraisal; #TA113;Inhaled insulin for treatment of diabetes (types 1 and 2).December 2006.
Heine RJ, Diamant M, Mbanya JC, et al; Management of hyperglycaemia in type 2 diabetes: the end of recurrent failure? BMJ. 2006 Dec 9;333(7580):1200-4.
Summary of Product Characteristics, Avandia® 4mg and 8 mg Tablets, GlaxoSmithKline, electronic Medicines Compendium.
Toxbase; (registration is free for drs who are employed by an NHS practice)
Homko CJ, Reece EA; Insulins and oral hypoglycemic agents in pregnancy. J Matern Fetal Neonatal Med. 2006 Nov;19(11):679-86. [abstract]
Tameside and Glossop PCT; Guidelines for initiation and adjustment of insulin therapy in type 2 diabetes in general practice. May 2005.
Diabetes healthnet uk; Basic guidelines - insulin adjustment for multiple daily injections/basal bolus regimen. March 2006.
Northumbria NHS Health Care Trust diabetes protocol; Diabetes mellitus: Sick day rules for people on insulin. December 2006; Clear, concise advice for healthcare professionals.
Sick day rules for diabetic patients, DiabeteSuffolk.com; Excellent information for diabetic patients.
Martin NM, Meeran K; Inhaled insulin: concerns remain. BMJ. 2006 May 27;332(7552):1273-4.
Zib I, Raskin P; Novel insulin analogues and its mitogenic potential. Diabetes Obes Metab. 2006 Nov;8(6):611-20. [abstract]
Horvath K, Jeitler K, Berghold A, et al; Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005613. [abstract]
Retnakaran R, DeVries JH, Hanaire-Broutin H, et al; Continuous subcutaneous insulin infusion versus multiple daily injections: modeling predicted benefits in relationship to baseline A1c. Diabetes Care. 2005 Jul;28(7):1835-6.
Siebenhofer A, Plank J, Berghold A, et al; Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003287. [abstract]
Halimi S, Raskin P, Liebl A, et al; Efficacy of biphasic insulin aspart in patients with type 2 diabetes. Clin Ther. 2005;27 Suppl 2:S57-74. [abstract]
Home PD, Rosskamp R, Forjanic-Klapproth J, et al; A randomized multicentre trial of insulin glargine compared with NPH insulin in people with type 1 diabetes. Diabetes Metab Res Rev. 2005 Nov-Dec;21(6):545-53. [abstract]
Nathan DM; Counterpoint: No time to inhale: arguments against inhaled insulin in 2007. Diabetes Care. 2007 Feb;30(2):442-3.
Davidson J, Vexiau P, Cucinotta D, et al; Biphasic insulin aspart 30: Literature review of adverse events associated with treatment. Clin Ther. 2005;27 Suppl 2:S75-88. [abstract]
Hanaire H; Continuous glucose monitoring and external insulin pump: towards a subcutaneous closed loop. Diabetes Metab. 2006 Dec;32(5 Pt 2):534-8. [abstract]

Internet and further reading

Diabetes UK
Insulin Pumpers UK; Part of an international charity promoting the knowledge and use of insulin pump therapy to treat diabetes; This site is run by volunteers to help people with diabetes.

Pathological - Disease Processes

Tuesday, March 17, 2009