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 diabetes and type 2 diabetes.^2,3 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. The Dose Adjustment For Normal Eating and Exercise (DAFNE) education programme can facilitate good control.

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

Insulins are classified according to their duration of action:¹

Short-acting insulins

• Rapid-acting insulin analogues, e.g. 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.⁵ It probably also has some prolonged action.⁶ 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 (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.

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.⁷
• 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.⁸

Continuous subcutaneous insulin infusion, or insulin pump therapy^9,10

• 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.¹¹

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.¹²

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, 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.

Inhaled insulin^6,14

Inhaled insulin (Exubera®) is a hand-held device using a dry powder aerosol. Note: 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.⁵

It is contra-indicated in smokers (current smokers or <6 months' cessation) and in severe chronic obstructive pulmonary disease (COPD).⁶

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.¹⁵ 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: glitazones are contra-indicated with insulin.¹⁶
• 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.¹³

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.¹⁷ 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.¹⁸

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.¹⁹
After starting insulin, dose adjustment information will be useful for patients and their doctors,^19,20 and 'sick day' guidance is also required.²¹

Long-term 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.^22,23
• Some trials have found an increase in progression of retinopathy with insulin glargine²⁴ and lispro;²³ however, 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.

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.^8,25,26
• Long-acting insulin analogues may reduce nocturnal hypoglycaemia and weight gain,⁸ but some studies found them no better than conventional NPH insulin.^24,27
• Inhaled insulin as a bolus seems effective, but with possibly more severe hypoglycaemic episodes,¹⁴ and with worse HbA1c values than intensive injected regimens.²⁸
• Insulin pumps improve HbA1c values slightly overall,¹⁰ but seem to be of greater benefit to some patients, particularly those who previously had poorer glycaemic control.²⁹
• The newer treatments seem to be safe so far.^{8,10,14,25,30}

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

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

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 (i.e. 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 mol 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).

1. 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]
2. 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]
3. 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]
4. Diagnosis and management of type 1 diabetes in children, young people and adults, NICE Clinical Guideline (July 2004)
5. Inhaled insulin for the treatment of type 1 and type 2 diabetes, NICE Technology Appraisal (2006)
6. Morton-Eggleston E, Barrett EJ; Inhaled insulin. BMJ. 2006 May 6;332(7549):1043-4.
7. Type 2 diabetes - newer agents (partial update), NICE Clinical Guideline (May 2009); Type 2 diabetes - newer agents for blood glucose control in type 2 diabetes
8. 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]
9. Diabetes (type 1) - insulin pump therapy, NICE Technology appraisal (2003)
10. Pickup J, Keen H; Continuous subcutaneous insulin infusion in type 1 diabetes. BMJ. 2001 May 26;322(7297):1262-3.
11. Diabetes - insulin pump therapy, NICE Technology Appraisal Guidance (July 2008); Continuous subcutaneous insulin infusion for the treatment of diabetes (review)
12. 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.
13. National Service Framework; Insulin Pump Service; Report of the Insulin Pump Working Group, March 2007
14. Royle P, Waugh N, McAuley L, et al; Inhaled insulin in diabetes mellitus. Cochrane Database Syst Rev. 2003;(3):CD003890. [abstract]
15. 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.
16. Summary of Product Characteristics, Avandia® 4mg and 8 mg Tablets, GlaxoSmithKline, electronic Medicines Compendium.
17. Homko CJ, Reece EA; Insulins and oral hypoglycemic agents in pregnancy. J Matern Fetal Neonatal Med. 2006 Nov;19(11):679-86. [abstract]
18. Toxbase; (Registration is free for Drs who are employed by an NHS practice)
19. Tameside and Glossop PCT. Guidelines for Insulin Initiation and Adjustment of Insulin Therapy in Type 2 Diabetes in General Practice, May 2005
20. Diabetes healthnet uk; Basic guidelines - insulin adjustment for multiple daily injections/basal bolus regimen. March 2006.
21. Northumbria NHS Health Care Trust diabetes protocol; Diabetes mellitus: Sick day rules for people on insulin. December 2006; Clear, concise advice for healthcare professionals.
22. Martin NM, Meeran K; Inhaled insulin: concerns remain. BMJ. 2006 May 27;332(7552):1273-4.
23. Zib I, Raskin P; Novel insulin analogues and its mitogenic potential. Diabetes Obes Metab. 2006 Nov;8(6):611-20. [abstract]
24. 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]
25. 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]
26. Halimi S, Raskin P, Liebl A, et al; Efficacy of biphasic insulin aspart in patients with type 2 diabetes. Clin Ther. 2005;27 Suppl B:S57-74. [abstract]
27. 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]
28. Nathan DM; Counterpoint: No time to inhale: arguments against inhaled insulin in 2007. Diabetes Care. 2007 Feb;30(2):442-3.
29. 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.
30. 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 B:S75-88. [abstract]
31. 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]

• 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.
• Children with diabetes. Parents describe how they deal with a diabetic child including daily routines such as insulin injections and how children can life live to the full. A short video from NHS Choices. (June 2008)