Insulin Treatment Of Type Diabetes Mellitus

The Diabetes Control and Complications Trial (DCCT) published in the USA in 1993 established beyond all reasonable doubt that intensive insulin therapy delays the onset and slows the progression of diabetic microvascular complications. The achievement of good blood glucose control while avoiding hypoglycemia is therefore the therapeutic goal for most patients with type 1 DM. For the majority of patients this proves to be a major challenge despite considerable input from the diabetic team. Diabetic specialist nurses have assumed a major role in helping patients reach appropriate targets.

A large number of insulins are available to treat patients with type 1 DM and many new formulations have appeared in recent years and continue to appear. Insulin analogs have rightly secured a firm place in the insulin market. For the non-specialist clinician it is advisable to become familiar with commonly prescribed insulins and the regimens that are applied in their use. In clinical practice, only two classes of insulin are needed in the attempt to mimic physiologic insulin secretion: a rapid-acting formulation to cover meals and a longer-acting preparation to provide steady state basal levels between meals and overnight. Rapid and longer-acting insulins can be combined in the same cartridge as a fixed mixture (or premixed insulins). Rapid-acting insulins include soluble (regular) insulin that should be injected around 30min before a meal or rapid-acting insulin analogs (insulin lispro (Huma-log®, Eli Lilly), insulin aspart (Novo Rapid®, NovoNordisk) and insulin glulisine (Apidra®, Sanofi Aventis)) that can be injected at the time of the meal. Longer-acting insulin preparations include conventional NPH (isophane) insulin and the insulin analogs insulin glargine (Lantus®, Sanofi Aventis) and insulin detemir (Levemir®, NovoNordisk). In many countries, such as the UK, and more recently the USA, insulin delivery via a pen device, so called insulin pens, has become by far the most popular method of subcutaneous insulin administration. A list of commonly used insulin preparations is illustrated in Figure 50. Currently recommended insulin regimens are many and varied and include twice-daily insulins, basal-bolus regimens and continuous subcutaneous insulin infusion.

Twice-daily insulins - free or mixed

The simplest regimen is to inject insulin subcuta-neously twice a day, before breakfast and before the evening meal. Although patients' needs differ, in general two-thirds of the total daily insulin dose is given in the morning with one-third in the evening. Using conventional insulin preparations, the ability of injections performed 30-40 min before meals to match postprandial glucose excursions, although crude, is illustrated in Figure 60. The ratio of soluble to iso-phane insulin can be determined by the patient's subsequent blood glucose measurements (with a starting ratio of one-third soluble to two-thirds isophane). Fine-tuning of the insulin doses is possible, however, many patients find this difficult and there is a place for the use of fixed mixtures that are available in many ratios of soluble to isophane (10/90, 20/80, 30/70, 40/60, 50/50). Pre-mixed insulins are widely used in analog form (Humalog Mix 25®, NovoMix 30®).

It is widely recognized that such regimens have their drawbacks. Inflexibility is one as is the need to eat three meals a day with mid-meal snacks to avoid hypoglycemia owing to the persistence of the effect of the short-acting insulin. In addition, the peak effect of the evening intermediate insulin occurs between midnight and 03.00 when the need is least and then diminishes towards morning when insulin requirements are rising again. Increasing the before-dinner isophane to cope with pre-breakfast hyperglycemia leads to nocturnal hypoglycemia which may go unrecognized and is one of the biggest problems in the treatment of type 1 DM. To some extent, this can be counteracted by delaying the evening injection of isophane insulin to before bed.

Basal-bolus regimens

This regimen has become perhaps the most widely used in recent years. The rationale is that a long-acting insulin administered at bedtime provides a 'basal' insulin level that is supplemented before meals by short-acting insulin to cope with the rise in postprandial blood glucose.

Earlier regimens most commonly used NPH (iso-phane) as the basal insulin but, more recently, NPH has been increasingly replaced by insulin glargine

(Lantus®) and insulin detemir (Levemir®). Glargine can be given at any fixed time of day most commonly before bed or at breakfast. These later insulins exhibit more reproducibility in terms of their biological action compared to NPH. Some regimens incorporate the use of twice-daily injections of glargine or detemir. A major advantage of such regimens is that they allow the patient more flexibility with the timing of meals; if lunch is delayed, for instance, the injection of short-acting insulin can simply be given later. Patients should not, however, be tempted to miss either meals or the preceding insulin.

Although allowing greater flexibility, there is no overwhelming evidence that the multiple-injection regimen produces better glycemic control than twice-daily injections of short-acting insulin with isophane.

The short-acting insulin analogs have much shorter onsets of action than soluble insulin and shorter durations of action. One major advantage to patients is that they may be injected at the time of eating rather than 30-40 min beforehand. Furthermore, evidence suggests that their usage may be associated with less hypoglycemia occurring mid-morning, mid-afternoon and during the night. These insulins have rapidly become immensely popular with diabetic patients, especially the young. Humalog has usefully been formulated into a fixed mixture preparation (Humalog Mix 25) with a short to intermediate ratio of 25/75 and NovoRapid into a fixed mixture (NovoMix 30) with a short to intermediate ratio of 30/70.

There has been much debate regarding the importance of insulin species, centered on the hypothesis that the use of human insulin (produced by either enzymatic modification or recombinant-DNA technology) is associated with lack of hypoglycemia awareness. The hypothesis has tended to be patient-driven and the current consensus, based on a wealth of clinical studies, is that there is no scientific evidence to support such a contention. However, if patients express a wish to resume porcine insulin, they should be allowed to do so as no harm will result from such a switch.

Continuous subcutaneous insulin infusion

Continuous subcutaneous insulin infusion (CSII) attempts to emulate physiologic insulin secretion with low basal insulin delivery using a small portable battery-driven pump and a reservoir of short-acting soluble insulin. From the pump, a plastic delivery can-nula that ends in a fine-gauge 'butterfly' needle is usually inserted subcutaneously into the anterior abdominal wall. The site of implantation must be changed every 1-2 days to avoid local inflammation. The basal infusion is supplemented at mealtimes by a prandial boost activated by the patient. The basal rate and prandial boosts are determined according to each individual patient after a brief admission to hospital or by intensive outpatient education.

Continuous subcutaneous insulin requires a comprehensive education program prior to its use. The hospitals participating in the use of this technique are required to provide a 24-h telephone service so that pump patients can receive immediate advice.

Most patients using this method of treatment achieve excellent control of blood glucose levels. However, disadvantages include the logistic problems in setting up such a service, the problem of funding the pumps which are expensive and the possibility of system malfunction, usually related to the insulin syringe in the pump, cannula, needle or infusion site. Such problems may partly explain the incidence of ketoaci-dosis in patients treated by continuous subcutaneous insulin, although many experienced centers throughout the world are now reporting a significant decrease in ketoacidosis rates. Skin complications are also seen, but hypoglycemia is no more common than with conventional treatments despite the ability of CSII to produce a significant improvement in blood glucose control. At present, the use of insulin pumps should be considered for selected patients (such as, when conventional insulin injection treatment has failed with poor glycemic control, unstable blood glucose levels and significant recurrent hypoglycemia) and requires referral to centers specializing in this treatment modality. Increasing numbers of patients without any of the specific problems outlined above may opt for this form of treatment if appropriate funding is available and CSII usage is particularly high in the USA and certain countries of the European Union where such funding is available.

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