Conventional Intensified Insulin Therapy or Multiple Daily Insulin Injections MDI

In conventional intensified insulin therapy (MDI) using the basal-bolus approach with MDI, continuous basal insulin supply is obtained by once- or twice-daily subcutaneous injections of longer-acting preparations, supplemented by mealtime injections of more rapid-acting formulations.

Rapid-Acting (Mealtime) Insulins

These include structurally unchanged regular insulin preparations and short-acting insulin analogues (SIAs), which dissociate more rapidly than regular insulins and are absorbed faster. The glucose-lowering effect of rapid-acting insulins is enhanced by exercise within 1-3 h after the meal and by reducing the carbohydrate content of the meals.

Regular (Soluble) Insulins

Following subcutaneous injection of structurally unchanged regular insulin preparations, the native insulin tends to associate a hexameric form, which is slowly dissociated to single molecules and absorbed, thereby interfering with recreation of the physiological prandial insulin response (Table 1).

Table 1. Time course of action in T1DM of currently available subcutaneously injected insulin preparations.

Appearence

Onset

Peak Duration

Mealtime insulins

Human regular insulin Clear Short-acting analogues

Insulin Lispro Clear

Insulin Aspart Clear

Insulin Glusiline Clear

Basal insulins

Intermediate acting isophane Cloudy insulin (NPH) Long-acting insulin analogues Glargine Clear

Regular insulin needs to be injected 20-30 min before eating, or exaggerated postprandial hyper-glycaemia will result. Subcutaneous absorption of regular insulin continues well beyond the postprandial glycaemic response with a peak 2-3 h after injection (Table 1), resulting in continued elevated circulating insulin levels, which tend to cause hypo-glycaemia 3-5 h after the injection. Insulin dosages should be adjusted to optimize blood glucose levels 3-5 h after the injection, rather than 2 h postprandi-ally. To avoid hypoglycaemia it will often be needed for the patients to snack between meals.

Short-Acting Insulin Analogues: Insulin Lispro, Insulin Aspart and Insulin Glusiline

Much attention has been devoted to develop SIA with pharmacokinetic profiles that mimic prandial insulin responses. In the SIA Lispro (Humalog), lysine at position 28 and proline at position 29 of the B-region of regular human insulin were interchanged. In the SIA Aspart (NovoRapid), proline at position 29 of the B-region was replaced by aspartic acid, and in the SIA Glusiline (Apidra), the amino acid, asparagine was replaced by lysine at position 3 and lysine with glutamic acid at position

29 of the B-chain.

SIAs have lesser tendency toward self-association and are therefore absorbed more quickly, achieving peak plasma concentrations about twice as high and within approximately half the time compared with regular insulin (Table 1). When injected at the start of the meal, the pharmacoki-netic profile of SIA leads to lower glucose levels after meals than with regular insulins given up to

30 min beforehand. Another advantage is the possibility of injecting SIA up to 15 min after starting to eat without deterioration of prandial glycaemic control [5]. SIAs also have a shorter duration of action than regular insulin (Table 1), which reduces the need to snack between meals.

In a recent Cochrane review [6], the meta-analy-sis showed in adults with T1DM a small decrease in HbAlC of -0.1% with SIA compared with regular human insulin. Assuming that a reduction in HbA1C with SIA would result in a relative benefit similar to that found in DCCT [2], 650 patients would have to be treated with SIA for 1 year to prevent the development of retinopathy in one patient [6]. In terms of overall hypoglycaemia, comparable results were obtained with SIA and regular insulin; however, severe hypoglycaemia occurred less frequently in the SIA group than in the regular group [6]. Regarding quality of life (QOL), SIA showed improvement due to changes in the convenience, flexibility and continuation of treatment [6]. However, SIAs have higher cost than regular insulin. SIAs are judged safe during pregnancy. The short duration of action of SIA causes periods of hypoinsulinaemia between meals if the intervals between mealtime injections are long. Obtaining the potential benefits of SIA fully depends on the application of optimized basal insulin.

Basal Insulin Replacement

Basal Insulin Replacement with Intermediate Acting Neutral Protamine Hagedorn (NPH) Insulin

The most widely prescribed basal insulin globally is insulin combined with protamine [7], the so-called NPH insulin. The action profile of this preparation is, however, not optimal, with a peak effect at about 4-6 h and a duration of action of 8-16 h (Table 1). At a common dose of 0.3 U/kg, NPH insulin has been found to have a duration of around 13 h [8,9], which is insufficient to control hepatic glucose output to physiological levels. The peak of action of NPH insulin gives a potential risk of hypogly-caemia; however, it is the large variability in absorption of NPH insulin that poses the greatest problem. Thus, NPH insulin provides a considerable within-subject variability in T1DM assessed by the coefficient of variation (CV) for pharmacodynamic endpoints attaining 46-68% [10]. Variability of absorption arises from local changes at the injection sites in combination with the process of absorption after injection. In addition, there is often inadequate suspension and mixing of NPH insulin in pens before injection.

Basal Insulin Replacement with Long-Acting Analogues: Insulin Glargine and Insulin Detemir

The first of the long-acting insulin analogues to be used was insulin glargine (Fig. 1). This analogue is produced by the substitution of glycine for asparagine at position A21 of the insulin molecule and by the addition of two arginine molecules at position B30. These changes lead to a shift in the isoelectric point toward a neutral pH, which results

Intensified Insulin Therapy
Fig. 1. Molecular structures of the long-acting insulin analogues, detemir (upper part) and glargine (lower part).

in an insulin molecule that is less soluble at the injection site and that precipitates in the subcutaneous tissue to form a depot from which insulin is slowly released [11]. As compared with NPH insulin, insulin glargine results in prolonged insulin absorption and shows little peak activity, as demonstrated by differences in disappearance curves (Table 1).

Rates of absorption of insulin glargine at various sites do not differ. In the study of Lepore et al. [9] insulin glargine was found to have no peak and to have a mean (±SE) duration of action of 22 ±4 h. It is important not to over-interpret the pharmaco-dynamic studies, because the data presented are simply averages of the results obtained in a relatively small number of subjects. The onset or duration of action may be substantially longer or shorter in individual patients and especially the profiles of action are dependent on the dose of insulin. In studies in T1DM the effect of only one glargine dose on pharmacokinetic and pharmacodynamic has been reported [9,10], which does not give a legitimate impression of the action profile. In this context it is of interest to note that the time-action profiles of glargine and the other long-acting insulin analogue, detemir, are comparable in T2DM and vary critically with the insulin dose [12]. Glargine did not show the 'ideal' peakless profile with an equal distribution of the metabolic effect over 24 h in some studies [10,12]. Thus, a low glargine dose does not have a duration of action that covers 24 h in T1DM. Recently, it was found that using insulin glargine twice daily at breakfast and before dinner compared with glargine once daily at dinner time -taken with a rapid-acting insulin analogue at meal times - gave a better glycaemic profile with reduced pre-dinner hyperglycaemia in T1DM [13]. However, besides this study [13], all clinical studies have been carried out with only one daily glargine injection. Most clinical studies in T1DM, except two [14,15], have failed to show any clinically significant improvement in HbA1C with insulin glargine compared with NPH insulin [16-18], whereas the pre-breakfast blood glucose level in general is lower. Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine plus the SAI lispro, however, caused an overall improved glycaemic control in T1DM including HbA1C [14]. It is possible that experience in using the insulin analogues with adequate titration may allow improvement of HbA1C in T1DM to a relevant degree. Importantly, a reduction in the risk of hypogly-caemia, especially nocturnal hypoglycaemia, has been the rule with insulin glargine when compared with NPH insulin [14,16,17].

Insulin detemir is the second basal insulin that has been registered (Fig. 1). Its extended action is achieved by an entirely different principle from that attempted previously. Thus, a 14-C fatty acid, myristic acid, has been attached to the lysine residue at position B29, the threonine having been removed from position B30. The myristic acid side chain binds to albumin in the interstitium at the injection site and in the circulation providing the longer action profile. Insulin detemir has a lower in vivo potency compared with NPH insulin and glargine. Consequently, the commercial preparation of insulin detemir is formulated as 2,400 nM concentration (insulin NPH and insulin glargine both 600 nM) as has proven adequate in clinical studies. In T1DM insulin detemir (0.1-1.6 U/kg) has a linear dose-response relationship for both pharmacokinetic and pharmacodynamic measures [10]. Compared to NPH, detemir shows longer duration and lower maximum effect (Table 1). A recent study in T1DM using glucose clamp has demonstrated a lower within-subject variability of insulin detemir (CV 27%) than of insulin NPH (CV 68%) and insulin glargine (CV 48%) [10]. In most clinical studies twice-daily insulin detemir has been compared with twice-daily insulin NPH [19-24]. Regardless of whether detemir was administered at equal 12-h interval (morning + dinner) or with a longer interval (morning + bedtime), this improved overnight control with lower pre-break-fast glucose levels together with a lower risk of nocturnal hypoglycaemic events was seen [23,24]. The study of Home et al. [23] suggests that where nocturnal hypoglycaemia is a dominant problem, bedtime detemir may be a better choice than dinner detemir. Similar improvement in glycaemic control and hypoglycaemia as seen with twice-daily insulin detemir can be obtained when it is only given once daily in T1DM [25]. Thus, insulin detemir administered once daily at bedtime resulted in lower fasting blood glucose, less day-to-day variability in blood glucose and lower risk of nocturnal hypoglycaemia than NPH insulin [25]. Hermansen et al. [21], comparing the combination of insulin detemir + insulin aspart with the combination of NPH insulin + human regular insulin, found that the analogue regimen caused improvement in prandial glucose increments (Fig. 2, upper part), reduced plasma glucose variability at all pre-meal time points and lowered HbA1C more and caused less nocturnal hypoglycaemia than the human insulin regimen.

There is clinical evidence in favour of both insulin glargine and insulin detemir over NPH insulin in T1DM with reduced nocturnal hypogly-caemia and lower pre-breakfast blood glucose levels. Data indicate that the combination of SIA and one of the long-acting analogues compared with regular insulin + NPH insulin may even provide a small gain in overall glycaemic control

Nph Insulin Half Life

Fig. 2. Upper panel: Effects on 8-point plasma glucose profiles at the end of an 18 weeks study period of insulin analogues (insulin detemir + insulin aspart) versus traditional human insulin (NPH insulin + regular insulin) in T1DM (adapted with permission from Hermansen et al. Diabetologia 2004;47:622-629 [21]). Lower panel: Changes in weight and HbAlC with insulin detemir and NPH insulin in T1DM trials [19-25].

Fig. 2. Upper panel: Effects on 8-point plasma glucose profiles at the end of an 18 weeks study period of insulin analogues (insulin detemir + insulin aspart) versus traditional human insulin (NPH insulin + regular insulin) in T1DM (adapted with permission from Hermansen et al. Diabetologia 2004;47:622-629 [21]). Lower panel: Changes in weight and HbAlC with insulin detemir and NPH insulin in T1DM trials [19-25].

with lowering of HbAlC and self-monitored glucose profiles [14,21] (Fig. 2, upper part). It should be underlined, however, that the direct cost of long-acting analogues is higher than that of NPH insulin. Furthermore, the published clinical studies on insulin glargine and insulin detemir are all open-label, which may cause bias. Uniquely, there is a further advantage of insulin detemir over NPH insulin in body weight control [26]. In all studies published to date, insulin detemir shows a consis tent weight sparing effect compared with NPH insulin in both T1DM [19-25] (Fig. 2, lower part) and in T2DM. This may have important implications for treatment, as weight gain can be a barrier to compliance and thus jeopardize glycaemic control [26]. A weight sparing effect has not been reported with any consistency for any other insulin, including insulin glargine. The long-acting insulin analogues, insulin glargine or insulin detemir, should be considered in subjects with

T1DM with problems with hypoglycaemia, unawareness of hypoglycaemia or large plasma glucose variations on standard treatment with NPH insulin as basal insulin.

There are potential problems with insulin therapy in T1DM. In addition to hypoglycaemia and weight gain, there are a few more rare conditions after starting insulin therapy, for example, insulin oedema, and local reactions to insulin injection. Insulin oedema is a rare phenomenon seen at the start of insulin treatment in poorly controlled or previously untreated patients. Oedema is due to acute sodium and water retention. It usually disappears after a few days. At the injection sites a localized overgrowth of subcutaneous adipose tissue can develop in response to high local insulin concentrations (lipohypertrophy). It is a more frequent problem in patients in MDI regimen who inject repeatedly at the same site, for example, in the abdomen. Injection into the lipohypertrophic area may worsen the glycaemic control due to impaired insulin absorption. Lipoatrophy is loss of subcutaneous fat at the injection site, causing pitting of the skin. In addition, local reactions at the injection sites can occur with erythema, burning or tender subcutaneous nodules.

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