Article by Richard Graydon, M.D, PhD

INTRODUCTION — The Diabetes Control and Complications Trial (DCCT) and other smaller studies demonstrated that improved glycemic control with intensive insulin therapy in patients with type 1 diabetes mellitus led to graded reductions in retinopathy, nephropathy, and neuropathy. The Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study from the DCCT demonstrated that intensive insulin therapy also reduces cardiovascular morbidity and mortality. What was considered “intensive therapy” in the DCCT is now considered to be standard therapy for management of type 1 diabetes.

Optimal insulin therapy requires an understanding of insulin pharmacokinetics. A number of factors influence the pharmacokinetics of insulin, including: the insulin preparation, size of subcutaneous depot, injection technique, site of injection, and alterations in subcutaneous blood flow. These topics are reviewed in detail elsewhere.

Issues relevant to insulin therapy in patients with type 1 diabetes will be reviewed here. A review of its use in type 2 diabetes is found elsewhere. A general discussion of management of type 1 diabetes in children and adolescents is reviewed separately. Intensive insulin therapy for critically ill patients (who are not necessarily diabetic) is also reviewed elsewhere. Interactive cases focusing on insulin therapy are found elsewhere. A discussion of other medication (pramlintide) to be considered in the treatment of type 1 diabetes is presented elsewhere.PRETREATMENT CONSIDERATIONS — The term “conventional insulin therapy” is used to describe simpler non-physiologic insulin regimens, such as single daily injections, or two injections per day (usually a combination of regular or short-acting and NPH insulins, mixed together in the same syringe and given in fixed amounts before breakfast and dinner). The term “intensive insulin therapy” describes treatment with three or more injections per day or with continuous subcutaneous insulin infusion with an insulin pump.Intensive therapy aims to provide a more physiologic profile of insulin by administration of a basal level of insulin (delivered by daily or twice daily injections of a long-acting insulin preparation, or continuous subcutaneous delivery of a rapid insulin preparation via a pump) and premeal boluses of a short or rapid-acting insulin. The dose of the pre-meal bolus is determined by the ambient blood glucose level before the meal, the size and composition of the meal, and anticipated activity levels.

Intensive insulin therapy is recommended for the majority of patients with type 1 diabetes. However, it is important to emphasize that this regimen will be successful only if the patient is fully committed to it, has good understanding of the regimen, and is supported by a health care team with sufficient enthusiasm and expertise to educate the patient and to continuously monitor his or her progress.

Drawbacks to intensive insulin — Although intensive insulin therapy has clear benefits in patients with type 1 diabetes and probably has benefits in those with type 2 diabetes, it is important to consider the major drawbacks associated with this regimen:

A greater effort is required by the patient to manage and coordinate diet, activity, insulin administration, and blood glucose monitoring. The incidence of hypoglycemia may be increased up to threefold in patients with type 1 diabetes.Weight gain is more likely, which can limit patient compliance, particularly in women.

The cost of intensive insulin therapy (00 to 00/year) was about three times that of conventional treatment, based upon an analysis of the DCCT and costs from the early 1990s.

In spite of these drawbacks, intensive insulin therapy is recommended for the majority of patients with type 1 diabetes to prevent, slow, or even reverse the development of complications.

When to start intensive therapy — Studies suggest that intensive therapy should be started as early as possible following the diagnosis of type 1 diabetes. In 303 patients from the DCCT with early type 1 diabetes and residual beta-cell function who were randomly assigned to intensive or conventional insulin therapy, those receiving intensive therapy were slower to lose residual beta-cell function than the conventional therapy group (risk reduction 57 percent. In addition, intensive therapy in those with residual beta cell function resulted in a lower A1C, a 50 percent reduced risk for retinopathy progression, and a lower risk for severe hypoglycemia compared to those who received intensive therapy but did not have residual beta cell function.

CHOICE OF INSULIN REGIMEN — The approximate time of onset, peak activity, and duration of action of the most commonly used insulins are reviewed elsewhere.The choice of regimen is largely a matter of patient and physician preference. The basic requirements are a stable baseline dose of insulin (basal insulin) (whether an intermediate or long-acting insulin or given via continuous subcutaneous insulin infusion) plus adjustable doses of pre-meal short-acting insulin (regular) or rapid-acting insulin analogs (lispro, aspart, or glulisine).

In the DCCT, in which all supplies were free, patients in the intensive therapy group were allowed to choose between multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) and could switch between the two during the study. Fifty-nine percent of the patients in the intensive therapy group used a pump at least part of the time; however, the pump was used for only 34 percent of the time during the study. Glycemic control, frequency of severe hypoglycemia, and progression of microvascular disease were similar with either type of insulin therapy. Small trials comparing intensive insulin therapy using MDI versus CSII reported similar findings and additionally reported no difference in quality of life measures between treatment groups [6,7].Thus, the major decision in initiating intensive insulin therapy is whether the patient and physician are more comfortable with multiple daily injections or continuous subcutaneous insulin infusions. The choice between multiple daily injection regimens and insulin pump therapy should largely be predicated on patient preference and lifestyle.

Multiple daily injections — In the past, the most commonly used multiple-dose regimen (ie, “conventional insulin therapy”) consisted of twice-daily injections of short-acting (regular) and intermediate-acting insulin. This regimen was based on the concept that each of the four doses is covering one quarter of the day and results in a single peak of insulin absorption. This regimen is not physiologic and is no longer recommended unless the patient cannot or will not comply with an intensive insulin regimen.

Many different insulin regimens may be used to accomplish intensive insulin therapy. Some of the more common ones are shown in the table. The choice of basal and bolus insulins for a multiple daily injection (MDI) regimen depends upon patient preference, lifestyle, and cost concerns. Irrespective of the type of insulin chosen, these intensive insulin regimens should be monitored with frequent blood glucose determinations, at least four times per day.Insulin glargine — Insulin glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules in the B-chain of the insulin molecule. These modifications result in a change in the pH such that after subcutaneous administration, glargine precipitates in the tissue forming hexamers, which delays absorption and prolongs duration of action. The time-action profile for insulin glargine has virtually no peak (graph 4), which makes it a good basal insulin preparation for intensive insulin therapy [8-10].The therapeutic advantage of insulin glargine over NPH is modest. In a pooled analysis of trials comparing glargine with NPH in adults with type 1 diabetes, the weighted mean difference in A1C was -0.11 percent (95% CI -0.21 to -0.02), favoring glargine. There was no difference in the number of hypoglycemic episodes. It is unclear whether the modest benefits of glargine compared with NPH merit the added expense and inconvenience of not being able to mix it with other insulins (sometimes requiring an additional injection, when compared with NPH regimens). In addition, long-term safety is unknown.

In patients with type 1 diabetes (but not type 2), glycemic control is similar if once-daily glargine is given before breakfast, before dinner, or at bedtime but there is less nocturnal hypoglycemia with breakfast administration. This was illustrated in a randomized trial of 378 patients with type 1 diabetes who received pre-meal doses of insulin lispro in addition to one of the three glargine regimens. A1C was similar in the three groups, but nocturnal hypoglycemia occurred in 60 percent of patients taking glargine before breakfast, 72 percent before dinner, and 78 percent at bedtime.Although many patients can achieve stable basal serum insulin concentrations with a single daily injection of insulin glargine given in the morning or evening (regimens 3 and 4; this is not always the case. In my experience, about 20 percent of patients with type 1 diabetes need twice-daily glargine. Insulin detemir — Insulin detemir is another available long-acting insulin analog. It is an insoluble molecule with a fatty acid side chain that allows albumin binding, which results in prolongation in action. Insulin detemir is considerably less potent than human insulin and is formulated so that four detemir molecules have roughly the same potency as one molecule of human insulin. Its duration of action appears to be substantially shorter than that of insulin glargine [15], though still longer than NPH (table 1). In one study, a detemir dose of 0.29 units/kg provided the same effect as 0.3 units/kg NPH, but with a longer duration of action (16.9 versus 12.7 hours, respectively) [16]. Like NPH, twice-daily injections appear to be necessary in patients with type 1 diabetes.Glycemic control appears to be similar in trials comparing insulin detemir and NPH. In a pooled analysis of trials comparing detemir with NPH in patients with type 1 diabetes, there was no difference in A1C (weighted mean difference -0.06 percent, 95% CI -0.13 to 0.02). However, insulin detemir was associated with a slightly lower risk of severe hypoglycemia and nocturnal hypoglycemia. These modest advantages of insulin detemir may be offset by its higher cost and unknown long-term safety profile.Rapid-acting insulin — To produce an insulin preparation with a faster onset and shorter duration than regular insulin, modifications have been made in the insulin molecule to prevent it from forming dimers and other complexes that slow absorption and delay action. The resulting rapid-acting insulins (insulin lispro, aspart, and glulisine) have an onset of action within 5 to 15 minutes, peak action at 30 to 90 minutes, and a duration of action of two to four hours.

In patients with type 1 diabetes, rapid-acting insulin has the following advantages when compared to regular insulin [17]:It decreases the postprandial rise in blood glucose concentration.It is more convenient because it can be injected immediately before meals, whereas regular insulin should be given 30 to 45 minutes before meals to optimally match the glycemic excursions after a meal. In addition, the action of insulin lispro is not blunted by mixing with NPH insulin just before injection, as is the action of regular insulin [18].Despite these advantages, the results from clinical trials have been somewhat disappointing [19]. In a meta-analysis of 42 randomized controlled trials (involving 5925 patients with type 1 diabetes) that compared rapid-acting insulin analogues to regular insulin showed only a minor benefit of insulin analogs in terms of A1C values [20].In a subsequent pooled analysis of trials comparing lispro or aspart with regular insulin in patients with type 1 diabetes, the insulin analogs provided a similar small improvement in A1C (weighted mean difference -0.09 to -0.13 percent) [11]. It is unclear if this small improvement will provide clinical benefit. There are few data examining the effects of insulin analogs on long-term diabetic complications. In some [11,21], but not all [18], meta-analyses comparing rapid acting insulin analogs with regular insulin, there was a lower risk of severe hypoglycemia with use of lispro. Although the risk of severe hypoglycemia was not significantly different in a pooled analysis of trials comparing aspart and regular insulin [11], there was a lower risk of hypoglycemia with aspart compared with lispro when the insulin analogs were administered as a continuous subcutaneous insulin infusion [22].The rapid acting insulins are particularly useful in addressing unexpectedly high blood glucose levels (eg, between meals or in the setting of stress) because they will lower glucose levels more rapidly and without the prolonged effect of regular insulin [23-25].One disadvantage of rapid-acting insulins is their higher cost [17]. The teratogenicity and long term safety profile of short-acting insulins in pregnancy are unknown, although many diabetologists do prescribe rapid-acting insulins during pregnancy.Choosing basal/bolus insulin — The choice of basal and bolus insulin for a multiple daily injection regimen depends upon patient preference, lifestyle, and cost concerns. In short-term trials, there may be a modest glycemic benefit of analogs over conventional insulin. However, it is of uncertain clinical significance and long-term trials with diabetic complications as endpoints are lacking.As an example, in an 18-week trial in 595 adults with type 1 diabetes randomly assigned to NPH/regular versus detemir/aspart, there was a small but significant difference in A1C values (mean difference -0.22 percentage points) favoring the insulin analogs.