Glycaemic control in type 1 diabetic patients using optimised insulin aspart or human insulin in a randomised multinational study

Abstract

Insulin aspart (IAsp), is a rapid-acting analogue of human insulin (HI), for use in the meal related treatment of diabetes mellitus. The degree of glycaemic control achieved by IAsp in comparison with HI after algorithm-driven dose optimisation was tested over 3 months. The prospective, multicentre, randomised, open-label study with parallel groups was performed in 48 centres in 11 countries and included 423 basal-bolus treated patients with Type 1 diabetes. Main outcome measures were blood glucose control assessed by HbA_1c, nine-point self-monitored blood glucose profiles, insulin dose, quality of life, hypoglycaemia and adverse events. An algorithm-driven increase occurred in the dose and number of daily injections of basal insulin, particularly in the IAsp group. After 12 weeks of treatment, HbA_1c was significantly lower in IAsp compared to HI treated subjects by 0.17 (95% CI 0.30–0.04) (P<0.05). Comparison of the blood glucose profiles showed lower blood glucose levels with IAsp after breakfast (mean 8.4 vs 10.1 mmol/l; P<0.0001) and dinner (8.2 vs 9.3 mmol/l; P<0.01). There were no differences between treatments in the incidence of hypoglycaemic episodes or in the adverse event profiles. The WHO Diabetes Treatment Satisfaction Questionnaire score for perceived hyperglycaemia was lower with Iasp (P=0.005), and patients found the insulin aspart treatment more flexible (P=0.022). The current study underlines the need for optimising the basal insulin regimen in order to take full advantage of the pharmacoodynamics of IAsp.

Introduction

The overriding importance of good glycaemic control in diabetes was confirmed by the Diabetes Control and Complications Trial (DCCT), which showed that effective blood glucose control in Type 1 diabetic patients can prevent or delay the onset of long-term complications [1]. Although the introduction of intensified insulin therapy (i.e. pre-prandial bolus injections of soluble insulin and basal insulin supplementation by a long- or intermediate-acting insulin) improved glycaemic control, it did so at the expense of a three-fold rise in the incidence of severe hypoglycaemic episodes [2]. The physiological rapid and appropriate insulin release of non-diabetic individuals in response to postprandial glucose absorption, however, is impossible to mimic with injection of unmodified human insulin.

Thus, two fundamental attributes of an effective meal-related injected insulin must be rapid absorption into the circulation and prompt postprandial waning of absorption to avoid between-meal hypoglycaemia. Although subcutaneously (SC) injected soluble human insulin (HI) acts similarly to the endogenously produced hormone, it may fail on both counts; its absorption is delayed by self-association into hexamers [3] with resulting delayed arrival in the circulation and prolongation of its effect after the postprandial glucose level falls. Injection of HI 30 min before a meal may help to solve the first of these problems [4], [5], though only a minority of patients regularly manage to conform to this schedule [6].

Insulin aspart (IAsp) is a rapidly absorbed rapid-acting analogue of HI with the potential, similar to that of other rapid-acting insulin analogues, to decrease the meal-related excursions of blood glucose concentration. Its primary structure is identical to that of HI except for the substitution of an aspartate moiety for the proline at position 28 on the B chain. This change reduces the tendency of self-association into hexamers [7] and, therefore, promotes more rapid absorption from the subcutaneous depot [3]. Binding of monomeric IAsp to the insulin receptors and release from them is not affected by the B28 substitution since the region B27–30 is not involved in insulin receptor interaction [8], [9], [10]. The more rapid absorption should ensure early depletion of the injection depot, and thus earlier falls in concentration in the circulation, thus reducing the risk of between-meal hypoglycaemia. Pharmacokinetic and pharmacodynamic studies of IAsp in healthy and diabetic individuals have indicated that the assumptions regarding rapid absorption and prompt disappearance are correct [3], [11], [12], [13], [14], and clinical trials have confirmed this by demonstrating equal or improved metabolic control and/or reduced rate of major hypoglycaemia when compared to a HI based regimen [15], [16], [17]. In these earlier studies no changes in the number of basal insulin injections were recommended, although IAsp treatment was frequently accompanied by an increase of basal insulin dose.

Recent pharmacodynamic and clinical trials with rapid acting insulin analogues suggest that appropriate basal insulin supplementation is the crucial factor in achieving better glycaemic control in Type 1 diabetic patients [18], [19], [20], [21], [22], [23]. Therefore, in the trial reported here, the dose and number of insulin injections were recommended to be changed according to dose adjustment algorithms for both IAsp and HI, thus standardising optimisation of treatment.

The objective of the present study was to assess the degree of glycaemic control achieved by IAsp compared to HI, after algorithm-driven dose optimisation in 423 meal-time+basal-treated patients with Type 1 diabetes after the first 12 treatment weeks of a 64 week long trial [24], [25]. The open-label design allowed the time of injection for both meal-time insulins to be in line with their individual recommendations, human insulin 15–30 min before meals and insulin aspart at meal-time. Glycaemic control was assessed by both glycated haemoglobin (HbA_1c) and blood glucose measurements. Furthermore, incidence of hypoglycaemia, safety profiles and treatment satisfaction were compared between the two treatment groups.