A comparison of preprandial insulin glulisine versus insulin lispro in people with Type 2 diabetes over a 12-h period

Abstract

A comparison of the plasma glucose and insulin day profiles between two prandial rapid-acting insulin analogues, insulin glulisine (glulisine) and insulin lispro (lispro), in 18 obese subjects with Type 2 diabetes.

Subjects (body mass index: males, 36.7 [33.2–43.8] kg/m²; females, 40.0 [35.7–46.5] kg/m²) received subcutaneous glulisine or lispro (0.15 U/kg) at 4-h intervals immediately (within 2 min) before three standard test meals during each of two 12-h, randomised, open-label, crossover studies (7 ± 2-day interval between each).

Overall, preprandial-subtracted glucose concentrations (area under the curve) were similar on the glulisine and lispro study days. However, the mean of the three maximal preprandial subtracted plasma glucose concentrations (ΔGLU_max) were lower with glulisine versus lispro (12%; p < 0.01). Mean concentrations of insulin analogue were significantly higher post-meal with glulisine (p < 0.01 for all). Post hoc analysis showed a significantly faster absorption rate for glulisine versus lispro in the first 30 min post-meal (estimated difference 0.48 μU/min; p < 0.0001). Only two cases of hypoglycaemia were reported; both from one subject during the lispro day.

When glulisine is injected immediately before a meal in obese patients with Type 2 diabetes, glulisine achieves significantly lower glucose excursions over lispro. Significantly faster absorption with higher and sustained post-meal levels of insulin analogue was achieved at every meal with glulisine versus lispro.

Introduction

The primary goal of insulin therapy in Type 2 diabetes mellitus (T2DM) is to achieve tight glycaemic control by supplementing the insulin deficit in a manner that is as close to the normal insulin secretion pattern as possible. The key features of a normal insulin profile involve a sustained and relatively constant basal level of insulin secretion, along with a meal-stimulated peak (30–60 min) of insulin secretion that slowly decays over the subsequent 2–3 h. Basal-bolus insulin therapy, involving the use of a combination of rapid- and long-acting insulin analogue preparations replicates this pattern and provides a physiological form of insulin replacement therapy [3]. Although regular human insulin (RHI) has traditionally been used as bolus (prandial) insulin, its pharmacological profile does not resemble the profile of endogenous insulin release [4]. It has an onset of action of 30 min and a duration of action of 6–8 h—resulting in a recommendation that it must be given at least 30 min prior to a meal [5], [6].

Insulin glulisine (glulisine) is a new rapid-acting insulin analogue developed to more closely resemble physiological insulin release after meals and, therefore, improve prandial glycaemic control [7]. Glulisine differs in structure from RHI by the replacement of asparagine with lysine at position 3 and of lysine with glutamic acid at position 29 on the B chain of the human insulin molecule [8]. It has previously been demonstrated that glulisine provides better glycaemic (HbA_1c) control versus RHI in patients with Type 1 diabetes mellitus (T1DM) when administered 0–15 min pre-meal and equivalent control when given immediately after the meal [7]. Furthermore, when compared with insulin lispro (lispro), glulisine shows equivalent glycaemic control in patients with T1DM [9]. Similarly, glulisine displays a more rapid onset and a shorter duration of action when compared with RHI in patients with T2DM [10], which is associated with improved HbA_1c and lower post-breakfast and post-dinner blood glucose levels versus RHI [11].

Obesity is frequently associated with T2DM [12], [13] and it is thus important that insulin analogues maintain their pharmacokinetic (PK) and pharmacodynamic (PD) characteristics regardless of body fat, skin thickness or body mass index (BMI). However, increasing the subcutaneous (sc) fat layer at the injection site may delay the rate of insulin absorption [14]. A study of obese subjects without diabetes showed that increasing skin thickness (sc fat layer) and BMI had a detrimental effect on the PK profiles of both lispro and RHI, whereas the time-action profile of glulisine was less affected [15]. There was a positive correlation between skin thickness or BMI and PD parameters for lispro and RHI. In contrast, the time-action profile of glulisine did not demonstrate any significant correlation with either anthropometric measure and may provide advantages to patients with T2DM. The present exploratory study in obese patients with T2DM compared the PK and PD profiles of glulisine with lispro when administered sc before three standard meals during a 12-h period.