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Insulin Glulisine

A Review of its Use in the Management of Diabetes Mellitus

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Summary

Abstract

Insulin glulisine (Apidra®) is a human insulin analogue approved for the improvement of glycaemic control in adults, adolescents and children with diabetes mellitus. It has similar binding properties, and is associated with a faster onset but similar level of glucose disposal, to regular human insulin (RHI). Insulin glulisine and insulin lispro have similar effects on glucose levels.

Insulin glulisine is effective when compared to other short- and rapid-acting insulins, demonstrating either noninferiority, no significant difference, or superiority in primary endpoints in studies involving patients with type 1 and type 2 diabetes. It is more effective and has a faster onset and shorter duration of activity than RHI. Insulin glulisine is as effective as insulin lispro in patients with type 1 diabetes; however, there is a need for further, well designed head-to-head comparisons with insulin lispro in patients with type 2 diabetes and with insulin aspart in patients with type 1 or type 2 diabetes to fully establish the place of insulin glulisine in the management of diabetes. Insulin glulisine has a flexible administration period, as it can be administered immediately before or after meals. Hypoglycaemia, a common risk with insulins, occurs at a similar rate among recipients of insulin glulisine to that seen with other insulins. Thus, insulin glulisine is an effective and well tolerated option for the treatment of patients with type 1 and type 2 diabetes.

Pharmacological Properties

Human insulin was altered to form insulin glulisine by replacing asparagine with lysine at position B3 and lysine with glutamic acid at position B29. The majority of in vitro and in vivo studies have shown that the binding of insulin glulisine to the insulin receptor (to therapeutic effect) and to the insulin-like growth factor-1 receptor (to mitogenic effect) is similar to that of RHI.

Insulin glulisine is associated with a faster glucose-lowering effect than RHI, but shows a similar level of glucose disposal overall, in patients with type 1 or type 2 diabetes. Insulin glulisine and insulin lispro appear similar with regard to speed and extent of glucose lowering in patients with type 1 or type 2 diabetes. In clinical trials in patients with type 1 or type 2 diabetes, insulin glulisine was associated with preprandial blood glucose levels that were at least as low as comparator agents, and on occasion significantly lower than those seen with RHI or (with basal insulin glargine) premixed insulin. Body mass index (BMI) does not appear to have an effect on blood glucose control in volunteers.

The majority of clinical trials reported (where stated) no significant difference between insulin glulisine and comparator agents in terms of change in body-weight. Insulin glulisine appears to be associated with a closer approximation of normal microvascular blood flow and endothelial function than RHI, and end-organ metabolic effects associated with the administration of insulin glulisine, insulin lispro and RHI appear to be similar.

Insulin glulisine appears to have a similar total systemic availability to RHI, but with faster absorption, in patients with type 1 and type 2 diabetes, whereas it does not differ from insulin lispro with regard to these parameters in these patient populations. Patients with type 1 and type 2 diabetes had a maximum serum insulin glulisine concentration (Cmax) of 120 and 92 μU/mL, a time to Cmax of 51 and 83 minutes, and an area under the insulin glulisine concentration-time curve from time zero to endpoint of 16120 and 18408 μU · min/mL. Timing of administration (with regard to meal) and injection site did not appear to have significant effects on pharmacokinetic parameters.

Insulin glulisine, administered by subcutaneous injection, has an approximate absolute bioavailability of 70% and is associated with low plasma protein binding. After intravenous administration, the volume of distribution and elimination of insulin glulisine appears to be similar to those of RHI, but after subcutaneous administration the elimination is more rapid than with RHI. Insulin glulisine has a total clearance of 927 mL/min after intravenous administration and its metabolism is unlikely to differ from that of RHI.

Age, BMI and ethnicity do not appear to have any effect on the pharmacokinetic parameters of insulin glulisine. A reduction in the dosage of insulin may be required in the presence of renal impairment. The pharmacokinetic effects of insulin glulisine have not been investigated in patients with impaired liver function.

Therapeutic Efficacy

Several well designed trials have investigated the efficacy of insulin glulisine (with and without basal insulin) versus comparator agents (with and without basal insulin) in patients with type 1 and type 2 diabetes. In patients with type 1 diabetes, insulin glulisine was noninferior to insulin lispro (in both adult and paediatric patients) and to RHI (in adult patients). In adult patients with type 2 diabetes, insulin glulisine was noninferior (and superior in one study) to RHI and (with basal insulin glargine) more effective than premixed insulin. The primary endpoint in most clinical trials, where stated, was the change in glycosylated haemoglobin (HbA1c) levels from baseline to the end of the study period.

There were no significant differences between pre- and postprandial administration, or between pre-breakfast and pre-main meal administration, among patients with type 2 diabetes. Postprandial insulin glulisine was noninferior to preprandial in the primary endpoint in patients with type 1 diabetes; however, within this wide noninferiority margin (0.4% difference in change in HbA1c), preprandial insulin glulisine was shown to be significantly superior to postprandial administration.

When administered using continuous subcutaneous insulin infusion (CSII), insulin glulisine appeared to be as effective as insulin aspart in patients with type 1 diabetes. A basal-bolus regimen of insulin glargine and insulin glulisine was more effective than a sliding-scale regimen of RHI in hospitalized patients with type 2 diabetes.

Tolerability

Insulin glulisine was well tolerated in clinical studies of patients with type 1 and type 2 diabetes. Hypoglycaemia generally occurred at a similar rate and incidence among insulin glulisine versus comparator insulin recipients among adult and paediatric patients with type 1 diabetes and in adult patients with type 2 diabetes. No significant difference was reported between insulin glulisine and comparator agents in the overall incidence of adverse events, the incidence of serious adverse events or discontinuation due to adverse events in clinical trials. Discontinuation due to adverse events was rare, as were adverse events other than hypoglycaemia. No significant laboratory test differences from baseline were reported in insulin glulisine recipients.

Patients with type 1 diabetes receiving insulin glulisine showed a slight decrease in cross-reactive insulin antibody levels at endpoint versus baseline; no such difference was reported among patients with type 2 diabetes.

Patients receiving insulin glulisine via CSII did not significantly differ from those receiving insulin aspart via CSII with regard to the incidence of catheter occlusions or the rate of or time between catheter changes.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Karly P. Garnock-Jones & Greg L. Plosker

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Karly P. Garnock-Jones & Greg L. Plosker

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  1. Karly P. Garnock-Jones
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Corresponding author

Correspondence to Karly P. Garnock-Jones.

Additional information

Various sections of the manuscript reviewed by: D.S.H. Bell, Division of Endocrinology and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA; B.W. Bode, Atlanta Diabetes Associates, Atlanta, Georgia, USA; K. Kaku, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan; M. Landin-Olsson, Department of Endocrinology, University Hospital, Lund, Sweden; S.M. Setter, Department of Pharmacotherapy, Washington State University, Spokane, Washington, USA; G. Tamas, 1st Department of Medicine, Semmelweis University, Budapest, Hungary.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘insulin glulisine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE or AdisBase search term was ‘insulin glulisine’. Searches were last updated 11 May 2009.

Selection: Studies in patients with type 1 or type 2 diabetes mellitus who received insulin glulisine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Insulin glulisine, type 1 diabetes mellitus, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Garnock-Jones, K.P., Plosker, G.L. Insulin Glulisine. Drugs 69, 1035–1057 (2009). https://doi.org/10.2165/00003495-200969080-00006

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