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Inhaled Human Insulin (Exubera®)

A Review of its Use in Adult Patients with Diabetes Mellitus

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Summary

Abstract

Inhaled human insulin (Exubera® (insulin human [rDNA origin]) Inhalation Powder) has recently been approved in the European Union and the US for preprandial use in adult patients with diabetes mellitus. This formulation of insulin has a more rapid onset, but similar duration, of glucose-lowering activity compared with subcutaneously administered regular human insulin.

Preprandial inhaled human insulin provided glycaemic control that was comparable to preprandial subcutaneous regular insulin when added to long- or intermediate-acting subcutaneous basal insulin in patients with type 1 diabetes mellitus. Inhaled human insulin is also effective when administered alone, when combined with oral antihyperglycaemic therapy, or when combined with basal subcutaneous insulin in patients with type 2 diabetes mellitus. Comparable rates of hypoglycaemia occurred in patients treated with inhaled human insulin and in those treated with subcutaneous regular human insulin. Patients treated with inhaled human insulin demonstrated a greater decline in pulmonary function (forced expiratory volume in 1 second [FEV1], carbon monoxide diffusing capacity [DLco]) than patients treated with comparator antihyperglycaemic agents; the mean difference between the treatment groups that favoured the comparators was noted within the first several weeks of treatment, and did not change over a 2-year treatment period. This agent has also been associated with significant improvements in some quality-of-life and treatment satisfaction scores, especially when compared with subcutaneous mealtime insulin regimens. Inhaled human insulin is an effective and well tolerated formulation suitable for preprandial use in combination with basal subcutaneous insulin in patients with type 1 diabetes. It is also well tolerated and effective in patients with type 2 diabetes when administered alone, when combined with oral antihyperglycaemic therapy, or when combined with basal subcutaneous insulin.

Pharmacological Properties

In healthy volunteers and in patients with diabetes, plasma concentrations of insulin increase more rapidly after administration of inhaled human insulin than after a subcutaneous injection of regular human insulin. With inhaled human insulin, the maximal antihyperglycaemic effect occurred after approximately 2 hours, and the duration of action was around 6 hours. Inhaled human insulin had a significantly faster onset of glucose-lowering effect than subcutaneous regular insulin (p < 0.001). Times to maximal glucose-lowering effect were comparable for inhaled human insulin and the rapid-acting insulin lispro, but shorter for inhaled than for regular insulin (p < 0.01). The duration of glucose-lowering effect of inhaled human insulin was comparable to that of subcutaneously administered regular insulin, but longer than that of subcutaneously administered insulin lispro (p < 0.01). Intra-individual reproducibility of glycaemic response is at least as good as that with subcutaneous regular insulin. Cigarette smoking substantially increases systemic exposure to inhaled human insulin; inhaled human insulin is contra-indicated in patients who smoke or who have smoked 6 months prior to starting therapy.

Therapeutic Efficacy

In 24-week phase III trials in patients with type 1 diabetes treated with basal insulin, the reduction in glycosylated haemoglobin (HbA1c) values (0.1–0.5 percentage points from baseline) in recipients of preprandial inhaled human insulin was comparable to that with subcutaneous regular insulin. The percentage of patients achieving HbA1c values of <7% was comparable between the two treatment groups.

In patients with type 2 diabetes inadequately controlled with diet and exercise alone, HbA1c values below 8% were achieved in 83% of patients treated with inhaled human insulin. Mean HbA1c values were reduced by 2.3% over the 24 weeks of treatment. Mean HbA1c reductions were maintained to a greater extent with inhaled human insulin than with oral antihyperglycaemic treatment in a 104-week extension study in type 2 diabetic patients not responding to oral antihyperglycaemic monotherapy. In patients with type 2 diabetes poorly controlled by combination oral antihyperglycaemic therapy, reductions in HbA1c levels from baseline were significantly greater with inhaled human insulin (as monotherapy or in combination with oral antihyperglycaemic agents) than with oral antihyperglycaemic agents alone. Use of inhaled human insulin before meals with basal ultralente insulin at bedtime was similar to treatment with mixed subcutaneous neutral protamine Hagedorn (NPH)/regular insulin in controlling HbA1c in patients with type 2 diabetes previously treated with subcutaneous insulin.

Inhaled human insulin was associated with significant improvements in some quality-of-life and treatment satisfaction scores in patients with diabetes, especially when compared with subcutaneous mealtime insulin regimens.

Tolerability

Rates of hypoglycaemia were comparable in recipients of inhaled human insulin or subcutaneous regular insulin in randomised clinical trials. Treatment of diabetic patients with inhaled human insulin was generally associated with increases in bodyweight (0.1–3.6kg); however, the increase was numerically less than that with subcutaneous regular insulin. Patients treated with inhaled human insulin demonstrated a greater decline in pulmonary function (FEV1 and DLco) than patients treated with comparator antihyperglycaemic agents. The mean difference between the treatment groups that favoured the comparators was noted within the first several weeks of treatment, and did not change over a 2-year treatment period. It is recommended that patients should have pulmonary function assessments prior to initiating inhaled insulin therapy and at periodic intervals thereafter. An increased incidence of cough, which occurs within seconds to minutes of inhalation, has been reported, but this has been of mild to moderate severity and has tended to decrease in frequency over time. Greater insulin antibody production with inhaled human insulin than with subcutaneous regular human insulin given at mealtimes has been reported in patients with diabetes, but this appears to have no clinical relevance in terms of glycaemic control or pulmonary function.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, 1311, New Zealand

    Christopher Dunn & Monique P. Curran

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  1. Christopher Dunn
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Correspondence to Monique P. Curran.

Additional information

Various sections of the manuscript reviewed by: K. Capoccia, University of Washington, Seattle, Washington, USA; N. Freemantle, University of Birmingham, Birmingham, United Kingdom; I.A. Harsch, University of Erlangen, Erlangen, Germany; T. Heise, Profil Institut für Stoffwechselforschung, Neuss, Germany; T.K. Mandal, Xavier University of Louisiana, New Orleans, Louisiana, USA; D.R. Owens, Diabetes Research Unit, Llandough Hospital, Penarth, United Kingdom; T. Quattrin, State University of New York at Buffalo, Buffalo, New York, USA; H. Sadri, Department of Clinical Pharmacology, Health Outcomes and Pharmacoeconomics Research Centre (HOPE), Sunnybrook Hospital, Toronto, Ontario, Canada.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘inhaled insulin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). 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 search terms were ‘inhaled insulin’ or ‘insulin inhalation’. EMBASE search terms were ‘inhaled insulin’ or ‘insulin inhalation’. AdisBase search terms were ‘inhaled insulin’ or ‘insulin inhalation’. Searches were last updated 17 May 2006.

Selection: Studies in patients with type 1 or 2 diabetes mellitus who received inhaled insulin. 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: Inhaled human insulin, type 1 diabetes mellitus, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Dunn, C., Curran, M.P. Inhaled Human Insulin (Exubera®). Drugs 66, 1013–1032 (2006). https://doi.org/10.2165/00003495-200666070-00019

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