Two-Year Safety and Efficacy of Inhaled Human Insulin in Adult Diabetics

Abstract and Introduction

Abstract

Objective: The purpose of this study was to evaluate the long-term (2-year) safety and efficacy of inhaled human insulin (Exubera [insulin human (rDNA origin)] inhalation powder) (EXU) in adult patients with type 1 diabetes.
Research Design and Methods: Patients were randomly assigned to receive EXU (n = 290) or subcutaneous (SC) insulin (n = 290), plus basal (intermediate- or long-acting) insulin. The primary end point was the annual rate of decline in pulmonary function (forced expiratory volume in 1 s [FEV₁] and carbon monoxide diffusing capacity [DL_CO]).
Results: The mean ± SEM annual rates of change between months 0 and 24 were –0.051 ± 0.005 l/year with EXU and –0.034 ± 0.005 l/year with SC insulin (significant mean difference –0.017 ± 0.007 l/year [90% CI –0.028 to –0.005]) for FEV₁ and –0.437 ± 0.073 ml · min · mmHg · year with EXU and –0.287 ± 0.065 ml · min · mmHg · yearwith SC insulin (nonsignificant mean difference –0.150 ml · min · mmHg · year [–0.310 to 0.011]) for DL_CO. The mean annual rates of change in FEV₁ between months 3 and 24 were –0.041 ± 0.005 and –0.031 ± 0.006 l/year in the EXU and SC insulin groups, respectively (nonsignificant mean difference –0.011 l/year [–0.023 to 0.002]), indicating that the significant difference between the treatment groups in FEV₁ developed during the first 3 months and was not progressive thereafter. Adverse event profiles were similar except for a higher incidence of cough (usually mild and unproductive) in patients receiving EXU (37.6 vs. 13.1%) that decreased to 1.3% by month 24. Glycemic control was sustained in both groups (adjusted mean treatment difference in change from baseline A1C at month 24 0.25 ± 0.07% [0.13–0.37]). Although the overall hypoglycemic events were comparable between groups (4.0 vs. 3.8 events/subject-month), the incidence of severe hypoglycemic events was lower with EXU than with SC insulin (2.8 vs. 4.1 events/100 subject-months, risk ratio 0.67 [0.57–0.79]). Body weight increased to a significantly lesser extent with EXU (adjusted mean treatment difference –1.25 ± 0.36 kg [–1.85 to –0.66]).
Conclusions: Treatment group differences in lung function between EXU and SC insulin in adult patients with type 1 diabetes are small, develop early, and are nonprogressive for up to 2 years of therapy.

Introduction

Intensive insulin therapy reduces the risk of diabetes complications. However, insulin therapy is often delayed because of anxiety about injections, hypoglycemia, or weight gain. As a result, many type 1 and type 2 diabetic patients do not achieve treatment goals and continue to live with a risk of complications. If left unchecked, this failure to achieve glycemic control will place an increasing burden on global health care resources as the worldwide prevalence of diabetes escalates.

Pulmonary delivery of insulin may overcome some of the obstacles to intensive glycemic control by eliminating the need for prandial insulin injections. Inhaled human insulin (Exubera [insulin human (rDNA origin)] inhalation powder; Pfizer) (EXU) was approved for use in adult patients with type 1 or type 2 diabetes in the U.S. and European Union in January 2006. EXU has a time-action profile with onset of action closer to meals than subcutaneous (SC) regular insulin. Clinical trials have demonstrated that EXU is as effective and well tolerated as SC insulin in adult type 1 diabetic patients for up to 6 months.

Pulmonary function is an important aspect of the safety profile for medications delivered via the lungs. By using nonstandardized lung function testing, trials of EXU in adult type 1 diabetic patients identified small treatment group differences in lung function over 6 months, favoring SC insulin. A subsequent short-term (3-month) study in type 1 diabetic patients using standardized methodology showed that these differences occurred early and were not progressive after 2–4 weeks, were clinically insignificant, and resolved within 2 weeks of discontinuation of treatment.

The aim of the present study was to compare the long-term (2-year) safety and efficacy of EXU versus SC insulin in adult patients with type 1 diabetes using highly standardized pulmonary function tests, trained coordinators, and centralized data collection. This was a comparative trial designed to estimate the difference in annual rates of lung function decline between EXU and SC insulin.