Antibody response to inhaled insulin in patients with type 1 or type 2 diabetes. An analysis of initial phase II and III inhaled insulin (Exubera) trials and a two-year extension trial

Objective: To compare antibody responses to inhaled human insulin vs. sc human insulin and to determine whether insulin antibody binding is associated with adverse clinical consequences. Research Design and Methods: Insulin antibody data from initial phase II/III trials were analyzed comparing the efficacy and safety of inhaled insulin with various agents, including sc insulin. Additionally, data from a 24-month extension of the phase III studies were examined. Data were pooled into the following three groups based on insulin treatment status at baseline: patients with type 1 diabetes, and patients with type 2 diabetes using insulin and not using insulin at baseline. Ig class analysis was also performed on randomly selected sera from type 1 patients at the end of the initial trials. Results: In the initial trials, greater insulin antibody binding was observed in patients receiving inhaled insulin vs. sc insulin. The greatest antibody responses to inhaled insulin were observed in patients with type 1 diabetes [ nonparametric comparison of medians at the end of the study, 22.0% binding ( unadjusted 95% confidence interval: 19.5, 24.5)], and the lowest responses were observed in non-insulin-using patients with type 2 diabetes in which there was no difference in median values at the end of the study. There were no correlations between antibody binding and glycemic control ( measured using glycosylated hemoglobin), insulin dose requirements, hypoglycemic events, or pulmonary function ( measured by changes in forced expiratory volume in 1 sec and diffusion capacity of carbon monoxide). Antibody responses were IgG in type. Differences in antibody levels observed in patients with type 1 vs. type 2 diabetes were maintained over the 24-month extension trials. Peak antibody levels across all groups were generally observed after 6 - 12 months of insulin therapy. Inhaled insulin therapy was not associated with a greater incidence of allergy or other hypersensitivity reactions. Conclusion: Inhaled insulin was observed to produce a larger antibody response than sc insulin. Insulin antibody binding has not been associated with adverse clinical consequences in trials to date.