Lung Cancer-Related Mortality With Inhaled Insulin or a Comparator: Follow-Up Study of patients previously enrolled in Exubera Controlled Clinical Trials (FUSE) Final Results.

OBJECTIVE: The Follow-Up Study of patients previously enrolled in Exubera controlled clinical trials (FUSE) was designed to evaluate whether patients previously treated with Exubera (EXU; insulin human [rDNA origin], inhaled powder) in controlled clinical trials died because of incident primary lung cancer at a substantially higher rate than patients treated with a comparator. RESEARCH DESIGN AND METHODS: FUSE is a hybrid, randomized, controlled trial/cohort study including participants of 17 prior EXU clinical trials. Pooled patient data from these trials were used, and the subset of patients enrolled in the follow-up cohort study was followed prospectively for 2 years in order to evaluate the incidence of fatal and nonfatal primary lung cancers and all-cause mortality. RESULTS: There were 24,409 person-years (PY) of observation among 7,439 trial patients, with 4,017 PY (16.5%) from the period after the trials but before the prospective follow-up and 5,299 PY (21.7%) from the prospective follow-up. Just over half of the 2,631 patients (51.6%) in the prospective follow-up were randomized to EXU in the original trial. The incidence density ratio was 2.8 (95% CI 0.5, 28.5) for lung cancer-related mortality and 3.7 (95% CI 1.0, 20.7) for incident primary lung cancer. The hazard ratio for all-cause mortality was 0.81 (95% CI 0.60, 1.10). CONCLUSIONS: These data cannot exclude an increased risk of lung cancer-related mortality associated with EXU use. If real, the absolute increased risk of lung cancer-related mortality was small (0.48 cases per 1,000 PY). For all-cause mortality-the most reliably measured end point with the clearest interpretation-EXU users did not experience an excess all-cause death rate (relative or absolute) compared with users of other diabetes treatments over the study period.

Safety and efficacy of inhaled human insulin (exubera) during discontinuation and readministration of therapy in adults with type 2 diabetes: a 3-year randomized controlled trial.

OBJECTIVE: This study assessed pulmonary safety following discontinuation and readministration of inhaled human insulin {Exubera [EXU] [Pfizer Inc., New York, NY] (insulin human [recombinant DNA origin]) inhalation powder} in adults with type 2 diabetes (T2DM). METHODS: Patients were randomized to receive EXU (n = 316) or subcutaneous (SC) insulin (n = 311) for 2 years (comparative phase), followed by 6 months of SC insulin (washout phase) and 6 months of original therapy (readministration). Highly standardized lung function tests were performed throughout all phases. RESULTS: Small, nonprogressive treatment group differences were observed to occur early during the comparative phase for parameters such as change from baseline for forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)). These differences resolved during washout and recurred to the same small magnitude during readministration. Both treatment groups maintained similar glycemic control and hypoglycemic event rates. In the EXU group, insulin antibody (IAb) levels reached a plateau at 9 months, declined to near baseline levels during washout, and increased during readministration to levels observed in the comparative phase. CONCLUSIONS: FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy were consistent with a reversible, nonprogressive, and nonstructural pathologic effect on lung function in adults with T2DM. EXU readministration was not associated with an augmented IAb response.

Safety and efficacy of inhaled human insulin (Exubera) during discontinuation and readministration of therapy in adults with type 1 diabetes: A 3-year randomized controlled trial.

OBJECTIVE: To assess pulmonary safety during discontinuation and readministration of inhaled human insulin (EXU; Exubera((R)) insulin human [rDNA origin]) Inhalation Powder) therapy in adults with type 1 diabetes. METHODS: Patients were randomized to receive basal insulin plus either pre-meal EXU (n=290) or a short-acting subcutaneous (SC) insulin (n=290) for 2 years (comparative phase), followed by 6 months of SC insulin (washout) and 6 months of their original therapy (readministration). Highly standardized lung function tests were performed throughout. RESULTS: Small treatment group differences favoring SC insulin in change from baseline forced expiratory volume in 1s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)) occurred early and were non-progressive. These differences resolved during washout and recurred at the same magnitude during readministration. Both groups maintained glycemic control, and hypoglycemic event rates were similar. In the EXU group, insulin antibody (IAb) levels plateaued at 12 months, declined to near baseline levels during washout and increased during readministration to levels observed in the comparative phase. CONCLUSIONS: FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy are consistent with a reversible, non-progressive and non-pathological effect on lung function. EXU readministration is not associated with an augmented IAb response.

Two-year safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 1 diabetes.

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 (s.c.) 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 s.c. 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 x min(-1) x mmHg(-1) x year(-1) with EXU and -0.287 +/- 0.065 ml x min(-1) x mmHg(-1) x year(-1) with s.c. insulin (nonsignificant mean difference -0.150 ml x min(-1) x mmHg(-1) x year(-1) [-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 s.c. 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 s.c. 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 s.c. insulin in adult patients with type 1 diabetes are small, develop early, and are nonprogressive for up to 2 years of therapy.