Cough 
In clinical trials, cough of mild to moderate severity was the most common pulmonary symptom associated with inhaled insulin. In a meta-analysis, cough was reported more frequently in patients receiving inhaled insulin compared with patients treated with subcutaneous insulin and/or an oral antihyperglycemic agent (16.9 versus 5%, respectively; risk ratio 3.52).  Cough generally occurred within seconds or minutes of inhaled insulin administration and was mild to moderate in severity. Cough was seen to diminish with time on therapy.11 Only 1-1.6% of trial subjects discontinued with inhaled insulin therapy due to cough.12 It has been reported that cough is not associated with an increased level of insulin antibodies.11

Forced Expiratory Volume in 1 Second 
In short-term studies of 12-24 weeks, exposure to inhaled insulin has been associated with small but consistent reductions in FEV1 compared with comparator groups treated with subcutaneous insulin and/or oral agents.13-18 The magnitude of reduction in FEV1 was similar in both type 1 and type 2 diabetes patients.

In a 12-week study on type 1 diabetes patients, inhaled insulin produced a 65ml decline in baseline FEV1 compared with 53ml in subcutaneous insulintreated patients. The decline in FEV1 occurred early and was not progressive (the slope of the FEV1 versus time curve was similar in the inhaled insulintrated group and the control group). Moreover, differences in FEV1 between the treatment groups resolved within two weeks of discontinuation of inhaled insulin.15 Similarly, in a 24-week cross-over study, small reductions in baseline FEV1 were observed within two weeks of initiating inhaled insulin therapy and were reversible upon discontinuation of therapy.¹⁸ 

The results of a longer-duration study of inhaled insulin in type 1 diabetes patients indicate that the initial reductions in FEV1 occurred within the first three months of therapy and were significantly different between treatment groups following one year of therapy (mean annual rates of decline in FEV1 following one year of therapy were -0.051l/year with inhaled insulin and -0.034l/year with subcutaneous insulin). However, this decline was not progressive. After two years of therapy, the mean annual rates of change in FEV1 were -0.041l/year and -0.031l/year in the inhaled insulin and subcutaneous insulin groups, respectively (non-significant mean difference).¹⁹ The interim analysis of a long-term study assessing pulmonary safety following discontinuation and re-administration of inhaled insulin human therapy in adults with type 1 diabetes indicates that small, nonprogressive treatment group differences in change from baseline FEV1 occurred early during the comparative phase and were resolved upon discontinuation of inhaled insulin. The patients in the study received either inhaled insulin or subcutaneous insulin for up to two years in an ongoing, open-label study (comparative phase), followed by six months of subcutaneous insulin (follow-up phase) and a six-month extension phase during which all patients received their original randomized therapy.²⁰

The FDA’s statistical review of the safety of the inhaled insulin included a pooled analysis of data from phase II and III studies for type 1 diabetes. The pooled data included data from six separate studies involving 686 adult subjects in the inhaled insulin groups and 692 subjects in the comparator subcutaneous insulin group. At years one and two, there was a significant difference in FEV1 between the inhaled insulin and comparator groups, in favor of the comparator.²¹

The effect of inhaled insulin on FEV1 has also been extensively studied in the type 2 diabetes population. In a 12-week study assessing the safety and efficacy of inhaled insulin in type 2 diabetes, there was no significant difference in small reductions in FEV1 between the inhaled insulin group and the oral-agent group.¹³ In a 24-week study, inhaled insulin was compared with subcutaneous insulin in patients with type 2 diabetes. Mean changes in FEV1 were small and comparable between the two treatment groups.¹⁴ It must be noted that within these clinical trials, dyspnea has been observed in approximately 4% of patients on the inhaled insulin Exubera compared with 3% on comparator drugs. There were a few outliers in the studies who did not show a significant drop in FEV1; in most of these cases there was the compounding influence of other factors, particularly congestive heart failure.

In two studies of longer duration, the pulmonary safety of inhaled insulin as adjunctive therapy with oral agents was assessed in type 2 diabetes patients. A pooled analysis of the data revealed that changes from baseline FEV1 were slightly larger for the inhaled insulin group compared with the oral-agent group at 24 weeks, but this difference did not increase further at 52 weeks.²² Indeed, the adjusted difference between groups decreased at 36 weeks and there was no discernable treatment group difference in FEV1 12 weeks after discontinuing two years of therapy.²³ An interim analysis of data presented at the American Diabetes Association (ADA) 67th Scientific Sessions indicates that inhaled insulin produces a small non-progressive difference in FEV1 compared with subcutaneous insulin over two years. The type 2 diabetes patients received inhaled insulin for up to two years in an ongoing, open-label study (comparative phase), followed by six months of subcutaneous insulin (follow-up phase) and a six-month extension phase during which all patients returned to their original randomized therapy. Treatment group differences occurred early during the comparative phase, were completely resolved upon discontinuation of inhaled insulin, and recurred to the same magnitude during the extension phase.²⁴

An FDA pooled analysis, which included results from eight studies involving 1,277 (inhaled insulin groups) and 1,132 (comparator groups receiving either subcutaneous insulin and/or oral antihyperglycemic agents) type 2 diabetes patients, showed that the absolute difference between inhaled insulin and comparator groups at one year was statistically different in favor of the comparator groups). At two years, the differences were comparable between groups.²¹ Thus, inhaled insulin therapy produces small, significant decrements in FEV1, with absolute differences of 44 and 41ml at one and two years, respectively, compared with comparator groups. These changes occurred early, were non-progressive, and resolved following discontinuation of inhaled insulin.