We thank Prof. Chantelau (1) for his inquiry about serum free insulin levels in our study (2). Free insulin levels were measured in the fasting state (i.e., before trial drug administration) at baseline and at weeks 12 and 24. These free insulin levels (resulting from both the constant intravenous insulin infusion that was maintained throughout the in-patient study days as well as any residual concentration remaining from the previous dose of subcutaneous or inhaled insulin) did not show changes from baseline to posttreatment values (mean of weeks 12 and 24) with either treatment (median baseline 16.6, 16.4; posttreatment 18.0, 18.4 uU/ml; inhaled and subcutaneous insulin, respectively).

Free insulin concentrations would not be expected to reconcile the lack of glucose changes observed in this study with pharmacokinetic changes observed in previous studies cited by Prof. Chantelau. In fact, the referenced investigations not only showed relationships between antibodies and free insulin levels, but also with postprandial glucose and other pharmacodynamic parameters (36). If insulin levels showed changes in the absence of glucodynamic consequences, the significance and/or accuracy of the insulin data would necessarily be called into question.

We also do not agree that use of the euglycemic clamp technique is the reason no glucodynamic correlates with insulin antibodies were demonstrated in our study. Importantly, the primary end point of the study, postprandial glucose, was not measured with the glucose clamp technique. Furthermore, the clamp technique is precise enough to determine glucodynamic changes secondary to insulin antibodies as was in fact demonstrated in one of the studies cited by Prof. Chantelau (6). We agree with others that the euglycemic clamp technique is the gold standard for assessment of pharmacodynamic responses to insulin (7, 8).

The difference in glucodynamic results from this study compared with others may be related to methodologic differences (including prospective study design and optimization of test drug doses for test meal), as well as the ranges of insulin antibody levels achieved (as discussed in our article). Nevertheless, the results of this study show that insulin antibody levels measured prospectively during treatment with inhaled insulin are not associated with relevant changes in insulin pharmacodynamics or with adverse clinical effects.

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