Julio Rosenstock, MD; Bernard Zinman, MD; Liam J. Murphy, MD; Stephen C. Clement, MD; Paul Moore, MD; C. Keith Bowering, MD; Rosa Hendler, MD; Shu-Ping Lan, MPH; William T. Cefalu, MD
Potential Financial Conflicts of Interest: Employment: S.-P. Lan (Pfizer Inc.); Consultancies: J. Rosenstock (Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin), B. Zinman (Eli Lilly Inc., sanofi-aventis, Pfizer Inc.), C.K. Bowering (Eli Lilly Inc., GlaxoSmithKline, Novo Nordisk, AstraZeneca); W.T. Cefalu (sanofi-aventis, Pfizer Inc.); Honoraria: J. Rosenstock (Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin), B. Zinman (Eli Lilly Inc., sanofi-aventis, Pfizer Inc.), L.J. Murphy (Eli Lilly Inc., Pfizer Inc., GlaxoSmithKline, sanofi-aventis); C.K. Bowering (Eli Lilly Inc., GlaxoSmithKline, Novo Nordisk, AstraZeneca, Pfizer Inc., sanofi-aventis), W.T. Cefalu (sanofi-aventis, Pfizer Inc.); Stock ownership or options (other than mutual funds): S.-P. Lan (Pfizer Inc.); Grants received: J. Rosenstock (Merck, Pfizer Inc., sanofi-aventis, Novo Nordisk, Eli Lilly Inc., GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Sankyo, MannKind), B. Zinman (Pfizer Inc.), S.C. Clement (Pfizer Inc.), C.K. Bowering (GlaxoSmithKline, AstraZeneca, Pfizer Inc., sanofi-aventis), R. Hendler (Pfizer Inc.), W.T. Cefalu (Pfizer Inc.).
Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK, et al. Efficacy and Safety of Inhaled Insulin Therapy. Ann Intern Med. 2006;144:533-534. doi: 10.7326/0003-4819-144-7-200604040-00019
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Published: Ann Intern Med. 2006;144(7):533-534.
We agree that a limitation of our study was the open-label design. However, a double-blind study was not feasible because 1) it was not possible to manufacture a suitable placebo for inhaled human insulin, 2) it seemed inappropriate to blind treatment when individualized flexible-dose titration is needed, and 3) patients or physicians would have very easily unblinded the placebo or inhaled insulin because of the latter's immediate effect on blood glucose levels.
Ours was a proof-of-concept study that was designed in 1998 according to good clinical practices at the time and was based on a previous study of similar design (1). We do not believe there were any ethical issues for patients who were randomly assigned to the control group because microvascular complications are associated with long-term hyperglycemia, and there is no evidence that a relatively short period of inadequate glucose control will have a deleterious effect. The reality is that many patients who have type 2 diabetes with poor glycemic control continue to take oral agents instead of initiating insulin therapy (2). We continued the study for 3 months to provide sufficient time to show an effect (1) while minimizing the control group's exposure to hyperglycemia. Furthermore, all participants had the option of receiving inhaled human insulin by enrolling in an open-label extension of the trial.
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