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Rapid Responses to:
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Electronic letters published:
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Rosenstock et al response to letters
Letter to editor
Is the era of insulin injections for diabetes patients drawing to a close?
Editor's Reply
Inhaled insulin and glycemic control
Curiousity about Timing of Inhaled Insulin Publication
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Julio Rosenstock, MD Dallas Diabetes and Endocrine Center, Bernard Zinman, Liam J. Murphy, Stephen C. Clement, Paul Moore, C. Keith Bowering, Rosa Hendler, Shu-Ping Lan, and William T. Cefalu.
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juliorosenstock{at}dallasdiabetes.com Julio Rosenstock, et al.
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TO THE EDITOR We would like to thank Annals readers for their interest in our paper (1) and take this opportunity to address some of the points raised in their letters. We agree that a limitation of the study was the open-label design. However, a double-blind study was not feasible for three principal reasons: (i) it was not possible to manufacture a suitable placebo for inhaled human insulin (INH), (ii) it seemed inappropriate to blind treatment when individualized flexible dose titration is needed, and (iii) given the immediate effects of INH on blood glucose, unblinding INH or placebo by patients or physicians would have been very easy. Ours was a proof-of-concept study, designed in 1998, according to good clinical practices at the time, and based on a previous study of similar design. (2) We do not believe there were any ethical issues for patients randomized to the control group as 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 with type 2 diabetes continue on oral agents rather than initiate insulin therapy despite poor glycemic control. (3) A 3-month duration was selected as a compromise between sufficient time to show an effect,(2) and minimizing exposure to hyperglycemia in the control group. Further, all subjects had the option to receive INH by enrolling in an open-label extension upon study completion. In response to concerns regarding the timing of the publication, we would like to reaffirm the Editor's Reply of 9 November 2005 and definitively state that the publication of this paper was not engineered to coincide with the FDA Advisory Committee report on Exubera. It is essential that data such as these are subject to rigorous scientific scrutiny in a peer review journal. Indeed, the paper was subject to two rounds of review by Annals over several months, which also required the submission of additional analyses and thus it would be impossible to predict if publication would coincide with the FDA Advisory Committee report. As highlighted in the associated Editorial,(4) we were also pleasantly surprised at the robust response to INH despite what might appear to be a "non-traditional" approach. Further, the effects observed with INH extended beyond the predicted pharmacokinetics with substantial improvements in fasting plasma glucose, which probably contributes to the robust effects on HbA1c reductions. Where INH could really have an impact will be if healthcare professionals and patients start to use insulin much earlier and more aggressively in adults with type 2 diabetes. The availability of INH as a treatment option has already been shown to significantly increase the proportion of patients who would theoretically choose insulin overall when failing to achieve glycemic control on diet and/or oral antidiabetic agents.(5) We agree with the viewpoint expressed in the associated Editorial,(3) in the end it will be patient acceptance and preference that will determine the future use of Exubera. 1. Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK, Hendler R, Lan SP, Cefalu WT. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2005;143:549- 558. 2. Weiss et al Weiss SR, Cheng SL, Kourides IA, Gelfand RA, Landschulz WH, for the Inhaled Insulin Phase II Study Group: Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial. Arch Intern Med 2003; 163:2277-2282. 3. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004;27:1535-1540. 4. Comi RJ. Treatment of type 2 diabetes mellitus: a weighty enigma. Ann Intern Med 2005;143:609-610. 5. Freemantle N, Blonde L, Duhot D, Hompesch M, Eggertsen R, Hobbs R, Martinez L, Ross S, Bolinder B, Striddle E. Availability of inhaled insulin promotes greater perceived acceptance of insulin therapy in patients with type 2 diabetes. Diabetes Care 2005;28:427-428. Conflict of Interest:Consultancies: Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin); Honoraria: Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin; Grants received: Merck, Pfizer Inc., sanofi-aventis, Novo Nordisk, Eli Lilly Inc., GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Sankyo, MannKind. |
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Balavenkatesh Kanna, MD, MPH Weill Medical College of Cornell University, Lincoln Hosiptal NY, Neeti Mishra
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bvkanna{at}aol.com Balavenkatesh Kanna, et al.
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In reference to the interesting study by Rosenstock et al (1), we have the following comments. The study included type 2 diabetes patients with a wide range of body mass index (BMI). In patients with type 2 diabetes, obesity is associated with poor treatment response to insulin. (2) As higher BMI may be a potential confounder of the study’s primary outcome namely change in baseline Hemoglobin A1C (HbA1C), a stratified analysis based on pre-defined BMI strata would provide valuable information regarding the effect of inhaled insulin among patients within different BMI strata. In addition, analysis of the confounding effects of dietary restriction and exercise regimen on diabetic control is also necessary. As in any open label study, performance and observation biases of the un- blinded patients receiving the new inhaled insulin treatment as well as the treatment administering investigators may have a significant impact on outcome measurements. (3) Lastly, mean outcome HbA1C levels are affected by outliers that can increase error rates and cause alteration of estimates in statistical testing. (4) Therefore, readers will be interested to view the distribution of the pre and post treatment HbA1C levels of the study groups. Conflict of Interest:None declared |
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Dr Shamsul A Bhuiyan, MD , Dr.Carlos Javier Mencias Vera, MD, Dr. Shahabuddin Haq, MBBS
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drshamsul44{at}yahoo.com Dr Shamsul A Bhuiyan, et al.
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Probably not, at least not yet. Even so, some researchers exploring alternative delivery systems believe that inhaled insulin is now on the fast track and could emerge as a viable, noninvasive avenue for administering insulin. We found this study (by Julio Rosenstock et al) encouraging. Rosenstock et al. reported that inhaled insulin improved overall glycemic control and hemoglobin A1C (HbA1c) level in patients with type 2 diabetes when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer. There was little unclear point about this study, At the bottom author Julio Rosenstock et al mentioned that, a preliminary report of this study was submitted to the American Diabetes Association 62nd Annual Meeting and Scientific Sessions, San Francisco, California, 14–18 June 2002. This means that this article is published after 3 years. This is confusing! We are disappointed by the design of the study and wonder about the editors’ decision to publish it at this time. Study method would be more appropriate if it was double blinded and one group of patient taking placebo inhaler, while other group taking insulin inhaler. Duration of study is really short, which is not encouraging to see long- term control of glycemic effect. Only use of inhaler insulin would give more accurate conclusion. For more than 80 years, patients with type 1 and type 2 diabetes have relied on subcutaneous injections as the route for exogenous insulin administration. But inhaled intrapulmonary delivery of insulin appears to be a promising option and perhaps a way to maintain glycemic control without the need for injections before meals. Although inhaled insulin is not a new idea—it was first suggested in the 1920s—encouraging findings from recent studies, including phase 3 trials, captured considerable attention at the American Diabetes Association’s (ADA’s) 65th Scientific Sessions(1). Another study (2) was done 1993 at Johns Hopkins University School of Hygiene and Public Health where they found that approximately 1.0 U of aerosolized insulin per kilogram of body weight, delivered by oral inhalation and deposited predominantly within the lungs, is well tolerated and can effectively normalize plasma glucose levels in patients with NIDDM. In conclusion I would like to say that Rosenstock et al study will encourage more other researchers about the inhaled insulin use in diabetes patients. Reference: 1. Richard Trubo Interest in Inhaled Insulin Grows JAMA, September 14, 2005; 294: 1195 - 1196. 2. B. L. Laube; A. Georgopoulos; G. K. Adams 3rd Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients JAMA, Apr 1993; 269: 2106 - 2109. Conflict of Interest:None declared |
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Harold Sox, MD, FACP American College of Physicians
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annals{at}acponline.org Harold Sox
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As a matter of editorial policy, we avoid doing anything that people would interpret as collusion with a commercial company to draw attention to their product. In this case, we knew that the FDA had not yet approved inhaled insulin, but we had no idea when it would announce its decision. We could not and did not engineer the publication date to coincide with the FDA announcement. Conflict of Interest:None declared |
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Yujiro Kida, MD, PhD Department of Anatomy II, Tsurumi University, School of Dental Medicine, Tetsuji Sato, DMD, PhD
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kida-yujiro{at}tsurumi-u.ac.jp Yujiro Kida, et al.
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Rosenstock et al. reported that inhaled insulin improved overall glycemic control and hemoglobin A1c (HbA1c) level in patients with type 2 diabetes when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer (1). As Comi RJ pointed out in editorial (2), it is very surprising that HbA1c level decreased from 9.3% to 7.9% in the patients using inhaled insulin alone without prescribing intermediate- or long- acting insulin. Although premeal inhaled insulin regimen replace intrinsic prandial insulin, intrinsic basal insulin secretion would not be restored by the regimen of Rosenstock and coworkers, because inhaled insulin act for 4 to 6 hours. Although the authors did not mention, it would often happen nocturnal hyperglycemia by their regimen. UKPDS showed that beta-cell failure is progressive; 50%of normal beta-cell function at diagnosis with a steady decline following diagnosis (3). Concomitantly, 53% of patients with type 2 diabetes initially treated with sulfonylureas required insulin therapy by 6 years, and almost 80% required insulin by 9 years (4). In the study by Rosenstock and colleagues, mean duration of diabetes in eligible patients was 9 to 10 years (1). Therefore, it is problem ethically that Rosenstock et al. set the group receiving only dual oral agent in spite of poor glycemic control, even if the study duration was 12 weeks. Conflict of Interest:None declared |
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Lorraine Tosiello, MD Overlook Hospital, Summit NJ, Priya Ravi, MD
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lorraine.tosiello{at}ahsys.org Lorraine Tosiello, et al.
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November 2, 2005 To the Editors: Like many general internists we have had our interest piqued about inhaled insulin for several years, with data eking out slowly, largely thru endocrinologic publications and meetings. So, we were delighted to see the issue addressed recently in “our journal”(1). However, after reading the article, we were disappointed by the design of the study and wonder about the editors’ decision to publish it at this time. Our concerns about the methodology include the following issues. First, there is a lack of blinding, which could introduce conscious and unconscious biases and could have been avoided by having a placebo inhaler for the group remaining on their oral agents. Second, the “control group” was clearly failing their regimen. A more rigorous arm of the study would have been to compare the clinical standard of care (ie: comparison to an added dose of intermediate acting insulin at bedtime.) Finally, the duration of the study is so short that it neither assuages our worries about metabolic worsening due to longterm insulin therapy nor our concern about pulmonary outcomes. The study as designed shows that in patients failing their oral regimen for Type 2 diabetes, the addition or substitution of insulin (in the innovative inhaled form) effects impressive short term glucose control. Most clinicians have been aware of the efficacy of insulin in this setting, but opt for insulin as a last resort specifically because of the metabolic issues of hyperinsulinemia and weight gain. We couldn’t help but note that the study was conducted 7 years ago (troglitazone could be part of the dual regimen) and also that the publication date of October 18, 2005 coincided with the FDA deliberations regarding approval for inhaled insulin. Could the anticipated media interest surrounding the FDA decision have influenced the editors’ enthusiasm for publishing the article at this time? Sincerely, Lorraine Tosiello, MD, FACP Priya Ravi, MD Department of Internal Medicine Overlook Hospital, Summit, NJ (1). Rosenstock J, Zinman B, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes. Ann Int Med. 2005;143:549-558. Conflict of Interest:None declared |
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