Correspondence

Inhaled Insulin for Diabetes Mellitus

N Engl J Med 2007; 356:2106-2108May 17, 2007

Article

To the Editor:

An important uncertainty about treatment with inhaled insulin is the potentially increased risk of lung cancer. In their Clinical Therapeutics article on inhaled insulin for diabetes mellitus, McMahon and Arky (Feb. 1 issue)1 report that short-term studies in animals have not shown a substantial effect on cell-proliferation indexes in the alveolar or bronchiolar areas of the lung. This is not quite correct. One of the short-term studies reports an increased rate of mitosis induced by inhaled insulin in rats.2

Presumably in response to this finding, Pfizer, the manufacturer of a dry-powder formulation of human insulin, proposed to conduct a 12-year prospective study “to compare lung cancer mortality between INH [inhaled insulin]–treated and non–INH-treated patients.”3 However, the rate of lung cancer depends on the rate of smoking 20 years earlier. It is therefore highly unlikely that we can expect a reliable result within 12 years.

McMahon and Arky report that “insulin acts as a weak growth factor when it binds to the type 1 insulin-like growth factor receptor.”1 It also can have a mitogenic effect mediated by its own receptors, especially if — like the insulin used for inhalation — it has a long average residence time at the receptor.4 Only 25% of the dose deposited in the lung is absorbed.1 This necessarily leads to high insulin concentrations in the alveolar and bronchiolar tissue. Studies of human bronchial epithelial cells suggest that insulin-receptor activation is in itself insufficient for malignant transformation. The insulin-receptor pathway, however, is thought to promote malignant progression of these cells once malignant transformation has been induced by other agents.5

Informing patients about the “unknown long-term adverse effects of this form of therapy”1 is not sufficient. One should point out that lung cancer has not been ruled out as one of the possible side effects. Only with this information do patients have the opportunity to make an informed choice of treatment.

Ernst von Kriegstein, M.D.
Lyraweg 1, D-29549 Bad Bevensen, Germany
ernst@kriegstein.de

Katharina von Kriegstein, M.D.
University College London, London WC1N 3BG, United Kingdom

Dr. E. von Kriegstein reports receiving consulting fees from Berlin-Chemie. No other potential conflict of interest relevant to this letter was reported.

5 References

1
McMahon GT, Arky RA. Inhaled insulin for diabetes mellitus. N Engl J Med 2007;356:497-502
Full Text | Web of Science | Medline

2
EMEA scientific discussion. London: European Medicines Agency, 2006. (Accessed April 17, 2007, at http://www.emea.eu.int/humandocs/PDFs/EPAR/exubera/058806en6.pdf.)

3
Pfizer. Advisory committee briefing document: EXUBERA. (Accessed April 17, 2007, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B1_01_01-Pfizer-Exubera.pdf.)

4
Shymko RM, Dumont E, De Meyts P, Dumont JE. Timing-dependence of insulin-receptor mitogenic versus metabolic signalling: a plausible model based on coincidence of hormone and effector binding. Biochem J 1999;339:675-683
CrossRef | Web of Science | Medline

5
Zhao YJ, Piao CQ, Wu LJ, Suzuki M, Hei TK. Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism. Carcinogenesis 2000;21:2005-2010
CrossRef | Web of Science | Medline

To the Editor:

McMahon and Arky do not recommend inhaled insulin in patients with asthma or chronic obstructive pulmonary disease because of unpredictable absorption. More important concerns may be an increased risk of airway smooth-muscle contraction that is dependent on the insulin concentration and significantly increased production of prostaglandin, especially prostaglandin F₂α.1 Whether such contraction precipitates or exacerbates chronic obstructive pulmonary disease or episodes of asthma is not known, but it represents a potential risk.

Another possible factor that eventually modifies the pharmacokinetics of inhaled insulin is the change in tidal-volume ventilation. In one experimental model,2 an increase in insulin absorption oscillating between 106 and 149% was observed when ventilation was achieved with use of different tidal volumes. For these reasons, the use of subcutaneous insulin is more prudent in these patients.

Cesar Augusto Guevara, M.D.
University of Valle, 25360 Cali, Colombia

2 References

1
Schaafsma D, Gosens R, Ris JM, Zaagsma J, Meurs H, Nelemans SA. Insulin induces airway smooth muscle contraction. Br J Pharmacol 2007;150:136-142
CrossRef | Web of Science | Medline

2
Petersen AH, Laursen T, Ahren B, Pieber TR, Clauson P, Wollmer P. The impact of large tidal volume ventilation on the absorption of inhaled insulin in rabbits. Eur J Pharm Sci 2007;30:351-357
CrossRef | Web of Science | Medline

To the Editor:

In regard to the case vignette in the article by McMahon and Arky: using basal insulin at bedtime to manage an elevated fasting blood glucose concentration is not necessarily the most appropriate decision. The relative contribution of postprandial hyperglycemia is about 50% in patients with a glycated hemoglobin value of 8.6%.1 As compared with basal insulin, preprandial lispro has a greater effect on metabolic control.2 One study showed that in patients in whom two oral agents were not effective, inhaled insulin resulted in a 1.7 percentage point mean reduction in glycated hemoglobin,3 which is similar to the reduction reported after the addition of basal insulin in patients in whom one or two oral agents were not effective.4 Furthermore, inhaled insulin induces a greater decrease in fasting plasma glucose concentrations than does short-acting insulin administered subcutaneously before meals.5 Finally, I would be concerned about keeping the thiazolidinedione because of an increased risk of fluid retention and heart failure in association with insulin and because there are no data providing support for this approach. The addition of inhaled insulin before meals with continued use of metformin and sulfonylurea seems to be a more rational and scientifically based decision and would be more acceptable to the patient.

Jorge L. Gross, M.D.
Hospital de Clínicas de Porto Alegre, 90035-903 Porto Alegre, Brazil
jorgegross@terra.com.br

Dr. Gross reports receiving consulting and lecture fees from Sanofi-Aventis, lecture fees from Novo Nordisk, and lecture fees and grant support from Merck Sharp & Dohme and Pfizer. No other potential conflict of interest relevant to this letter was reported.

5 References

1
Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 2003;26:881-885
CrossRef | Web of Science | Medline

2
Bastyr EJ III, Stuart CA, Brodows RG, et al. Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. Diabetes Care 2000;23:1236-1241
CrossRef | Web of Science | Medline

3
Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized control trial. Ann Intern Med 2005;143:549-558
Web of Science | Medline

4
Riddle M, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-3086
CrossRef | Web of Science | Medline

5
Rosenstock J, Foyt H, Klioze S, Ogawa M, St Aubin L, Duggan W. Inhaled human insulin (Exubera) therapy shows sustained efficacy and is well tolerated over a 2-year period in patients with type 2 diabetes (T2DM). Diabetes 2006;55:Suppl 1:A26-A26
Web of Science

To the Editor:

Although much effort has been devoted to understanding the use of oral inhalation of insulin in diabetes mellitus, the presence of insulin1 and insulin receptors2 in nasal mucus and their relationship to insulin in other body fluids in diabetes mellitus has only recently been discovered. Although my colleagues and I can offer no therapeutic data, our studies suggest that nasal inhalation of insulin may be a useful alternative to oral inhalation of the drug. This technique does not simply involve a change of orifice. It may offer a more effective delivery system. Our studies suggest that a complex feedback system exists between insulin in nasal mucus and the blood–brain barrier,2 such that nasal inhalation of insulin can affect insulin metabolism in the brain.

Robert I. Henkin, M.D., Ph.D.
Center for Molecular Nutrition and Sensory Disorders, Washington, DC 20016
doc@tasteandsmell.com

2 References

1
Velicu I, Henkin RI. Insulin is present in human saliva and nasal mucus. J Investig Med 2006;54:S385-S385
CrossRef | Web of Science

2
Henkin RI, Velicu I. Insulin receptors as well as insulin are present in saliva and nasal mucus. J Investig Med 2006;54:S378-S378
Web of Science

Author/Editor Response

The comments of von Kriegstein and von Kriegstein remind us of the need to offer our patients a balanced presentation of the possible risks and benefits before initiating treatment with inhaled insulin. We acknowledge that it is premature to be confident that there is no association between inhaled insulin and bronchial cancer. We agree with Guevara that patients with obstructive airway disease or asthma should not be treated with inhaled insulin until its safety has been demonstrated in clinical trials. For these reasons, prescribers will need to carefully examine the suitability of inhaled insulin for each patient.

Further research will be required before the safety of the approach suggested by Gross can be ensured. Basal insulin once daily and inhaled insulin thrice daily may be equally efficacious in reducing glycated hemoglobin concentrations; however, inhaled insulin is associated with a substantially higher risk of hypoglycemia.1,2 Current standards of care reserve preprandial insulin for patients with type 2 diabetes who do not reach their glycemic goal while being treated with a basal insulin.3

For a patient who is receiving a basal insulin, a decision to prescribe inhaled insulin rather than a subcutaneous short-acting insulin must be considered in the context of the paucity of long-term safety data and an awareness of the additional cost. Evidence provides support for the combination of basal insulin with a thiazolidinedione.4

We hope that researchers such as Henkin will continue to develop oral, buccal, transcutaneous, and nasal insulin formulations; other inhaled insulin preparations are being evaluated in advanced clinical trials. It is possible that these and other developments will ultimately help improve the management of diabetes for a growing population of patients who deserve the best evidence-based medicine available.

Graham T. McMahon, M.D., M.M.Sc.
Ronald A. Arky, M.D.
Harvard Medical School, Boston, MA 02115
gmcmahon@partners.org

4 References

1
Rosenstock J, Zinman B, Murphy LJ, et al. 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
Web of Science | Medline

2
Riddle M, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-3086
CrossRef | Web of Science | Medline

3
Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963-72. [Diabetes Care 2006;29:2816-8.]

4
Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;24:1226-1232
CrossRef | Web of Science | Medline

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