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
Note: 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.
Acknowledgments: The authors thank the investigators (Appendix 2) and coordinators who participated in this study and the General Clinical Research Center, MO1 RR 00125, Yale University.
Grant Support: By a research grant from Pfizer Inc. and the sanofi-aventis Group. The study was conducted by investigators and their institutions contracted by and under the direction of the sponsors (Pfizer Global Research and Development and the sanofi-aventis Group). The investigators were responsible for recruiting patients, adhering to the study procedures described in the protocol, keeping records of study drug, capturing and recording data, and accurately completing and signing the case report forms supplied by the sponsors.
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.).
Requests for Single Reprints: Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center, 7777 Forest Lane, Suite C618, Medical City Dallas, Dallas, TX 75230; e-mail, email@example.com.
Current Author Addresses: Dr. Rosenstock: Dallas Diabetes and Endocrine Center, 7777 Forest Lane, Suite C618, Medical City Dallas, Dallas, TX 75230.
Dr. Zinman: Department of Medicine, Mount Sinai Hospital, L 5-024, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Dr. Murphy: Department of Internal Medicine, University of Manitoba, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R8, Canada.
Dr. Clement: Department of Endocrinology, Georgetown University Hospital, Building D, Room 232, 4000 Reservoir Road NW, Washington, DC 20007.
Dr. Moore: Austin Diagnostic Clinic, 12221 MoPac Expressway North, 2nd Floor, South Entrance, Austin, TX 78758-2483.
Dr. Bowering: Multidisciplinary Diabetic Foot Clinic, Royal Alexandra Hospital, 10240 Kingsway Avenue, Edmonton, Alberta T5H 3V9, Canada.
Dr. Hendler: Department of Internal Medicine, Yale University School of Medicine, Fitkin 1, 333 Cedar Street, PO Box 208020, New Haven, CT 06520-8020.
Ms. Lan: Pfizer Inc., MS 6025-A4269, 50 Pequot Avenue, New London, CT 06320.
Dr. Cefalu: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808.
Author Contributions: Conception and design: J. Rosenstock, B. Zinman.
Analysis and interpretation of the data: J. Rosenstock, B. Zinman, S.-P. Lan.
Drafting of the article: J. Rosenstock, W.T. Cefalu.
Critical revision of the article for important intellectual content: J. Rosenstock, B. Zinman, L.J. Murphy, P. Moore, C.K. Bowering, R. Hendler, S.-P. Lan, W.T. Cefalu.
Final approval of the article: J. Rosenstock, B. Zinman, L.J. Murphy, S.C. Clement, P. Moore, C.K. Bowering, R. Hendler, W.T. Cefalu.
Provision of study materials or patients: J. Rosenstock, B. Zinman, L.J. Murphy, S.C. Clement, P. Moore, C.K. Bowering, R. Hendler, W.T. Cefalu.
Statistical expertise: S.-P. Lan.
Obtaining of funding: J. Rosenstock, B. Zinman.
Administrative, technical, or logistic support: J. Rosenstock, B. Zinman.
Collection and assembly of data: J. Rosenstock, S.C. Clement, B. Zinman.
Patients with type 2 diabetes who do not achieve glycemic control with oral agent therapy eventually require insulin.
To determine the effect on glycemic control of inhaled insulin alone or added to dual oral therapy (insulin secretagogue and sensitizer) after failure of dual oral therapy.
Open-label, randomized, controlled trial.
48 outpatient centers in the United States and Canada.
309 patients with type 2 diabetes, no clinically significant respiratory disease, and hemoglobin A1c level of 8% to 11% who were receiving dual oral therapy.
Primary end point was change in hemoglobin A1c level from baseline to 12 weeks. Secondary outcomes included hemoglobin A1c level less than 8% and less than 7%, hypoglycemia, weight, lipid levels, pulmonary function, insulin antibody binding, and adverse events.
Inhaled insulin (Exubera; Pfizer Inc. [New York, New York], sanofi-aventis Group [Paris, France], and Nektar Therapeutics [San Carlos, California]), titrated to blood glucose, administered alone (n = 104) or added to dual oral agents (n = 103) versus oral therapy alone (n = 99).
Reductions in hemoglobin A1c level were greater with inhaled insulin. Adjusted treatment group differences for inhaled insulin plus oral agents and inhaled insulin alone compared with continued oral agent therapy were −1.67 percentage points (95% CI, −1.90 to −1.44 percentage points; P < 0.001) and −1.18 percentage points (CI, −1.41 to −0.95 percentage point; P < 0.001), respectively. Hemoglobin A1c level less than 7% was achieved by 32% (inhaled insulin plus oral agents) and by 1% (oral agent therapy) of patients (adjusted odds ratio, 44.7 [CI, 6.0 to 335.2]). Hypoglycemia, mild weight gain, mild cough, and insulin antibodies were more frequent with inhaled insulin than with oral agent therapy alone. Pulmonary function was similar in all groups.
This study evaluated only patients with hemoglobin A1c levels of 8% to 11%, did not compare inhaled insulin with other insulins or oral therapy except a dual regimen of secretagogue and sensitizer, and lasted only 12 weeks.
Inhaled insulin improved overall glycemic control and hemoglobin A1c level when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer. Consistent with other insulin therapies, hypoglycemia and mild weight gain occurred. Pulmonary function showed no between-group differences.
Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK, 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. doi: 10.7326/0003-4819-143-8-200510180-00005
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Published: Ann Intern Med. 2005;143(8):549-558.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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