Two-year pulmonary safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 2 diabetes

Julio Rosenstock, William T Cefalu, Priscilla A Hollander, Andre Belanger, Freddy G Eliaschewitz, Jorge L Gross, Solomon S Klioze, Lisa B St Aubin, Howard Foyt, Masayo Ogawa, William T Duggan, Julio Rosenstock, William T Cefalu, Priscilla A Hollander, Andre Belanger, Freddy G Eliaschewitz, Jorge L Gross, Solomon S Klioze, Lisa B St Aubin, Howard Foyt, Masayo Ogawa, William T Duggan

Abstract

Objective: The purpose of this study was to evaluate the 2-year pulmonary safety of inhaled human insulin (Exubera [EXU]) in 635 nonsmoking adults with type 2 diabetes.

Research design and methods: Patients were randomly assigned to receive prandial EXU or subcutaneous insulin (regular or short-acting) plus basal (intermediate- or long-acting) insulin. The primary end points were the annual rate of decline in forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)).

Results: Small differences in FEV(1) favoring subcutaneous insulin developed during the first 3 months but did not progress. Adjusted treatment group differences in FEV(1) annual rate of change were -0.007 l/year (90% CI -0.021 to 0.006) between months 0 and 24 and 0.000 l/year (-0.016 to 0.016) during months 3-24. Treatment group differences in DL(CO) annual rate of change were not significant. Both groups sustained similar reductions in A1C by month 24 (last observation carried forward) (EXU 7.7-7.3% vs. subcutaneous insulin 7.8-7.3%). Reductions in fasting plasma glucose (FPG) were greater with EXU than with subcutaneous insulin (adjusted mean treatment difference -12.4 mg/dl [90% CI -19.7 to -5.0]). Incidence of hypoglycemia was comparable in both groups. Weight increased less with EXU than with subcutaneous insulin (-1.3 kg [-1.9 to -0.7]). Adverse events were comparable, except for a higher incidence of mild cough and dyspnea with EXU.

Conclusions: Two-year prandial EXU therapy showed a small nonprogressive difference in FEV(1) and comparable sustained A1C improvement but lower FPG levels and less weight gain than seen in association with subcutaneous insulin in adults with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00136916.

Figures

Figure 1
Figure 1
Mean change in FEV1 (A) and DLCO (B) from baseline. Treatment group difference: EXU − subcutaneous insulin (SC).
Figure 2
Figure 2
Adjusted mean adjusted change in A1C (A), FPG (B), and body weight (C) from baseline.

References

    1. DeFronzo RA, Bergenstal RM, Cefalu WT, Pullman J, Lerman S, Bode BW, Phillips LS, Exubera Phase III Study Group: Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise. Diabetes Care 28:1922–1928, 2005
    1. Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering K, Hendler R, Lan S-P, 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 143:549–558, 2005
    1. Barnett AH, Dreyer M, Lange P, Serdarevic-Pehar M: An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with metformin as adjunctive therapy in patients with type 2 diabetes poorly controlled on a sulfonylurea. Diabetes Care 29:1282–1287, 2006
    1. Barnett AH, Dreyer M, Lange P, Serdarevic-Pehar M: An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with glibenclamide as adjunctive therapy in patients with type 2 diabetes poorly controlled on metformin. Diabetes Care 29:1818–1825, 2006
    1. Barnett AH, Dreyer M, Lange P, Serdarevic-Pehar M, Exubera Phase 3 Study Group: Long-term tolerability of inhaled human insulin (Exubera) in patients with poorly controlled type 2 diabetes. Int J Clin Pract 61:1614–1625, 2007
    1. Hollander PA, Blonde L, Rowe R, Mehta AE, Milburn JL, Hershon KS, Chiasson J-L, Levin SR, for the Exubera Phase 3 Study Group: Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 27:2356–2362, 2004
    1. Jensen RL, Teeter JG, England RD, Howell HM, White HJ, Pickering EH, Crapo RO: Sources of long-term variability in measurements of lung function: implications for interpretation and clinical trial design. Chest 132:396–402, 2007
    1. Jensen RL, Teeter JG, England RD, Howell HM, White HJ, Pickering EH, Crapo RO: Instrument accuracy and reproducibility in measurements of pulmonary function. Chest 132:388–395, 2007
    1. MacIntyre N: Finding signals amidst the noise in pulmonary function testing. Chest 132:367–368, 2007
    1. Wise RA, Teeter JG, Jensen RL, England RD, Schwartz PF, Ahrens RC, MacIntyre NR, Riese RJ, Crapo RO: Standardization of the single-breath diffusing capacity in a Multicenter Clinical Trial. Chest 132:1191–1197, 2007
    1. Hankinson JL, Odencrantz JR, Fedan KB: Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 159:179–187, 1999
    1. Crapo RO, Morris AH, Clayton PD, Nixon CR: Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir 18:419–425, 1982
    1. Miller A, Thornton JC, Warshaw R, Anderson H, Teirstein SA, Selikoff IJ: Single breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state. Am Rev Respir Dis 127:270–277, 1983
    1. American Thoracic Society: Standardization of Spirometry, 1994 update. Am J Respir Crit Care Med 152:1107–1136, 1995
    1. American Thoracic Society: Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique—1995 update. Am J Respir Crit Care Med 152:2185–2198, 1995
    1. Mahler DA, Weinberg DH, Wells CK, Feinstein AR: The measurement of dyspnea: contents, interobserver agreement, and physiologic correlations of two new clinical indices. Chest 85:751–758, 1984
    1. Skyler JS, Jovanovic L, Klioze S, Reis J, Duggan W, Inhaled Human Insulin Type 1 Diabetes Study Group: Two year safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 1 diabetes mellitus. Diabetes Care 30:579–585, 2007
    1. Fletcher C, Peto R: The natural history of chronic airflow obstruction. BMJ 1:1645–1648, 1977
    1. Dockery DW, Ware JH, Ferris BG Jr, Glicksberg DS, Fay ME, Spiro A 3rd, Speizer FE: Distribution of forced expiratory volume in one second and forced vital capacity in healthy, white, adult, never-smokers in six U.S. cities. Am Rev Respir Dis 131:511–520, 1985
    1. Ryan G, Knuiman M, Divitini ML, Ryan G, Bartholomew HC, Musk AW: Decline in lung function and mortality: the Busselton Health Study. J Epidemiol Community Health 53:230–234, 1999
    1. Davis WA, Knuiman M, Kendall P, Grande V, Davis TME: Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care 27:752–757, 2004
    1. Weynand B, Jonckheere A, Frans A, Rahier J: Diabetes mellitus induces a thickening of the pulmonary basal lamina. Respiration 66:14–19, 1999
    1. Farina J, Furio V, Fernandez-Acenero MJ, Muzas MA: Nodular fibrosis of the lung in diabetes mellitus. Virchows Arch 427:61–63, 1995
    1. Hisa CC, Raskin P: Lung function changes related to diabetes mellitus. Diabetes Technol Ther 9(Suppl. 1):S73–S82, 2007
    1. Witek TJ, Mahler DA: Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 56:248–255, 2003
    1. Fineberg SE, Kawabata T, Finco-Kent D, Liu C, Krasner A: Antibody response to inhaled insulin in patients with type 1 or type 2 diabetes. An analysis of initial phase II and III inhaled insulin (Exubera) trials and a two-year extension trial. J Clin Endocrinol Metab 90:3287–3293, 2005
    1. Heise T, Bott S, Tusek C, Stephan J-A, Kawabata T, Finco-Kent D, Liu C, Krasner A: The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin: a prospective randomized pharmacodynamic study. Diabetes Care 28;2161–69, 2005
    1. Teeter JG, Riese RJ: Dissociation of lung function changes with humoral immunity during inhaled human insulin therapy. Am J Respir Crit Care Med 173:1194–1200, 2006

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa