Inhaled Technosphere® Insulin in Comparison to Subcutaneous Regular Human Insulin: Time Action Profile and Variability in Subjects with Type 2 Diabetes

Background: This study assessed time action profile and within- and between-subject variability of inhaled Technosphere® Insulin (TI) compared with subcutaneous regular human insulin (sc RHI). Methods: Thirteen subjects with type 2 diabetes (age 56 ± 7 years, body mass index 30.4 ± 3.0 kgm−2; hemoglobin A1c 6.9 ± 0.9%; mean ± SD) participated in this six-period crossover isoglycemic glucose clamp study. In randomized order, each subject received three single doses of TI and sc RHI on separate study days. Results: Inhalation of TI resulted in a higher maximum serum insulin concentration (858 vs 438 pmol·liter−1; p = 0.0001) and shorter intervals to maximum insulin concentration (17 vs 135 minutes; p = 0.0001) than sc RHI. Overall, 48 units of TI and 24 units of sc RHI provided comparable 3-hour insulin exposure (INS area under the curve0–3 h55.8 vs 60.0 nmol·min·liter−1, respectively). Time to maximum metabolic effect was shorter (79 vs 293 minutes; p < 0.0001), and percentage of glucose disposal during the first 3 hours was higher for TI compared with sc RHI (59 vs 27%). Within-subject variabilities of insulin exposure following inhalation of TI for 2 and 3 hours and end of study period were 19, 18, and 16% as compared with 27, 25, and 15% after sc RHI injection (p = not significant). Conclusion: Technosphere Insulin has a more rapid onset of action than sc RHI. About 60% of the glucose-lowering effect of TI occurs during the first 3 hours after application. In contrast, <30% of the glucose-lowering effect of sc RHI occurs in this period. Technosphere Insulin demonstrated a lower intrasubject variability during the 3-hour postprandial period, without reaching statistical significance.

[1]  T. Forst,et al.  Pulmonary insulin delivery by means of the Technosphere™ drug carrier mechanism , 2005, Expert opinion on drug delivery.

[2]  P. Home.  Contributions of basal and post-prandial hyperglycaemia to micro- and macrovascular complications in people with type 2 diabetes , 2005, Current medical research and opinion.

[3]  H Gin,et al.  Reproducibility and variability in the action of injected insulin. , 2005, Diabetes & metabolism.

[4]  王姮,et al.  Inhaled insulin , 2005 .

[5]  L. Heinemann,et al.  Review: Current status of the development of inhaled insulin , 2004 .

[6]  T. Heise,et al.  Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin. , 2004, Diabetes technology & therapeutics.

[7]  S. Mudaliar,et al.  Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes. , 2003, Diabetes care.

[8]  A. Ceriello.  The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications , 2003, Diabetologia.

[9]  L. Heinemann,et al.  Absorption and metabolic effect of inhaled insulin: intrapatient variability after inhalation via the Aerodose insulin inhaler in patients with type 2 diabetes. , 2002, Diabetes care.

[10]  J. Tuomilehto,et al.  Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. , 2002, European heart journal.

[11]  L. Heinemann,et al.  Rapid and long-acting analogues as an approach to improve insulin therapy: an evidence-based medicine assessment. , 2001, Current pharmaceutical design.

[12]  M. Ellmerer,et al.  Dose-response relation of liquid aerosol inhaled insulin in Type I diabetic patients , 2001, Diabetologia.

[13]  M. Hanefeld,et al.  Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. , 2000, Diabetes care.

[14]  L. Heinemann,et al.  Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer. , 2000, Diabetes care.

[15]  L. Bouter,et al.  Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study , 1999, Diabetologia.

[16]  M. Hanefeld,et al.  Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals. , 1999, Atherosclerosis.

[17]  L. Heinemann,et al.  Time–action Profile of Inhaled Insulin , 1997, Diabetic medicine : a journal of the British Diabetic Association.

[18]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[19]  P Hildebrandt,et al.  Subcutaneous absorption of insulin in insulin-dependent diabetic patients. Influence of species, physico-chemical properties of insulin and physiological factors. , 1991, Danish medical bulletin.

[20]  J. Davidson,et al.  Factors Influencing the Absorption, Serum Insulin Concentration, and Blood Glucose Responses After Injections of Regular Insulin and Various Insulin Mixtures , 1981, Diabetes Care.

[21]  Inhaled Insulin as alternative delivery system for subjects with diabetes – A literature review , 2009 .

[22]  J. Patton,et al.  The lungs as a portal of entry for systemic drug delivery. , 2004, Proceedings of the American Thoracic Society.

[23]  L. Heinemann,et al.  Technosphere/Insulin--proof of concept study with a new insulin formulation for pulmonary delivery. , 2002, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[24]  Lutz Heinemann,et al.  Variability of insulin absorption and insulin action. , 2002, Diabetes technology & therapeutics.

[25]  A. Pfützner,et al.  Technosphere/Insulin--a new approach for effective delivery of human insulin via the pulmonary route. , 2002, Diabetes technology & therapeutics.

[26]  M. Rawlins,et al.  Inhaled insulin , 2006, The Lancet.