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

Abstract

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 curve_{0–3 h}55.8 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.

Keywords

absorption diabetes inhaled insulin postprandial glucose Technosphere Insulin variability

References

The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329 (14): 977–86.

de Vegt

Dekker

Ruhe

Stehouwer

Nijpels

Bouter

Heine

. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia. 1999; 42 (8): 926–31.

Hanefeld

Koehler

Schaper

Fuecker

Henkel

Temelkova-Kurktschiev

. Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals. Atherosclerosis. 1999; 144 (1): 229–35.

Temelkova-Kurktschiev

Koehler

Henkel

Leonhardt

Fuecker

Hanefeld

. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care. 2000; 23 (12): 1830–4.

Ceriello

. The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications. Diabetologia. 2003; 46 Suppl 1: M9–16.

Home

. Contributions of basal and post-prandial hyperglycaemia to micro- and macrovascular complications in people with type 2 diabetes. Curr Med Res Opin. 2005; 21 (7): 989–98.

Qiao

Pyorala

Nissinen

Lindstrom

Tilvis

Tuomilehto

. Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. Eur Heart J. 2002; 23 (16): 1267–75.

Heise

Heinemann

. Rapid and long-acting analogues as an approach to improve insulin therapy: an evidence-based medicine assessment. Curr Pharm Des. 2001; 7 (14): 1303–25.

Hirsch

. Insulin analogues. N Engl J Med. 2005; 352 (2): 174–83.

10.

Heinemann

Traut

Heise

. Time-action profile of inhaled insulin. Diabet Med. 1997; 14 (1): 63–72.

11.

Heise

Kapitza

Hompesch

Heinemann

. Inhaled insulin as alternative delivery system for subjects with diabetes—a literature review. Av Diabetol. 2005; 21: 91–102.

12.

Patton

Bukar

Nagarajan

. Inhaled insulin. Adv Drug Deliv Rev. 1999; 35 (2–3): 235–47.

13.

Heinemann

Klappoth

Rave

Hompesch

Linkeschowa

Heise

. Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer. Diabetes Care. 2000; 23 (9): 1343–7.

14.

Perera

Kapitza

Nosek

Fishman

Shapiro

Heise

Heinemann

. Absorption and metabolic effect of inhaled insulin: intrapatient variability after inhalation via the Aerodose insulin inhaler in patients with type 2 diabetes. Diabetes Care. 2002; 25 (12): 2276–81.

15.

Kim

Mudaliar

Chinnapongse

Chu

Boies

Davis

Perera

Fishman

Shapiro

Henry

. Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes. Diabetes Care. 2003; 26 (10): 2842–7.

16.

Kapitza

Hompesch

Scharling

Heise

. Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin. Diabetes Technol Ther. 2004; 6 (4): 466–72.

17.

Pfützner

Forst

. Pulmonary insulin delivery by means of the Technosphere drug carrier mechanism. Expert Opin Drug Deliv. 2005; 2 (6): 1097–106.

18.

Heinemann

Heise

. Current status of the development of inhaled insulin. Br J Diabetes Vasc Dis. 2004; 4: 295–301.

19.

Pfützner

Mann

Steiner

. Technosphere/Insulin—a new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technol Ther. 2002; 4 (5): 589–94.

20.

Steiner

Pfützner

Wilson

Harzer

Heinemann

Rave

. Technosphere/Insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes. 2002; 110 (1): 17–21.

21.

Rave

Heise

Pfützner

Boss

. Coverage of postprandial blood glucose excursions with inhaled technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes Care. 2007; 30 (9): 2307–8.

22.

Heinemann

. Variability of insulin absorption and insulin action. Diabetes Technol Ther. 2002; 4 (5): 673–82.

23.

Galloway

Spradlin

Nelson

Wentworth

Davidson

Swarner

. Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care. 1981; 4 (3): 366–76.

24.

Hildebrandt

. Subcutaneous absorption of insulin in insulin-dependent diabetic patients. Influence of species, physico-chemical properties of insulin and physiological factors. Dan Med Bull. 1991; 38 (4): 337–46.

25.

Gin

Hanaire-Broutin

. Reproducibility and variability in the action of injected insulin. Diabetes Metab. 2005; 31 (1): 7–13.

26.

Patton

Fishburn

Weers

. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 2004; 1: 338–44.

27.

Brunner

Balent

Ellmerer

Schaupp

Siebenhofer

Jendle

Okikawa

Pieber

. Dose-response relation of liquid aerosol inhaled insulin in type I diabetic patients. Diabetologia. 2001; 44 (3): 305–8.