Fast track — ArticlesEfficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study
Introduction
The beneficial effects of good glycaemic control on chronic complications of diabetes have been firmly established in type 1 diabetes by the results of the Diabetes Control and Complications Trial (DCCT)1 and the Stockholm Diabetes Intervention Study (SDIS).2 The DCCT investigators' goal of maintaining glycaemic status “as close to normal as safely possible” is identical to that recommended in 1923, shortly after the discovery of insulin.3 Yet, the control achieved in the DCCT was not sustained during the first 5 years of follow-up.4 Thus, sustained glycaemic control remains an unfulfilled quest for patients with type 1 diabetes and the health-care professionals who care for them.
Insulin therapy is essential in type 1 diabetes mellitus. The DCCT and SDIS, along with many other studies,5, 6 showed that effective glycaemic control requires at least two, and generally three or more, insulin injections daily. The intensive regimens used in these studies rely heavily on frequent use of preprandial short-acting soluble insulin. Yet, despite the studies showing its benefits, aggressive insulin therapy has been slow to gain acceptance in clinical practice.7 One limitation is the inconvenience and poor acceptability by patients of a programme of many daily injections.
Inhaled intrapulmonary delivery of insulin offers a potential alternative to preprandial insulin injections. This form of insulin delivery was attempted as early as 1925.8 Since 1971, several studies have shown that single doses of aerosolised insulin are well tolerated, and that about 10–30% of the inhaled dose of insulin is absorbed into the circulation.9, 10, 11, 12 To maximise the efficiency and reproducibility of pulmonary insulin delivery, a new drypowder insulin formulation and aerosol delivery device have been developed (Inhale Therapeutic Systems, San Carlos, CA, USA).13 We did a proof-of-concept study to test the efficacy of this approach in patients with insulindeficient, C-peptide-negative, type 1 diabetes mellitus. The aim was to determine whether preprandial inhaled insulin can be used as a substitute for preprandial insulin injections without loss of glycaemic control.
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Patients
Men and women with type 1 diabetes were screened at ten centres in the USA. These centres included six academic health centres, one private practice, and three independent clinical research centres (Beth Israel Hospital, Boston, MA; Chicago Center for Research, Chicago, IL; Dallas Diabetes and Endocrine Center, Dallas, TX; Diabetes & Glandular Disease Research Associates, San Antonio, TX; Duke University Medical Center, Durham, NC; Radiant Research, Austin, TX; University of Miami, Miami, FL;
Results
Of the 73 patients enrolled, one withdrew before randomisation during the inpatient assessment period, and two assigned subcutaneous insulin dropped out before study completion (figure 1). One of these moved away from the study site after having had a single postrandomisation HbA1c measurement at 1 month. The other patient withdrew consent 25 days after randomisation because the frequent clinic visits were interfering with personal activities. Of the 40 patients who were screened but not
Discussion
Effective treatment of type 1 diabetes requires a programme of insulin therapy that separately considers basal and preprandial insulin replacement and provides insulin adequately for each meal. Yet, the pharmacokinetics of conventional regular insulin do not match physiological prandial insulin availability.15, 16 To match insulin availability with meals requires injections 20–30 min before eating, if using regular insulin.17, 18 The availability of insulin analogues, such as insulin lispro19
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