Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial.

BACKGROUND: Insulin therapy is often a delayed strategy in patients with type 2 diabetes mellitus because it is associated with weight gain, hypoglycaemia, and the need for subcutaneous injections. We aimed to assess the efficacy and safety of prandial Technosphere inhaled insulin compared with twice daily biaspart insulin. METHODS: In this randomised, open-label, parallel-group study, adult patients with type 2 diabetes mellitus and poor glycaemic control despite insulin therapy, with or without oral antidiabetes drugs, were enrolled from ten countries between Feb 23, 2006, and Aug 8, 2007. Patients were randomly allocated in a 1:1 ratio to receive 52 weeks' treatment with: prandial Technosphere inhaled insulin powder plus bedtime insulin glargine; or twice daily premixed biaspart insulin (70% insulin aspart protamine suspension and 30% insulin aspart of rDNA origin). The primary endpoint was a comparison of change in glycosylated haemoglobin (HbA(1c)) from baseline to week 52 between treatment groups; the non-inferiority margin was 0.4%. Analysis was by per protocol for non-inferiority testing of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00309244. FINDINGS: 334 patients were allocated to inhaled insulin plus insulin glargine, and 343 to biaspart insulin; 107 patients on inhaled insulin plus insulin glargine and 85 on biaspart insulin discontinued the trial. 211 patients on inhaled insulin plus insulin glargine and 237 on biaspart insulin were included in per-protocol analyses. Change in HbA(1c) with inhaled insulin plus insulin glargine (-0.68%, SE 0.077, 95% CI -0.83 to -0.53) was similar and non-inferior to that with biaspart insulin (-0.76%, 0.071, -0.90 to -0.62). The between-group difference was 0.07% (SE 0.102, 95% CI -0.13 to 0.27). Patients had significantly lower weight gain and had fewer mild-to-moderate and severe hypoglycaemic events on inhaled insulin plus insulin glargine than on biaspart insulin. The safety and tolerability profile was similar for both treatments, apart from increased occurrence of cough and change in pulmonary function in the group receiving inhaled insulin plus insulin glargine. INTERPRETATION: This study is part of a large clinical development programme addressing the efficacy and tolerability of use of Technosphere inhaled insulin in a wide variety of patients. FUNDING: MannKind.

Technosphere insulin technology.

The ideal prandial insulin would possess characteristics of the insulin response profile seen in healthy individuals without diabetes. Approximating the early-phase insulin response that is lost in diabetes is challenging for injected insulins, especially achieving rapid insulin absorption and a favorable duration of metabolic effect. Technosphere (MannKind Corp., Valencia, CA) inhalation powder is a novel delivery platform that enables large peptides to be delivered via the pulmonary route. Technosphere Insulin (TI), a formulation of regular human insulin, has been specifically designed to facilitate efficient transport via the inhaled route. TI is rapidly absorbed (time to maximum effect of approximately 15 min) and has a rapid onset of action. The metabolic effect of TI peaks approximately 1 h after administration, substantially earlier than what has been reported for other insulins. The majority of the glucose-lowering activity of TI is delivered in the first 3 h. In preliminary studies, TI was well tolerated. Phase 3 studies are under way to evaluate the long-term efficacy and safety of TI in patients with type 1 and type 2 diabetes.

Insulin pharmacokinetics following dosing with Technosphere insulin in subjects with chronic obstructive pulmonary disease.

OBJECTIVES: Insulin exposure after inhalation has been reported to be altered significantly in subjects with chronic obstructive pulmonary disease (COPD). In this study, the rate and extent of insulin exposure was compared in healthy volunteers and subjects with COPD following administration of Technosphere * Insulin (TI), a dry powder insulin formulation for pulmonary delivery. METHODS: Insulin pharmacokinetics were evaluated in an open-label, single-dose, hyperinsulinemic-euglycemic glucose clamp study in 19 nondiabetic, nonsmoking healthy subjects (mean age [±SD] = 50.9 ± 14.1 years, body mass index = 29.1 ± 3.5 kg/m(2), forced expiratory volume in 1 second (FEV(1)) = 3.52 ± 1.02 L) and 17 nondiabetic subjects with mild-to-moderate COPD (mean age = 60.0 ± 9.0 years, body mass index = 28.5 ± 5 kg/m(2), FEV(1) = 2.56 ± 0.83 L). Subjects received a single 30-U dose of TI. Serial blood samples were obtained for insulin and C-peptide determination through 480 min after dosing. Insulin concentrations were adjusted for endogenous insulin by C-peptide correction; pharmacokinetic parameters were estimated using the corrected values. RESULTS: For the COPD and non-COPD groups, respectively, mean peak insulin (C(max)) was 34.7 µU/mL and 39.5 µU/mL (p = 0.29), median t(max) was 15 and 12 min (p = 0.24), and mean insulin exposure from time 0 to 240 min (AUC(0-240)) was 2037 µU/mL · min and 2279 µU/mL · min (p = 0.47). Cough was the most common respiratory adverse event observed. One instance of hypoglycemia was reported and was attributed to trial procedure. CONCLUSIONS: The rapid insulin absorption and the resulting insulin pharmacokinetic profile following TI inhalation were not significantly altered in the mild-to-moderate COPD population studied; however, long-term safety and efficacy of TI have not been established in patients with mild or moderate COPD. Longer-term experience is needed to fully characterize the effects of COPD on insulin PK following TI administration.