Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin.

Barriers to the use of prandial insulin regimens include inadequate synchronization of insulin action to postprandial plasma glucose excursions as well as a significant risk of hypoglycemia and weight gain. Technosphere® insulin (TI) is an inhaled ultra-rapid-acting human insulin that is quickly absorbed in the alveoli. With a time to maximum plasma drug concentration of approximately 14 min and a time to maximum effect of 35 to 40 min, TI more closely matches the postprandial insulin concentrations seen in nondiabetic individuals. Studies have shown that long-term administration of prandial TI in combination with long-acting basal insulin results in reductions in hemoglobin A1c comparable to conventional subcutaneously injected prandial insulins but with improved control of early postprandial BG. Furthermore, TI has been associated with less weight gain and a lower incidence of hypoglycemia, which may enhance patient satisfaction and acceptability of insulin therapy. This review discusses the clinical properties of TI and proposes strategies for optimal use.

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.

Efficacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents.

OBJECTIVE: This double-blind, placebo-controlled, randomized, multicenter, parallel-group study compared the efficacy, safety, and tolerability of Technosphere insulin with Technosphere powder as placebo in insulin-naive type 2 diabetic patients whose diabetes was suboptimally controlled with oral antidiabetic agents. RESEARCH DESIGN AND METHODS: Patients (n = 126) were randomly assigned to 12 weeks of therapy with Technosphere insulin or Technosphere powder after lifestyle education on nutrition, exercise, and instructions on inhaler use. The primary efficacy outcome was change in A1C from baseline to study end, and the secondary efficacy outcome was area under the curve for postprandial glucose levels during a meal test at treatment weeks 4, 8, and 12. RESULTS: A1C reduction from a mean baseline of 7.9% was greater with Technosphere insulin than with Technosphere powder (-0.72 vs. -0.30%; P = 0.003). Postprandial glucose excursions were reduced by 56% with Technosphere insulin compared with baseline, and maximal postprandial glucose levels were reduced by 43% compared with Technosphere powder. Incidences of hypoglycemia, hyperglycemia, cough, and other adverse events were low in both groups. Body weight was unchanged in both groups. CONCLUSIONS: Technosphere insulin was well tolerated and demonstrated significant improvement in glycemic control with clinically meaningful reductions in A1C levels and postprandial glucose concentrations after 12 weeks of treatment.

Randomized forced titration to different doses of technosphere insulin demonstrates reduction in postprandial glucose excursions and hemoglobin A1c in patients with type 2 diabetes.

BACKGROUND: Individuals with type 2 diabetes mellitus have impairments in early insulin release, resulting in increased postprandial glucose excursions and suboptimal glycemic control. Studies with Technosphere Insulin (TI) indicate that it has rapid systemic absorption and a short duration of glucose-lowering activity, making it well suited for controlling postprandial glucose levels. METHODS: The goal of this phase 2b, prospective, multicenter, double-blind, placebo-controlled study was to characterize the dose response of four different doses (equivalent to 3.6, 7.3, 10.9, and 14.6 U subcutaneous regular human insulin) of prandial TI or Technosphere powder alone administered before each of three meals daily, in combination with insulin glargine over an 11-week treatment period, in patients with type 2 diabetes and suboptimal glycemic control. RESULTS: The study enrolled 227 patients. In all dose groups, TI demonstrated statistically significant dose-dependent reductions in hemoglobin A1c (HbA1c) versus baseline (-0.4, -0.5, -0.5, and -0.6 for 3.6, 7.3, 10.9, and 14.6 U equivalents, respectively; p < 0.05 in all groups), as well as versus placebo or Technosphere powder alone (-0.40, -0.67, -0.70, and -0.78 for 3.6, 7.3, 10.9, and 14.6 U equivalents, respectively; p < 0.04 in all groups). It reduced the postprandial maximum glucose concentration within each treatment group (statistically significant in all but the TI 3.6 U-equivalent group) and reduced the postprandial area under the glucose curve (statistically significant for the TI 10.9 and 14.6 U-equivalent groups) versus placebo. There were no cases of severe hypoglycemia, while mild/moderate hypoglycemia was observed most frequently in the highest dosage groups, as expected. Rates of cough were low and comparable among all groups. No clinically relevant changes in pulmonary function tests, body weight, or high-resolution computerized axial tomography and magnetic resonance imaging were observed. CONCLUSIONS: This study demonstrated that, over 11 weeks, TI plus basal insulin glargine is well tolerated and results in dose-dependent reductions in postprandial glucose and HbA1c levels.

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 kg.m(-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.

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.

Variations of whole blood viscosity using Rheolog-a new scanning capillary viscometer.

BACKGROUND: Whole blood viscosity (WBV) values identify subjects at high risk for initial or recurrent cardiovascular events. However, these measurements have been limited to specialized centers. A new type of viscometer, Rheolog, was designed to overcome the difficulties encountered in WBV measurements using the standard rotational viscometer in a clinical environment. METHODS: We evaluated the 14-day variability of WBV measured by Rheolog in a single-center study of 24 healthy male subjects aged 18-75 years. WBV was measured through an 11-h period on study days 1, 8, and 14. An additional fasting WBV test was performed on study days 3, 5, and 11. RESULTS: Average morning measurements were higher than afternoon measurements at all shear rates. Both inter- and intraindividual variations were higher in the morning than later in the day, but the differences between pooled mean values were not significant. Interindividual variations at fasting were higher than the pre-meal or overall variations. There was a small nonsignificant increase in mean viscosity following each meal. CONCLUSION: WBV measurements using Rheolog have potential for clinical application because of the convenience and low variability of measurements over time.