Improved Postprandial Glucose with Inhaled Technosphere Insulin Compared with Insulin Aspart in Patients with Type 1 Diabetes on Multiple Daily Injections: The STAT Study

Abstract

Background: The majority of therapies have generally targeted fasting glucose control, and current mealtime insulin therapies have longer time action profiles than that of endogenously secreted insulin. The primary purpose of this study was to assess both glucose time-in-range (TIR: 70-180 mg/dL) and postprandial glucose excursions (PPGE) in 1-4 h using a real-time continuous glucose monitor (CGM) with Technosphere insulin (TI) versus insulin aspart in patients with type 1 diabetes (T1DM) on multiple daily injections (MDI).

Research design and methods: This pilot, investigator-led, collaborative, open-label, multicenter, clinical research trial enrolled 60 patients with T1DM with HbA1c levels ≥6.5% and ≤10%. Individuals were randomized to treatment with titrated TI (n = 26) or titrated insulin aspart (n = 34), stratified by baseline HbA1c levels (≤8% or >8%). All were required to wear a real-time CGM throughout the trial. All patients in the TI group were advised to take supplemental inhalations at 1 and 2 h after meals if indicated based on postprandial glucose (PPG) values. The coprimary outcomes were assessed both in the full intent-to-treat population and in those individuals randomized to TI who were compliant with supplemental doses ≥90% of the time (n = 15). The CGM data were analyzed using linear regression models.

Results: Overall, those treated with TI versus aspart achieved comparable TIR, but less time spent in hypoglycemia (<60 and <50 mg/dL, both P < 0.05). In the TI-compliant group (n = 15), TIR was significantly greater (62.5% ± 2.6% vs. 53.8% ± 1.7%, P = 0.009) and time in hyperglycemia >180 mg/dL was lower (34.2% ± 2.7% vs. 41.0% ± 1.7%, P = 0.045) as compared with the aspart group. PPG was also significantly lower in the TI cohort at 60 and 90 min postmeal, and PPGE were lower in the TI-compliant group as compared with the aspart group over 1-4-h postmeal (P < 0.05). In addition, there was weight gain in the aspart group compared with weight loss in the TI group (P = 0.006) despite higher prandial TI insulin dose.

Conclusions: We conclude that using TI appropriately at mealtimes with supplemental dosing improves prandial glucose (TIR and 1-4 h) control without any increase in time in hypoglycemia or weight gain in patients with T1DM on MDI. The study results support a larger study using a treat-to-target design to confirm these findings. Clinical trial reg. no. NCT03143816, clinicaltrials.gov .

Keywords: Continuous glucose monitoring.; Insulin aspart; Postprandial hyperglycemia; Technosphere Insulin; Time in range; Type 1 diabetes.

Conflict of interest statement

H.K.A. received a research grant from MannKind Corporation through the University of Colorado related to this study. S.K.G. received research grants from MannKind Corporation, Eli Lilly, Novo Nordisk, Merck, Lexicon, Medtronic, Dario, NCI, T1D Exchange, NIDDK, JDRF, Animas, Dexcom, and Sanofi through University Colorado; received consulting fees for advisory boards from MannKind, Dexcom, Eli Lilly, Novo Nordisk, Sanofi, Roche, Merck, Lexicon, and Medtronic. T.S.B. received research grant from Abbott, Ambra, Ascensia, BD, Boehringer Ingelheim, Calibra Medical, Companion Medical, Dance Biopharm, Dexcom, Eli Lilly, Glooko, Glysens, Kowa, Lexicon, MannKind, Medtronic, Novo Nordisk, Sanofi, Senseonics, Taidoc, Versartis, and Xeris; received consulting honoraria from Abbott, Astra Zeneca, Ascensia, BD, Calibra, Capillary Biomedical, Eli Lilly, Intarcia, Medtronic, Novo Nordisk, and Sanofi; and received speaking honoraria from Abbott, Eli Lilly, Medtronic, Novo Nordisk, and Sanofi. L.J.K. received research grants from Sanofi, Gan and Lee, Oramed, Lilly, Novo Nordisk, Janssen, MannKind, Dexcom, Medtronic, Senseonics, Abbott, Pfizer, and Mylan. A.P. received research support from Astra Zeneca, Dexcom, and MannKind, speaker's bureau from Novo Nordisk; participated on advisory boards for Abbott Diabetes Care, Becton Dickinson, Boehringer Ingelheim, Eli Lilly and Company, Lexicon, Livongo, Medscape, Merck, Novo Nordisk, OptumHealth, Sanofi, and Science 37. B.W.B. received research grant by Atlanta Diabetes Associates from Abbott, Becton Dickinson, Dexcom, GSK, Diasome, Jannsen, Lexicon, Lilly/Boehringer Ingelheim, MannKind, Medtronic, NIH, Novo Nordisk, Sanofi, and Senseonics; consultant fee from Adocia, Intarcia, Janssen, Medtronic, MannKind, Novo Nordisk, Sanofi; speaker's bureau from Astra Zeneca, Lily/Boehringer Ingelheim, Jannsen, Medtronic, Novo Nordisk, and Sanofi; and has stocks of Aseko. A.R. and J.S.B. do not have any conflict of interests.

Figures

FIG. 1.

Study design.

FIG. 2.

Mean premeal and postprandial bolus dose, comparison of insulin aspart and TI groups. In linear regression models with repeated measures, adjusted for age, sex, study site, study week, and treatment group, the TI group used a similar premeal bolus, but a significantly larger additional bolus dose when compared with the aspart group. In addition, the TI group took planned postprandial supplemental doses per protocol (PP bolus). Average postprandial bolus was significantly higher in the TI group. PP, post-prandial; TI, Technosphere Insulin.

FIG. 3.

Comparison of insulin aspart and TI groups for TIR, postprandial glucose excursions, and SD. (A) TIR (70-180 mg/dL) as a percentage of a 24-h day by treatment group and compliance. TIR was significantly higher in TI-compliant group compared with TI-noncompliant and aspart groups. (B) PPGE, defined as the peak increase in CGM glucose in the 1–4 h after meals, in mg/dL by treatment group and compliance. The TI-compliant group had significantly less post-prandial glucose excursion (PPGE) compared with aspart group. (C) Glucose SD during daytime (6am–midnight) and nighttime (midnight–6am) by treatment group and compliance. CGM glucose SD during daytime (6 AM to midnight) were significantly lower in the TI-compliant group compared with the aspart group. (D) PPGE, defined as the peak increase in CGM glucose in the 1–4 h after each meal, by treatment group and meal. PPGE was significantly lower in the TI-compliant group compared with the aspart group at breakfast and lunch but not at dinner. CGM, continuous glucose monitor; PPGE, post-prandial glucose excursions; SD, standard deviation; TIR, time-in-range.

FIG. 4.

2-h Postprandial AUC and TIR by time of day, comparison of insulin aspart and TI groups. (A) The AUC for 2 h PPG was significantly lower in the TI-compliant and the TI-noncompliant groups than the aspart group. (B) The TIR (70-180 mg/dL) as a percentage of a 24 h day was significantly higher in the TI group than in the aspart group during the day, but was not different at night. AUC, area under the curve.

FIG. 5.

Mean CGM glucose, comparison of insulin aspart and TI groups. Mean postprandial CGM glucose by treatment group and compliance. PPG values were significantly lower at 60 and 90 min in the TI group compared with the aspart group. PPG values were significantly lower at 60, 90, and 120 min after meals in the TI-compliant group compared with the aspart group.