Key publication slides Bode BW, et al. Improved postprandial glycemic control with faster-acting insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion. Diabetes Technology and Therapeutics. 2017;19:25-33. Key publication slides No FXCX

Background and Objectives For patients with T1D, CSII (also known as insulin pump therapy) is associated with improved glycaemic control compared with multiple daily injections1 However, excessive PPG excursions remain an issue with CSII,2 underscoring the need for a mealtime insulin with faster onset of action Ultra-fast-acting IAsp is a new formulation of IAsp designed to accelerate insulin absorption3,4 When delivered by CSII, ultra-fast-acting IAsp increases early insulin exposure and glucose-lowering effect compared with IAsp in patients with T1D4 Total glucose-lowering effect is similar for ultra-fast-acting IAsp and IAsp4 The aim of this study was to compare ultra-fast-acting IAsp and IAsp in patients with T1D Both were delivered by CSII Comparison was based on 2-hour PPG response following a standardized meal test5 1. Misso ML, et al. Cochrane Database Syst Rev. 2010;1:CD005103. 2. James ML, et al. J Diabetes Sci Technol. 2016;10:1287-93. 3. Heise T, et al. Diabetes Obes Metab. 2015;17:682-88. 4. Heise T, et al. Diabetes Obes Metab. 2017;19:208-15. 5. Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33. CSII, continuous subcutaneous insulin infusion; IAsp, insulin aspart; PPG, postprandial glucose; T1D, type 1 diabetes.

Study Design: Randomized, double-blind, crossover trial 43 patients received faster IAsp or IAsp via CSII for 2 weeks Primary endpoint: mean change in PPG 2 hours after a standardized meal test Patients with T1D Aged ≥ 18 years HbA1c ≤ 9.0% BMI ≤ 35 kg/m2 Treated with CSII for ≥ 3 months Faster IAsp (via CSII for 2 weeks) IAsp (via CSII for 2 weeks) IAsp (via CSII for 2 weeks) Faster IAsp (via CSII for 2 weeks) BMI, body-mass index; HbA1c, glycated haemoglobin A1c. Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33.

Results: PPG Profiles With Ultra-Fast-Acting IAsp vs IAsp in CSII Baseline-adjusted PG −20 20 40 60 80 100 120 140 3 6 9 12 15 −1 1 2 3 4 5 6 7 50 100 150 200 250 PG (mmol/L) Baseline-adjusted PG (mmol/L) PG (mg/dL) Baseline-adjusted PG (mg/dL) IAsp Ultra-fast-acting IAsp IAsp Ultra-fast-acting IAsp 30 60 90 120 150 180 210 240 −60 −30 30 60 90 120 150 180 210 Nominal time (minutes) Nominal time (minutes) Reproduced from Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33. © Bruce W. Bode, et al., 2017; Published by Mary Ann Liebert, Inc. PG, plasma glucose.

Results: Better Control of PPG With Ultra-Fast-Acting IAsp vs IAsp in CSII Compared with IAsp, ultra-fast-acting IAsp provided a significantly greater glucose-lowering effect in the first 2 hours following a standardized meal test Mean change in PG was approximately 25% lower with ultra-fast-acting IAsp vs IAsp (3.03 mmol/L [54.68 mg/dL] vs 4.02 mmol/L [75.52 mg/dL])a ETD (95% CI): −0.99 mmol/L (−1.95; −0.03) [−17.84 mg/dL (−35.21; −0.46)]; p = 0.044 One hour post-meal PG level was 1.64 mmol/L [29.47 mg/dL] lower with ultra-fast-acting IAsp than with IAsp (p = 0.006) aData are least-squares means. ΔPGav, 0–2 hours, was calculated as AUCPG,0–2hours/2-hour PGPre-dose, where AUCPG,0–2 hours was the area under the PG concentration–time profile; mean change after 2 weeks. AUC, area under the curve; CI, confidence interval; ETD, estimated treatment difference. Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33.

Results: 2-Week Continuous Glucose Monitoring Data Confirm Earlier Onset of Action With Ultra-Fast-Acting IAsp vs IAsp Early PPG excursion was lower with ultra-fast-acting IAsp vs IAsp after all meals, especially breakfast Mean and peak postprandial IG levels (0–4 hours) were similar for ultra-fast-acting IAsp and IAsp after all meals 0.5 1.0 1.5 2.0 2.5 p = 0.004 p < 0.001 p = 0.015 p = 0.017 p = 0.523 p = 0.064 p = 0.320 Ultra-fast-acting IAsp IAsp 10 15 20 30 35 45 5 25 40 IG (mmol/L) IG (mg/dL) 26:19 IG over 1 hour IG over 1 hour IG over 1 hour IG over 1 hour IG over 2 hours IG over 2 hours IG over 2 hours IG over 2 hours After all meals After breakfast After lunch After dinner Mean change (increment) in IG over 2 weeks of treatment. Error bars represent standard error (mean). IG, interstitial glucose. Reproduced from Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33. © Bruce W. Bode, et al., 2017; Published by Mary Ann Liebert, Inc.

Duration of low IG levels per 24 hours Results: Less Time Spent in Hypoglycaemic State With Ultra-Fast-Acting IAsp vs IAsp Ultra-fast-acting IAsp was associated with less time spent with low glucose level over a 24-hour period ≤ 3.9 mmol/L (70 mg/dL) p = 0.557 p = 0.148 p = 0.039 p = 0.008 < 3.5 mmol/L (63 mg/dL) < 3.0 mmol/L (54 mg/dL) 26:19 Ultra-fast-acting IAsp IAsp < 2.5 mmol/L (45 mg/dL) 2 4 6 8 10 12 14 16 18 20 22 24 Duration of low IG levels per 24 hours Reproduced from Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33. © Bruce W. Bode, et al., 2017; Published by Mary Ann Liebert, Inc. Error bars represent standard error (mean).

Conclusions Compared with IAsp, PPG control was improved with ultra-fast-acting IAsp when used in a CSII setting in patients with T1D Ultra-fast-acting IAsp was associated with: Significantly smaller change in PPG in the first 2 hours following a standardized meal test Significantly lower PPG level 1 hour after a standardized meal test Improved PPG control after all meals, especially breakfast Shorter duration of time spent in hypoglycaemic state over a 24-hour period Bode BW, et al. Diabetes Technol Ther. 2017;19:25-33.