Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart

Abstract

Aims: To evaluate the pharmacokinetics and pharmacodynamics of faster-acting insulin aspart and insulin aspart in a randomized, single-centre, double-blind study.

Methods: Fifty-two patients with type 1 diabetes (mean age 40.3 years) received faster-acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose-clamp conditions, in a three-way crossover design (3-12 days washout between dosing).

Results: Faster-acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5-fold greater with faster-acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster-acting insulin aspart had a significantly greater glucose-lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUC(GIR), 0-30 min) ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUC(GIR, 0-2 h)) was 10% greater for faster-acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose-lowering effects, indicating similar overall potency.

Conclusions: Faster-acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose-lowering effect, with similar potency.

Trial registration: ClinicalTrials.gov NCT01618188.

Keywords: faster-acting insulin aspart; pharmacodynamics; pharmacokinetics; postprandial glucose; type 1 diabetes.

Figure 1

Mean (± standard error of the mean) concentration–time profiles for faster‐acting insulin aspart and insulin aspart from (A) 0–7 h and (B) 0–2 h (early phase).

Figure 2

Glucose‐lowering effect (raw mean glucose infusion rate profiles) of faster‐acting insulin aspart and insulin aspart from (A) 0–7 h and (B) 0–2 h (early phase).

Figure 3

Early glucose‐lowering effect [mean glucose infusion rate (GIR) profiles] of (A) faster‐acting insulin aspart and insulin aspart and (B) insulin aspart and human insulin (data on file and adapted from Heinemann et al. 1997 20). The GIR endpoint [area under the curve (AUC)_{GIR, 0–30 min}] for both studies was analysed using a linear mixed‐model with treatment and period as fixed effects, and subject as a random effect. Ratios and corresponding confidence intervals (CIs) were estimated using Fieller's method.