Pharmacological properties of faster-acting insulin aspart vs insulin aspart in patients with type 1 diabetes receiving continuous subcutaneous insulin infusion: A randomized, double-blind, crossover trial

Abstract

Aim: To evaluate the pharmacological characteristics of faster-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) during continuous subcutaneous insulin infusion (CSII).

Methods: In this randomized, double-blind, crossover trial, 48 men and women aged 18 to 64 years with type 1 diabetes mellitus (T1DM) received faster aspart and IAsp as a 0.15 U/kg bolus dose via CSII, on top of a basal rate (0.02 U/kg/h), in a glucose clamp setting (target 5.5 mmol/L).

Results: After a CSII bolus dose, the pharmacokinetic/pharmacodynamic profiles for faster aspart were left-shifted compared with those for IAsp. For faster aspart vs IAsp, the early glucose-lowering effect (area under the curve for glucose infusion rate [GIR]_0-30min ) was approximately 2-fold higher (least squares means 24.9 vs 11.4 mg/kg; estimated ratio faster aspart/IAsp 2.18, 95% confidence interval [CI] [1.33; 5.04]; P = .002), onset of glucose-lowering effect (time to early 50% of maximum GIR) occurred 11.1 minutes earlier (41.1 vs 52.3 minutes; 95% CI faster aspart - IAsp [-15.4; -6.9]; P<.001), and offset of glucose-lowering effect (time to late 50% of maximum GIR) occurred 24.0 minutes earlier (214.7 vs 238.7 minutes; 95% CI [-38.9; -9.1]; P=.002). Likewise, significantly greater early exposure and significantly earlier onset and offset of exposure were observed for faster aspart vs IAsp. Faster aspart and IAsp were both well tolerated.

Conclusions: In patients with T1DM using CSII, faster aspart better mimics the endogenous prandial insulin secretion and action than does IAsp. Faster aspart therefore has the potential to provide clinical benefits over current rapid-acting insulins in the insulin pump setting.

Keywords: insulin pump therapy; pharmacodynamics; pharmacokinetics; type 1 diabetes.

Figure 1

Mean serum insulin aspart concentration after a bolus dose of 0.15 U/kg faster aspart or insulin aspart administered by CSII. Variability bands show the s.e.m. The full blue/grey arrows indicate that the estimated onset and offset of exposure occurred earlier for faster aspart vs insulin aspart as reflected by the endpoints time to 50% of maximum insulin aspart concentration in the early part of the pharmacokinetic profile (t_{Early 50% Cmax}; estimated difference [95% CI] faster aspart – insulin aspart −11.8 minutes [−14.4; −9.2]; P < .001) and time to 50% of maximum insulin aspart concentration in the late part of the pharmacokinetic profile (t_{Late 50% Cmax}; −35.4 minutes [−47.0; −23.8]; P < .001). Moreover, as indicated by the dashed arrow, a left shift of the time of maximum insulin aspart concentration was also observed for faster aspart vs insulin aspart (t_max; −25.7 minutes [−34.3; −17.1]; P < .001). For graphical reasons, there are some discrepancies between the length of the arrows and the actual estimated mean treatment differences. This is attributable to the fact that the estimated mean treatment differences are derived from all participants’ individual treatment differences, while the mean serum insulin aspart concentration profiles are derived as the mean of all individual serum insulin aspart concentrations at each time point. Faster aspart, n = 44; insulin aspart, n = 46.

Figure 2

Mean glucose‐lowering effect after a bolus dose of 0.15 U/kg faster aspart or insulin aspart administered by CSII. Variability bands show the s.e.m. Faster aspart, n = 44; insulin aspart, n = 46.

Figure 3

Early exposure (A) and early glucose‐lowering effect (B) for faster aspart vs insulin aspart after a bolus dose of 0.15 U/kg administered by CSII. n = 44 for faster aspart and n = 45 (AUC_{GIR ,0‐1.5h} and AUC_{GIR ,0‐2h}) or 46 (all other endpoints) for insulin aspart. The treatment ratio for AUC_{GIR ,0‐30min} and AUC_{GIR ,0‐1h} was calculated using Fieller's method. LS, least squares.