Fast-Acting Insulin Aspart: A Review of its Pharmacokinetic and Pharmacodynamic Properties and the Clinical Consequences

Abstract

Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) with two added excipients, l-arginine and niacinamide, to ensure formulation stability with accelerated initial absorption after subcutaneous administration compared with previously developed rapid-acting insulins. The pharmacokinetic/pharmacodynamic properties of faster aspart have been characterised in clinical pharmacology trials with comparable overall methodology. In subjects with type 1 (T1D) or type 2 (T2D) diabetes, the serum IAsp concentration-time and glucose-lowering effect profiles are left-shifted for faster aspart compared with IAsp. In addition, faster aspart provides earlier onset, doubling of initial exposure, and an up to 2.5-fold increase in initial glucose-lowering effect within 30 min of subcutaneous injection, as well as earlier offset of exposure and effect. Similar results have been shown using continuous subcutaneous insulin infusion (CSII). The improved pharmacological properties of faster aspart versus IAsp are consistent across populations, i.e. in the elderly, children, adolescents and the Japanese. Thus, the faster aspart pharmacological characteristics more closely resemble the mealtime insulin secretion in healthy individuals, giving faster aspart the potential to further improve postprandial glucose control in subjects with diabetes. Indeed, change from baseline in 1-h postprandial glucose increment is in favour of faster aspart versus IAsp when used as basal-bolus or CSII treatment in phase III trials in subjects with T1D or T2D. This review summarises the currently published results from clinical pharmacology trials with faster aspart and discusses the potential clinical benefits of faster aspart compared with previous rapid-acting insulin products. Key PointsDespite the advantages of rapid-acting insulins over regular human insulin with respect to pharmacokinetic/ pharmacodynamic properties, there is still a need for accelerated insulin absorption and action to better mimic mealtime insulin secretion in the healthy state.Faster aspart provides an overall left-shift of the pharmacokinetic/pharmacodynamic profiles resulting in earlier onset, twice as large initial exposure, and up to 2.5-fold greater initial glucose-lowering effect within the first 30 min, as well as earlier offset of exposure and effect compared with insulin aspart.In phase III trials, the better resemblance of faster aspart pharmacological characteristics to healthy endogenous mealtime insulin secretion has been shown to lead to improved postprandial glycaemic control in subjects with diabetes relative to previously developed rapid-acting insulins.

Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-Blind, Crossover Study in Men With Type 1 Diabetes

“…Similarity was observed between AT247, IAsp, and faster IAsp in overall insulin exposure and overall glucose-lowering effect. This is also in accordance with the results of the pooled pharmacological analyses of faster IAsp versus IAsp ( 31 , 32 ) and confirms that the glucose-lowering potency is maintained and that only the time-concentration and time-action profiles are favorably changed.…”

“…Similarly to these second-generation insulin analogs, AT247 exhibited a faster offset of exposure by a left-shift of the late part of the pharmacokinetic time profile compared with IAsp and faster IAsp. The accelerated clearance of faster IAsp versus IAsp has already been well described ( 31 , 32 ). These reports showed that offset of faster IAsp was 12 min earlier than for IAsp ( P < 0.001), which is consistent with our results.…”

“…Compared with faster IAsp, AT247 resulted in a significant further shortening of t Late50%Cmax by 27 min. The duration of the glucose-lowering effect, measured by t Late50%GIRmax , has been reported to be 14 min earlier for faster IAsp versus IAsp ( P < 0.001) ( 31 , 32 ). In the current study, however, the mean differences in t Late50%GIRmax of 22 and 20 min comparing AT247 to IAsp and faster IAsp, respectively, were both not statistically significant.…”

“…A large number of people with type 1 diabetes still struggle with correct dosing based on carbohydrate meal content, postprandial hyperglycemia, late postprandial hypoglycemia ( 36 ), timing of prandial insulin injections ( 13 ), handling of hyperglycemia corrections, or appropriate dosing for meals with a high glycemic index. Faster IAsp with its enhanced pharmacological properties partly covers these unmet needs, as shown in a range of phase 3 trials ( 32 , 35 , 37 – 40 ). In these trials, faster IAsp demonstrated superior postprandial glucose control accompanied with comparable or slightly improved overall glucose control and comparable risk for hypoglycemia.…”

Super Bolus – A Remedy for A High Glycemic Index Meal in Children With Type 1 Diabetes on Insulin Pump Therapy?:&nbsp;Study&nbsp;Protocol for a Randomised Controlled Trial.

“…A statistically significant reduction in 2-hour postprandial glycemia after standardized meal was reported. 26,27 However, due to regulatory approval and availability the common use in clinical practice is limited. Lujif et al…”