Fast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences

Hanne Haahr; Tim Heise

doi:10.14341/DM12357

Fast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences

Hanne Haahr, Tim Heise

https://doi.org/10.14341/DM12357

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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.

Keywords

faster aspart, pharmacokinetic, pharmacodynamic, clamp

About the Authors

Hanne Haahr

Novo Nordisk A/S
Denmark

PhD

Competing Interests:

Search and analytical work and article preparation was funded by Novo Nordisk. Hanne Haar is an employee and shareholder of Novo Nordisk. Tim Hayes is a shareholder of Profil, a research funding firm from Adocia, Boehringer Ingelheim, Dance Pharmaceuticals, Eli Lilly, Gan & Lee Pharmaceuticals, Johnson & Johnson, Mars, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk, Pfizer, Poxel, Saniona, Sanofi, Wockhardt and Zealand Pharma. In addition, Tim Hayes is a member of advisory groups for Mylan and Novo Nordisk and has received speaker fees and travel grants from Eli Lilly and Novo Nordisk.

Tim Heise

Profil
Germany

MD, PhD

Competing Interests:

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Supplementary files

	1. Fig. 1. A conceptual model demonstrating the effect of various concentrations of zinc and nicotinamide in the composition of ultrafast aspart insulin on the rate of absorption after subcutaneous administration. AU - arbitrary units.
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	2. Fig. 2. Pharmacokinetic profiles with the use of ultrafast insulin aspart as compared with insulin aspart in patients with type 1 diabetes mellitus and type 2 diabetes mellitus. The average 5-hour (A), 6-hour (B) or 2-hour (C, D) serum concentration of iAsp depending on the time after subcutaneous injection of a dose of 0.2 U / kg for T1 (A, C) and 0, 3 U / kg for T2DM (B, D). Variation fluctuation limits indicate standard error. SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus. Adapted from Heise et al. [16] in accordance with the terms of the Creative Commons Attribution-NonCommercial 4.0 international license (http://creativecommons.org/licenses/by-nc/4.0/) and from Pieber et al. [17]
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	3. Fig. 3. Onset of action (A) and concentration at certain intervals (B) for ultra-fast acting insulin aspart as compared to insulin aspart after subcutaneous administration of a dose of 0.2 U / kg for patients with type 1 diabetes and 0.3 U / kg for patients with type 2 diabetes. Superfast insulin aspart - insulin aspart. bTo compare the treatment of ultrafast insulin aspart against insulin aspart. c Ultrafast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus; early 50% Cmax - time to reach 50% of the maximum concentration in the early phase of the pharmacokinetic profile ;, tmax - time to reach the maximum concentration; Food - units. Data from Heise et al. [16] and Pieber et al. [17].
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	4. Fig. 4. Pharmacodynamic profiles of ultrafast insulin aspart and insulin aspart in patients with type 1 diabetes and type 2 diabetes. Averaged indicators of a 5-hour (A), 6-hour (B) and 2-hour (C, D) profile for a decrease in glucose level after subcutaneous injection of 0.2 U / kg for T1 (A, C) and 0.3 U / kg at T2DM (B, D). Variation fluctuation limits indicate standard error. SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus; Food - units. Adapted from Heise et al. [16] in accordance with the terms of the Creative Commons Attribution-NonCommercial 4.0 international license (http://creativecommons.org/licenses/by-nc/4.0/) and from Pieber et al. [17]
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	5. Fig. 5. Onset of action (A) and sugar-lowering effect (B) for ultrafast insulin aspart compared with insulin aspart after subcutaneous injection of 0.2 Units / kg in patients with type 1 diabetes and 0.3 Units / kg in patients with diabetes 2 types. a Superfast insulin aspart - and Asp. bTo compare treatment with ultrafast insulin aspart versus ASP. c Ultrafast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; GIR - glucose infusion rate; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus; early 50% GIRmax - time to reach 50% of the maximum rate of glucose infusion in the early phase; tGIRmax - time to reach maximum glucose infusion rate; Food - units. Data taken from Heise et al. [16] and Pieber et al. [17]
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	6. Fig. 6. Suppression of endogenous glucose production by superfast insulin aspart as compared with aspart insulin during meals after individualized subcutaneous administration (0.06–0.28 U / kg) of insulin in patients with type 1 diabetes mellitus. The columns show the mean ± standard error. Comparison of treatments shows the relationship between ultrafast aspart insulin and iASP [95% CI] and the corresponding p values. DI - confidence interval; EPG - endogenous glucose production; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus. Adapted from Basu et al. [22]
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	7. Fig. 7. Average 5-hour serum insulin aspart concentration profiles versus time of administration of a bolus dose of 0.15 U / kg ultra-fast aspart insulin or iASP administered with PPII in addition to basal infusion. Variation fluctuation limits indicate standard error. The blue / gray arrows indicate that the calculated onset and end of action occurred earlier for ultrafast aspart insulin than for Aspart, which is reflected at the endpoints - an early 50% Cmax, tmax and a late 50% Cmax. PPII - continuous subcutaneous infusion of insulin; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; early 50% Cmax - time to reach 50% of the maximum concentration in the early phase of the pharmacokinetic profile; tmax - time to maximum concentration; t late 50% Cmax - time to reach 50% of the maximum concentration in the late phase of the pharmacokinetic profile; Food - units. Adapted from Heise et al. [20].
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	8. Fig. 8. Onset of action (A) and concentration at specific intervals (B) for ultra-fast acting insulin aspart as compared to insulin aspart after subcutaneous administration of 0.2 U / kg in children and adolescents with type 1 diabetes. a Superfast insulin aspart - and Asp. bTo compare treatment with ultrafast insulin aspart to iAsp. c Ultra-fast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus; early 50% Cmax - time to reach 50% of the maximum concentration in the early phase; tmax - time to reach maximum concentration; Food - units. Data from Fath et al. [23]
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	9. Fig. 9. Onset of action (A) and concentration at specific intervals (B) for ultra-fast acting insulin aspart as compared to insulin aspart after subcutaneous injection of 0.2 U / kg in elderly patients with type 1 diabetes mellitus. a Superfast insulin aspart - and Asp. bComparison of treatment for ultrafast insulin aspart and iAsp. c Ultra-fast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; GIR - glucose infusion rate; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - average value, least squares method; T1DM - type 1 diabetes mellitus; early 50% GIRmax - time to reach 50% of the maximum rate of glucose infusion in the early phase; tGIRmax - time to reach maximum glucose infusion rate; Food - units. Data from Heise et al. [24]
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	10. Fig. 10. Average 2-hour serum insulin aspart concentration profiles versus time (A) and average 2-hour glucose lowering profiles (B) for ultra-fast insulin aspart compared with insulin aspart after subcutaneous injection at a dose of 0.2 U / kg in Japanese with type 1 diabetes. SBDiAsp - ultra-fast insulin aspart; IASP - insulin aspart; T1DM - type 1 diabetes mellitus; Food - units. Adapted from Shiramoto et al. [25]
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	11. Fig. 11. Average 5-hour serum insulin aspart concentration profiles for 0.2 u / kg aspart administered subcutaneously in the abdomen, shoulder, or thigh of healthy volunteers. IASP - insulin aspart; Food - units. Adapted from Hövelmann et al. [26]
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	12. Fig. 12. An increase in postprandial glycemia for ultrafast insulin aspart compared with insulin aspart in patients with type 1 diabetes mellitus during a 4-hour test with a standard dietary load after 52 weeks of therapy with multiple injections of insulin (A) or after 16 weeks of treatment with PPI ( B) The study participants received a bolus dose of 0.1 U / kg followed by a liquid meal (approximately 80 g of carbohydrates) consumed over 12 minutes. The bars show ± standard error. * p <0.001; p = 0.001; * p = 0.01. PPII - continuous subcutaneous infusion of insulin; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; BCP - postprandial glucose; T1DM - type 1 diabetes mellitus; Food - units. From Mathieu et al. [28] and Klonoff et al. [29].
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Haahr H., Heise T. Fast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences. Diabetes mellitus. 2020;23(2):140-160. (In Russ.) https://doi.org/10.14341/DM12357

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).

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	Title	Fig. 1. A conceptual model demonstrating the effect of various concentrations of zinc and nicotinamide in the composition of ultrafast aspart insulin on the rate of absorption after subcutaneous administration. AU - arbitrary units.
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5511

	Title	Fig. 2. Pharmacokinetic profiles with the use of ultrafast insulin aspart as compared with insulin aspart in patients with type 1 diabetes mellitus and type 2 diabetes mellitus. The average 5-hour (A), 6-hour (B) or 2-hour (C, D) serum concentration of iAsp depending on the time after subcutaneous injection of a dose of 0.2 U / kg for T1 (A, C) and 0, 3 U / kg for T2DM (B, D). Variation fluctuation limits indicate standard error. SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus. Adapted from Heise et al. [16] in accordance with the terms of the Creative Commons Attribution-NonCommercial 4.0 international license (http://creativecommons.org/licenses/by-nc/4.0/) and from Pieber et al. [17]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5512

	Title	Fig. 3. Onset of action (A) and concentration at certain intervals (B) for ultra-fast acting insulin aspart as compared to insulin aspart after subcutaneous administration of a dose of 0.2 U / kg for patients with type 1 diabetes and 0.3 U / kg for patients with type 2 diabetes. Superfast insulin aspart - insulin aspart. bTo compare the treatment of ultrafast insulin aspart against insulin aspart. c Ultrafast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus; early 50% Cmax - time to reach 50% of the maximum concentration in the early phase of the pharmacokinetic profile ;, tmax - time to reach the maximum concentration; Food - units. Data from Heise et al. [16] and Pieber et al. [17].
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5513

	Title	Fig. 4. Pharmacodynamic profiles of ultrafast insulin aspart and insulin aspart in patients with type 1 diabetes and type 2 diabetes. Averaged indicators of a 5-hour (A), 6-hour (B) and 2-hour (C, D) profile for a decrease in glucose level after subcutaneous injection of 0.2 U / kg for T1 (A, C) and 0.3 U / kg at T2DM (B, D). Variation fluctuation limits indicate standard error. SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus; Food - units. Adapted from Heise et al. [16] in accordance with the terms of the Creative Commons Attribution-NonCommercial 4.0 international license (http://creativecommons.org/licenses/by-nc/4.0/) and from Pieber et al. [17]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5514

	Title	Fig. 5. Onset of action (A) and sugar-lowering effect (B) for ultrafast insulin aspart compared with insulin aspart after subcutaneous injection of 0.2 Units / kg in patients with type 1 diabetes and 0.3 Units / kg in patients with diabetes 2 types. a Superfast insulin aspart - and Asp. bTo compare treatment with ultrafast insulin aspart versus ASP. c Ultrafast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; GIR - glucose infusion rate; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus; T2DM - type 2 diabetes mellitus; early 50% GIRmax - time to reach 50% of the maximum rate of glucose infusion in the early phase; tGIRmax - time to reach maximum glucose infusion rate; Food - units. Data taken from Heise et al. [16] and Pieber et al. [17]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5515

	Title	Fig. 6. Suppression of endogenous glucose production by superfast insulin aspart as compared with aspart insulin during meals after individualized subcutaneous administration (0.06–0.28 U / kg) of insulin in patients with type 1 diabetes mellitus. The columns show the mean ± standard error. Comparison of treatments shows the relationship between ultrafast aspart insulin and iASP [95% CI] and the corresponding p values. DI - confidence interval; EPG - endogenous glucose production; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus. Adapted from Basu et al. [22]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5516

	Title	Fig. 7. Average 5-hour serum insulin aspart concentration profiles versus time of administration of a bolus dose of 0.15 U / kg ultra-fast aspart insulin or iASP administered with PPII in addition to basal infusion. Variation fluctuation limits indicate standard error. The blue / gray arrows indicate that the calculated onset and end of action occurred earlier for ultrafast aspart insulin than for Aspart, which is reflected at the endpoints - an early 50% Cmax, tmax and a late 50% Cmax. PPII - continuous subcutaneous infusion of insulin; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; early 50% Cmax - time to reach 50% of the maximum concentration in the early phase of the pharmacokinetic profile; tmax - time to maximum concentration; t late 50% Cmax - time to reach 50% of the maximum concentration in the late phase of the pharmacokinetic profile; Food - units. Adapted from Heise et al. [20].
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5517

	Title	Fig. 8. Onset of action (A) and concentration at specific intervals (B) for ultra-fast acting insulin aspart as compared to insulin aspart after subcutaneous administration of 0.2 U / kg in children and adolescents with type 1 diabetes. a Superfast insulin aspart - and Asp. bTo compare treatment with ultrafast insulin aspart to iAsp. c Ultra-fast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - the average value of the least squares method; T1DM - type 1 diabetes mellitus; early 50% Cmax - time to reach 50% of the maximum concentration in the early phase; tmax - time to reach maximum concentration; Food - units. Data from Fath et al. [23]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5518

	Title	Fig. 9. Onset of action (A) and concentration at specific intervals (B) for ultra-fast acting insulin aspart as compared to insulin aspart after subcutaneous injection of 0.2 U / kg in elderly patients with type 1 diabetes mellitus. a Superfast insulin aspart - and Asp. bComparison of treatment for ultrafast insulin aspart and iAsp. c Ultra-fast insulin aspart / iAsp. AUC is the area under the curve; DI - confidence interval; GIR - glucose infusion rate; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; OLS - average value, least squares method; T1DM - type 1 diabetes mellitus; early 50% GIRmax - time to reach 50% of the maximum rate of glucose infusion in the early phase; tGIRmax - time to reach maximum glucose infusion rate; Food - units. Data from Heise et al. [24]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5519

	Title	Fig. 10. Average 2-hour serum insulin aspart concentration profiles versus time (A) and average 2-hour glucose lowering profiles (B) for ultra-fast insulin aspart compared with insulin aspart after subcutaneous injection at a dose of 0.2 U / kg in Japanese with type 1 diabetes. SBDiAsp - ultra-fast insulin aspart; IASP - insulin aspart; T1DM - type 1 diabetes mellitus; Food - units. Adapted from Shiramoto et al. [25]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5520

	Title	Fig. 11. Average 5-hour serum insulin aspart concentration profiles for 0.2 u / kg aspart administered subcutaneously in the abdomen, shoulder, or thigh of healthy volunteers. IASP - insulin aspart; Food - units. Adapted from Hövelmann et al. [26]
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5521

	Title	Fig. 12. An increase in postprandial glycemia for ultrafast insulin aspart compared with insulin aspart in patients with type 1 diabetes mellitus during a 4-hour test with a standard dietary load after 52 weeks of therapy with multiple injections of insulin (A) or after 16 weeks of treatment with PPI ( B) The study participants received a bolus dose of 0.1 U / kg followed by a liquid meal (approximately 80 g of carbohydrates) consumed over 12 minutes. The bars show ± standard error. * p <0.001; p = 0.001; * p = 0.01. PPII - continuous subcutaneous infusion of insulin; SBDiAsp - ultra-fast insulin aspart; iAsp - insulin aspart; BCP - postprandial glucose; T1DM - type 1 diabetes mellitus; Food - units. From Mathieu et al. [28] and Klonoff et al. [29].
	Date	2020-06-25
Digital Object Identifier	https://doi.org/10.14341/DM12357-5522

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Diabetes mellitus

Fast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences

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