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

T Heise, U Hövelmann, L Brøndsted, C L Adrian, L Nosek, H Haahr, T Heise, U Hövelmann, L Brøndsted, C L Adrian, L Nosek, H Haahr

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.

© 2015 John Wiley & Sons Ltd.

Figures

Figure 1
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
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
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.

References

    1. Woerle HJ, Neumann C, Zschau S et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract 2007; 77: 280–285.
    1. International Diabetes Federation Guideline Development Group . Guideline for management of postmeal glucose in diabetes. Diabetes Res Clin Pract 2014; 103: 256–268.
    1. Nesher R, Cerasi E. Modeling phasic insulin release: immediate and time‐dependent effects of glucose. Diabetes 2002; 51(Suppl. 1): S53–59.
    1. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW. Physiological importance of deficiency in early prandial insulin secretion in non‐insulin‐dependent diabetes. Diabetes 1988; 37: 736–744.
    1. Del Prato S, Tiengo A. The importance of first‐phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev 2001; 17: 164–174.
    1. Luzi L, DeFronzo RA. Effect of loss of first‐phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol 1989; 257: E241–246.
    1. Heinemann L, Muchmore DB. Ultrafast‐acting insulins: state of the art. J Diabetes Sci Technol 2012; 6: 728–742.
    1. Brunner GA, Hirschberger S, Sendlhofer G et al. Post‐prandial administration of the insulin analogue insulin aspart in patients with type 1 diabetes mellitus. Diabet Med 2000; 17: 371–375.
    1. Heinemann L, Heise T, Wahl LC et al. Prandial glycaemia after a carbohydrate‐rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin. Diabet Med 1996; 13: 625–629.
    1. Heise T. Getting closer to physiologic insulin secretion. Clin Ther 2007; 29(Suppl. D): S161–165.
    1. Cobry E, McFann K, Messer L et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010; 12: 173–177.
    1. Luijf YM, van Bon AC, Hoekstra JB, Devries JH. Premeal injection of rapid‐acting insulin reduces postprandial glycemic excursions in type 1 diabetes. Diabetes Care 2010; 33: 2152–2155.
    1. Howey DC, Bowsher RR, Brunelle RL et al. [Lys(B28), Pro(B29)]‐human insulin: effect of injection time on postprandial glycemia. Clin Pharmacol Ther 1995; 58: 459–469.
    1. Lampe J, Penoyer DA, Hadesty S et al. Timing is everything: results to an observational study of mealtime insulin practices. Clin Nurse Spec 2014; 28: 161–167.
    1. Overmann H, Heinemann L. Injection‐meal interval: recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract 1999; 43: 137–142.
    1. Food and Drug Administration . Inactive ingredient search for approved drug products. 2013. Available from URL: . Accessed April 2015.
    1. Heise T, Hermanski L, Nosek L et al. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady‐state conditions in type 1 diabetes. Diabetes Obes Metab 2012; 14: 859–864.
    1. Heise T, Nosek L, Roepstorff C, Chenji S, Klein O, Haahr H. Distinct prandial and basal glucose lowering effects of insulin degludec/insulin aspart (IDegAsp) at steady state in subjects with type 1 diabetes. Diabetes Ther 2014; 5: 255–265.
    1. Workgroup on Hypoglycemia ADA . Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005; 28: 1245–1249.
    1. Heinemann L, Weyer C, Rave K et al. Comparison of the time‐action profiles of U40‐ and U100‐regular human insulin and the rapid‐acting insulin analogue B28 Asp. Exp Clin Endocrinol Diabetes 1997; 105: 140–144.
    1. Bruttomesso D, Pianta A, Mari A et al. Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients. Diabetes 1999; 48: 99–105.
    1. Rossetti P, Porcellati F, Fanelli CG et al. Superiority of insulin analogues versus human insulin in the treatment of diabetes mellitus. Arch Physiol Biochem 2008; 114: 3–10.
    1. Cengiz E. Undeniable need for ultrafast‐acting insulin: the pediatric perspective. J Diabetes Sci Technol 2012; 6: 797–801.
    1. Shah VN, Shoskes A, Tawfik B, Garg SK. Closed‐loop system in the management of diabetes: past, present, and future. Diabetes Technol Ther 2014; 16: 477–490.
    1. Muchmore DB, Vaughn DE. Accelerating and improving the consistency of rapid‐acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase. J Diabetes Sci Technol 2012; 6: 764–772.
    1. Krasner A, Pohl R, Simms P et al. A review of a family of ultra‐rapid‐acting insulins: formulation development. J Diabetes Sci Technol 2012; 6: 786–796.
    1. Heise T, Haahr H, Jensen L et al. Faster‐acting insulin aspart improves postprandial glycemia vs insulin aspart in patients with type 1 diabetes mellitus (T1DM). Diabetes 2014; 63(Suppl. 1): A34 (129‐OR).

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera