A review of the pharmacological properties of insulin degludec and their clinical relevance

Abstract

Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. To date, a large number of studies have been conducted to investigate the pharmacokinetic and pharmacodynamic properties of IDeg. Standardised methods for collection and analysis of blood samples (for pharmacokinetic endpoints) and euglycaemic clamp procedures (for pharmacodynamic endpoints) were applied across studies to enable cross-study evaluation of important pharmacokinetic and pharmacodynamic parameters. Data show that IDeg has a half-life of >25 h [compared with ~12 h for insulin glargine (IGlar)] and reaches steady state within 3 days of administration in all patient populations investigated. The pharmacokinetic profile of IDeg demonstrates an even distribution of exposure across one dosing interval. The pharmacodynamic profile of IDeg is flat and stable, demonstrated by an even distribution of glucose-lowering effect across all four 6-h intervals in a 24-h period (one dosing day). These properties were consistently demonstrated across different type 1 and type 2 diabetes mellitus patient populations, including those from different ethnic origins (both males and females with type 2 diabetes), the elderly, and patients with hepatic or renal impairment. IDeg has an ultra-long duration of action exceeding 42 h and demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar. This review discusses the pharmacokinetic and pharmacodynamic data accumulated thus far, and the relevance of these results from a clinical perspective.

Fig. 1

Conceptual model demonstrating action profiles with once-daily dosing of a basal insulin with duration of action a ≤24 h and b substantially longer than 24 h [14]

Fig. 2

Mechanism of protraction of insulin degludec (IDeg) and visualisation of IDeg using electron microscopy. a Schematic representation of the formation of IDeg multi-hexamers in the subcutaneous depot from di-hexamers in the pharmaceutical formulation [adapted from Jonassen et al. [16] (Fig. 5, p. 2,112), with kind permission from Springer Science + Business Media). b A transmission electron microscope image showing the effect of phenol on IDeg multi-hexamer linkage—the figure depicts elongated IDeg structures in the absence of phenol; the scale bar represents 200 nm (adapted and reprinted with permission from Steensgaard et al. [18]; Copyright 2014 American Chemical Society)

Fig. 3

Concentration–time profiles of insulin degludec 100 U/mL (IDeg U100) dosed at 0.4 U/kg in subjects with a type 1 diabetes mellitus [34] or b type 2 diabetes (data taken from Heise et al. [21]). Also shown are the concentration–time profiles for c IDeg U100 and IDeg 200 U/mL (IDeg U200) dosed at 0.4 U/kg in subjects with type 1 diabetes [reproduced from Korsatko et al. [20], Fig. 2a, p. 518], with kind permission from Springer Science + Business Media)

Fig. 4

Glucose infusion rate profiles with insulin degludec (IDeg) for subjects with a type 1 diabetes mellitus [23], b type 2 diabetes (reproduced from Heise et al. [21], with permission from John Wiley and Sons, Inc.) and c different race or ethnic backgrounds with type 2 diabetes (reprinted from Hompesch et al. [25], with permission from Elsevier)

Fig. 5

Duration of action of insulin degludec (IDeg) as indicated by the duration of blood glucose control during glucose clamp experiments in subjects with a type 1 diabetes mellitus (0.6 U/kg) [15] or b type 2 diabetes (reproduced from Heise et al. [21], with permission from John Wiley and Sons, Inc.)

Fig. 6

Subject-specific day-to-day variability in the area under the glucose infusion rate curve for insulin degludec (IDeg) or insulin glargine (IGlar) dosed at 0.4 U/kg during one dosing interval (0–24 h) at steady state (reproduced from Heise et al. [22], with permission from John Wiley and Sons, Inc.). CV coefficient of variation

Fig. 7

Day-to-day variability in glucose-lowering effect of insulin degludec (IDeg) and insulin glargine (IGlar) dosed at 0.4 U/kg over 24 h at steady state (reproduced from Heise et al. [22], with permission from John Wiley and Sons, Inc.). AUC _GIR area under the glucose infusion rate profile, CV coefficient of variation

Fig. 8

Simulated insulin degludec (IDeg) concentration–time profiles at steady state in smaller children (1–5 years), children (6–11 years), adolescents (12–17 years) and adults (18–65 years) over a 24-h dosing interval. The simulation was made using the final model from a joint analysis of the pharmacokinetic data from a single-dose trial with IDeg in children, adolescents and adults with type 1 diabetes mellitus (N = 36) [29] and steady-state population pharmacokinetic data obtained over 26 weeks in a clinical trial with IDeg in children and adolescents with type 1 diabetes (N = 169) [40]. The profiles shown are (median) for a typical subject in each age group [with body weight (BW) equal to the median BW in that age group]