Degludec: the new ultra-long insulin analogue

Abstract

The development of extended-action insulin analogues was motivated by the unfavorable pharmacokinetic (PK) profile of the conventional long-acting insulin formulations, generally associated with marked inter and intra patient variability and site- and dose-dependent effect variation. The new ultra-long insulin analogue degludec (IDeg) has the same amino acid sequence as human insulin except for the removal of threonine in the position 30 of the B chain (Des-B30, "De") and the attachment, via a glutamic acid linker ("glu"), of a 16-carbon fatty diacid (hexadecanoic diacid, "dec") to lysine in the position 29 of the B chain. These modifications allow that, after changing from the pharmaceutical formulation to the subcutaneous environment, IDeg precipitates in the subcutaneous tissue, forming a depot that undergoes a highly predictable gradual dissociation. Thus, once-daily dosing of IDeg results in a low peak: trough ratio, with consequent low intra-individual variability and plasmatic concentrations less critically dependent upon the time of injections. The clinical development program of IDeg (BEGIN) was comprised of 9 therapeutic confirmatory trials of longer duration (26-52 weeks) and showed that the efficacy of IDeg is comparable to insulin glargine in type 1 (T1D) and type 2 (T2D) diabetes patients across different age, body mass index and ethnic groups. This new ultra-long insulin analogue presents as advantages flexibility in dose timing and lower risk of hypoglycemia.

Keywords: Degludec; Extended-action insulin analogues; Hypoglycemia.

Fig. 1

The structural formula of insulin degludec. Adapted from Reference [15]

Fig. 2

In the solvent conditions in insulin degludec formulation, the presence of zinc and resorcinol determines the formation of hexamers, and the presence of zinc and phenol determines the formation of dihexamer (upper panel). In the subcutaneous tissue after insulin degludec injection, phenol depletion promotes the self-association of dihexamers to form linear multihexamers, which will precipitate (lower panel). The black bars between degludec hexamers represent the acyl modification of LysB29. Adapted from Reference [8] (Steensgaard et al.)

Fig. 3

Day-to-day variability in the glucose - lowering effect of insulin degludec (IDeg) and insulin glargine (IGlar) over 24 h at steady state as shown by the coefficient of variation (CV) for the pharmacodynamic endpoint (area under the curve for glucose infusion rates from 0–24 h). Adapted from Reference [13] (Heise et al.)

Fig. 4

Mean values of HbA1c observed in the 9 therapeutic confirmatory trials at baseline and at end of trial (EOT) for insulin degludec (IDeg) and comparators (insulin glargin, except in trials 3585 [insulin determir] and 3580 [sitagliptin]). FF: Fixed-flexible schedule; OADs: oral antidiabetic drugs; T1D: Type 1 diabetes; T2D: Type 2 diabetes. Adapted from Reference [15]

Fig. 5

The frequency of confirmed nocturnal hypoglycemia (between 00:01 and 5:59 am) with insulin degludec (IDeg) and comparators (insulin glargin, except in trial 3580 [sitagliptin]) in Type 2 diabetes patients participating in 6 therapeutic confirmatory trials. FF: Fixed-flexible schedule; PYE: patient years of exposure; T1D: Type 1 diabetes; T2D: Type 2 diabetes. Adapted from Reference [15]