Patient safety and minimizing risk with insulin administration - role of insulin degludec

Abstract

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long-term hypoglycemia or reduce diabetes-related complications.

Keywords: basal insulin; diabetes; hypoglycemia; safety.

Figures

Figure 1

Schematic representation of insulin degludec. DesB30 human insulin is acylated at the ε-amino group of LysineB29 with hexadecanoic acid via a γ-L-glutamic acid linker. Note: Reproduced from Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8):2104–2114. Copyright © 2012, the authors.

Figure 2

Schematic representation of the hypothesis for the mode of retarded absorption of insulin degludec. Insulin degludec is injected subcutaneously as a zinc phenol formulation containing insulin degludec dihexamers in the T3R3 conformation. Rapid loss of phenol changes the degludec hexamers to T6 configuration and multihexamer chains form. With slow diffusion of zinc, these chains break down into dimers, which quickly dissociate into readily absorbed monomers. Note: Reproduced from Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8): 2104–2114. Copyright © 2012, the authors.

Figure 3

Hypothetical examples of profiles of insulins with various half-lives. Notes: (A) Accumulation from first dose to steady state and (B) perturbations following various types of common dosing errors as indicated by arrows, when introduced at steady-state. When interpreting the effects of double-dosing (bottom row), it is important to note that different pharmacokinetic scales have been used for the rapid-acting and basal insulin curves. Fluctuations in insulin concentration (and therefore glucose-lowering action) are greatest, and dosing errors have the most acute effects, with basal insulin having a shorter half-life (eg, 6 hours) and duration of action. Fluctuations are dampened and dosing errors have less acute effects with insulin formulations having a longer half-life/duration of action. The half-lives for basal insulin shown in the figure correspond approximately to those of neutral protamine Hagedorn insulin (6 hours), insulin glargine (12.5 hours), and insulin degludec (25 hours). Reprinted from Endocrine Practice. Heise T, Meneghini LF. Insulin stacking versus therapeutic accumulation: understanding the differences. Endocr Pract. 2013;20(1):75–83. Copyright 2013, with permission from the American Association of Clinical Endocrinologists.