Clinical use of insulin degludec

Abstract

The limitations of current basal insulin preparations include concerns related to their pharmacokinetic and pharmacodynamic properties, hypoglycaemia, weight gain, and perception of management complexity, including rigid dosing schedules. Insulin degludec (IDeg) is a novel basal insulin with improved pharmacokinetic and pharmacodynamic properties compared to insulin glargine (IGlar) including a long half-life of ∼25 h and a duration of action >42 h at steady state, providing a flat and stable blood glucose-lowering effect when injected once daily. Evidence from phase 3a clinical trials with a treat-to-target design in patients with type 1 and type 2 diabetes has shown that IDeg has similar efficacy to IGlar, with a 9% and 26% reduction in risk of overall and nocturnal hypoglycaemia, respectively (in the pooled population) during the entire treatment period, and a 16% and 32% reduction during the maintenance period, respectively. Given its pharmacodynamic properties, IDeg offers a broad dosing window, allowing for flexible dose administration, if required. Two different formulations of IDeg are available (100 units/mL [U100] and 200 units/mL), the latter providing the same IDeg dose as the U100 formulation in half the injection volume. The unique pharmacokinetic profile of IDeg facilitates glycaemic control while minimising the risk of nocturnal hypoglycaemia.

Inpatient hyperglycemia management: the opportunities of a new basal insulin

“…A flat and stable glucoselowering effect with IDeg that is evenly distributed across the 24-h dosing interval has also been shown in patients with type 2 diabetes (T2DM). 11 Importantly, the ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in patients with type 1 diabetes (T1DM) and T2DM are maintained in various subpopulations, such as the elderly and those with hepatic or renal impairment (including those with endstage renal disease). 11…”

“…Similarly, nocturnal hypoglycemia was defined as confirmed episodes of hypoglycemia occurring between 00:01 h and 05:59 h, in order to minimize confounding by any hypoglycemia related to the prandial insulin component in the basal-bolus studies. 11 Hollander and colleagues tested long-term safety and efficacy of insulin degludec in basal-bolus scheme. Advanced T2DM patients were randomised to once-daily IDeg or IGlar, with mealtime insulin aspart±metformin±pioglitazone, and titrated to prebreakfast plasma glucose values of 3.9-4.9 mmol/L.…”

“…Following subcutaneous injection and thanks to phenol dispersion, IDeg the dihexamers self-associate to form a stable depot of multi-hexamer chains at the injection site. With the gradual diffusion of zinc, however, these chains are expected to gradually disassemble to release monomers from the terminal ends of multihexamers 11,12 (Figure 1). …”

“…8 However, IDet and IGlar exhibit significant residual within-patient variability in their pharmacokinetic and pharmacodynamic profiles that can lead to less predictable glucose lowering effects, which in turn contributes to the increased risk of hypoglycemia and can undermine dose titration. 11 Improvements in the pharmacokinetic properties of basal insulin analogues would entail a prolonged duration of action combined with a less variable pharmacodynamic effect, which might lead to more predictable glycaemic control, less hypoglycemia and greater dosing flexibility. 11…”

“…The implications of the promising pharmacokinetic and pharmacodynamic characteristics of IDeg have been investigated in a large clinical trial programme (BEGIN) involving more than 11,000 patients with T1DM and T2DM ( 11 This definition of hypoglycemia (that is, a low hypoglycemia cut-off level due to the low target plasma glucose level) was chosen to avoid false positives and to discriminate hypoglycemia with neuroglycopenic symptoms. Similarly, nocturnal hypoglycemia was defined as confirmed episodes of hypoglycemia occurring between 00:01 h and 05:59 h, in order to minimize confounding by any hypoglycemia related to the prandial insulin component in the basal-bolus studies.…”