Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady‐state conditions in type 1 diabetes

Serum, urine and dialysate concentrations of IDeg were measured using a specific sandwich enzyme-linked immunosorbent assay.

“Serum, urine and dialysate (where relevant) concentrations of IDeg were measured using a specific sandwich enzyme-linked immunosorbent assay [21, 22, 27, 28].”

IDeg demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar.

“The study demonstrated four-times lower within-subject variability (AUCGIR,τ,SS [glucose-lowering effect of IDeg at SS during one dosing interval (0–24 h)]) with IDeg [coefficient of variation (CV) 20 %] than IGlar (CV 82 %) (p < 0.0001).”

Overarching exclusion criteria across all trials included smoking and subjects with a history of recurrent severe hypoglycaemia or hypoglycaemic unawareness to minimise potential confounders.

“Overarching exclusion criteria across all trials also included smoking [24, 26] and subjects with a history of recurrent severe hypoglycaemia or hypoglycaemic unawareness [21, 22, 24, 25], again to minimise potential variables that might have a confounding influence on data interpretation.”

To ensure washout of other insulins prior to the first dose, subjects were not allowed to use IDet or IGlar for the preceding 48 h, and intermediate-acting insulins such as NPH or pre-mixed insulin products during the preceding 22 h.

“For example, to ensure the washout of all other insulins prior to administering the first dose of the trial drug, the subjects were not allowed to use IDet or IGlar for the preceding 48 h, and intermediate-acting insulins such as neutral protamine Hagedorn (NPH) or any pre-mixed insulin products during the preceding 22 h [20–22].”

The distinct mechanism of protraction of IDeg offers specific advantages in reducing within-subject variability, such as it remaining in solution after subcutaneous injection, unlike IGlar which forms microprecipitates after injection that must re-dissolve before absorption.

“Moreover, the distinct mechanism of protraction of IDeg offers specific advantages in reducing within-subject variability, such as it remaining in solution after SC injection, unlike IGlar which forms microprecipitates after injection that must re-dissolve before absorption [22].”

The property of IGlar forming microprecipitates that must re-dissolve before absorption is most likely one of the causes for the higher variability observed for IGlar.

“This latter property is most likely one of the causes for the higher variability observed for IGlar, as discussed in Sect. 2.”

The estimated difference between IDeg and IGlar in within-subject variation was driven by fluctuation in the majority of subjects receiving IGlar rather than any extreme variability demonstrated by outliers.

“The estimated difference between IDeg and IGlar in within-subject variation was driven by fluctuation in the majority of the subjects receiving IGlar rather than any extreme variability demonstrated by outliers, particularly for IGlar (Fig. 6) [22].”

The variability of IGlar was significantly higher and increased substantially 6-8 h after dosing, reaching a maximum at 14-16 h after dosing.

“In comparison, the variability of IGlar was significantly higher and increased substantially 6–8 h after dosing, reaching a maximum at 14–16 h after dosing [22].”

Within-subject variability was estimated using a linear mixed model on log-transformed pharmacodynamic endpoints derived from GIR profiles during the clamps.

“In this study, within-subject variability was estimated using a linear mixed model on log-transformed pharmacodynamic endpoints derived from the GIR profiles during the clamps [22].”

The risk of experiencing less than half the average effect on any given day (potential hyperglycaemia) was projected as <0.1% for IDeg and 17% for IGlar.

“Similarly, the risk of experiencing less than half the average effect on any given day (i.e. potential hyperglycaemia) was projected as <0.1 % for IDeg and 17 % for IGlar [22].”

Subject-specific CVs (%) for AUCGIR,τ,SS were consistently lower for IDeg than for IGlar when individual CVs were compared in ranked order.

“As shown in Fig. 6, subject-specific CVs (%) for AUCGIR,τ,SS were consistently lower for IDeg than for IGlar when the individual CVs (%) were compared in ranked order.”

Significantly lower within-subject variability in the level of maximum effect (GIRmax,SS) for IDeg (CV 18%) versus IGlar (CV 60%) (p < 0.0001) was reported.

“Significantly lower within-subject variability in the level of maximum effect (GIRmax,SS) for IDeg (CV 18 %) versus IGlar (CV 60 %) (p < 0.0001) was also reported [22].”

Day-to-day within-subject variability with IDeg at steady state in glucose-lowering effect was investigated in a randomised, single-centre, parallel-group, double-blind trial in subjects with T1DM treated with 0.4 U/kg IDeg or IGlar once daily.

“Day-to-day within-subject variability with IDeg at SS in glucose-lowering effect was investigated in a randomised, single-centre, parallel-group, double-blind trial in subjects with T1DM who were treated with 0.4 U/kg of IDeg or IGlar, administered once daily [22].”

The lower within-subject variability with IDeg was consistent throughout the 24-h period.

“Furthermore, this was consistent throughout the 24-h period.”

Within-patient variability for 2-h intervals of AUCGIR was consistently low with IDeg and significantly lower with IDeg than with IGlar over the entire 24-h dosing interval at steady state.

“As illustrated in Fig. 7, the within-patient variability for 2-h intervals of AUCGIR was consistently low with IDeg and significantly lower with IDeg than with IGlar over the entire 24-h dosing interval at SS [22].”

Although cytotoxicity measures are fundamental in assessing a drug's potential for hepatotoxicity in vitro, gene expression and various phenotypic changes can occur at much lower concentrations.

“although cytotoxicity measures are fundamental in the assessment of a drug’s potential for hepatotoxicity in vitro33,34, gene expression and various phenotypic changes can occur at much lower concentrations35,36.”