Day-to-Day and Within-Day Variability in Glucose-Lowering Effect Between Insulin Degludec and Insulin Glargine (100 U/mL and 300 U/mL): A Comparison Across Studies

Abstract

Background: Insulin degludec (IDeg) has significantly lower day-to-day and within-day variability compared to insulin glargine (IGlar) 100U/mL (U100) and 300U/mL (U300). Here, we report post hoc assessments to confirm the robustness of these observations while accounting for potential experimental confounders.

Methods: Two euglycemic clamp studies in type 1 diabetes patients, comparing IDeg to IGlar-U100 (Study A, parallel design, 54 patients; Study B, crossover, 22 patients) and one study comparing IDeg to IGlar-U300 (Study C, crossover, 57 patients), all dosed at 0.4U/kg, were evaluated. Pharmacodynamic parameters were assessed at steady state from glucose infusion rate (GIR) profiles following three 24-hour euglycemic clamps in Studies A (162 clamps) and C (342 clamps), and one 42-hour clamp in Study B (44 clamps).

Results: Pooled data (Studies A and B) showed that IDeg had an even distribution of glucose-lowering effect over the 24-hour dosing interval that was consistent with Study C. IGlar-U100 showed a constant decrease in glucose-lowering effect over 24 hours while IGlar-U300 had a lower effect in the middle of the dosing interval (6-18 hours). Relative within-day variability of IDeg was 40% and 37% lower than IGlar-U100 and -U300, respectively. Exclusion of profiles with low response in Study C (19/342 clamps) did not impact the difference in the distribution of glucose-lowering effect or within-day variability. Day-to-day variability was significantly lower with IDeg compared to IGlar-U100 and -U300 based on smoothed and unsmoothed GIR data.

Conclusions: Significantly lower relative within-day and day-to-day variability was confirmed irrespective of experimental considerations for IDeg compared to IGlar-U100 and IGlar-U300.

Keywords: day-to-day variability; degludec; glargine; within-day variability.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TH is a shareholder of Profil, which received research funds from Adocia, Biocon, Dance Pharmaceuticals, Eli Lilly, Johnson&Johnson, Julphar, Medimmune, Mylan, Nordic Bioscience, Novo Nordisk, Poxel, Roche Diagnostics, Saniona, Sanofi, Senseonics, SkyePharma, and Zealand Pharma. In addition, he is a member of advisory panels for Novo Nordisk and received speaker honoraria and travel grants from Eli Lilly, Novo Nordisk, and Sanofi. KK and HLH are employees and shareholders of Novo Nordisk A/S.

Figures

Figure 1.

Distribution of glucose-lowering effect with IDeg compared to IGlar-U100 and -U300 at a dose level of 0.4 U/kg. (a) Pooled data from Studies A and B (IDeg vs IGlar-U100). (b) Data from Study C (IDeg vs IGlar-U300) previously published. (c) Data from Study C (IDeg vs IGlar-U300), excluding 19 clamps 14 patients having low response while receiving IGlar-U300; No clamps with low response were seen following IDeg treatment.

Figure 2.

Relative within-day variability with IDeg compared to IGlar at a dose level of 0.4 U/kg. P ≤ .05 for all ratios. Only 1 patient had low response in Study B; hence, a sensitivity analyses was not conducted. Pooled analysis includes data from all patients in Studies A and B.

Figure 3.

Day-to-day variability in glucose-lowering effect (2-hour intervals) compared to IGlar-U100 and IGlar-U300. *P < .05. Difference between the treatments expressed as variance ratio IGlar/IDeg. Day-to-day variability (AUCGIR) expressed as CV% =(e(S2)−1)×100 where s is the within-patient variance.