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Randomized Controlled Trial
. 2017 Jul;19(7):1032-1039.
doi: 10.1111/dom.12938. Epub 2017 Apr 23.

Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes

Tim Heise  1 , Marianne Nørskov  2 , Leszek Nosek  1 , Kadriye Kaplan  2 , Susanne Famulla  1 , Hanne L Haahr  2
Affiliations
Randomized Controlled Trial

Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes

Tim Heise et al. Diabetes Obes Metab. 2017 Jul.

Abstract

Aim: To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes.

Materials and methods: In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period.

Results: Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively).

Conclusion: IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.

Keywords: insulin analogues; insulin therapy; pharmacodynamics; type 1 diabetes.

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Figures

Figure 1
Figure 1
Study design
Figure 2
Figure 2
Pharmacodynamic profiles: 24‐hour GIR profiles and distribution of glucose‐lowering effect at steady state for IDeg (A and C) and IGlar‐U300 (B and D). Shaded bands represent the standard error of mean in (A) and (B). (C) and (D) present AUCGIR for each 6‐hour interval as a percentage of AUCGIR ,τ, SS . *P < .0001 compared with the 0‐ to 6‐hour and 18‐ to 24‐hour intervals
Figure 3
Figure 3
Individual BG profiles for patients treated with IDeg (A) and IGlar‐U300 (B). Red dotted line = mean BG in each treatment group; number of patients = 57; BG target in the clamp was 5.5 mmol/L (100 mg/dL)
Figure 4
Figure 4
Patient‐specific day‐to‐day variability in AUCGIR ,τ, SS. SS, steady‐state
Figure 5
Figure 5
Day‐to‐day variability in glucose‐lowering effect over 24 hours at steady‐state. Differences between the treatments expressed as the variance ratio of IGlar‐U300:IDeg; a P < .05
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References

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