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

Abstract

AimTo 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 methodsIn 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.ResultsOverall, 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.

A comparative effectiveness study of degludec and insulin glargine 300 U/mL in insulin‐naïve patients with type 2 diabetes

“…They also have larger reductions in rates of hypoglycaemia and likelihood of hypoglycaemia, and a lower risk of treatment discontinuation compared with those initiating treatment with glargine U300. These data are consistent with previous observations from a pharmacokinetic/pharmacodynamic study of degludec and glargine U300 that identified the potential of degludec to result in a lower risk of hypoglycaemia and a relatively higher dose potency compared with glargine U300 …”

“…Prior to publication of the DELIVER D+ and BRIGHT studies, it was anticipated that use of degludec would result in lower rates of hypoglycaemia than use of glargine U300, as is the case in comparisons of degludec with insulin glargine U100. This assumption was based on the pharmacodynamic evidence that degludec has a lower day‐to‐day and within‐day variability of glucose‐lowering effect than glargine U300, which may enable tighter glycaemic control with a lower risk of hypoglycaemia . However, in the DELIVER D+ and BRIGHT studies, no differences were found in rate of hypoglycaemia between degludec and glargine U300.…”

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)

“…These properties have been demonstrated across different patient populations in several experimental laboratory studies [20, 21]. In the clinical setting, insulin degludec has consistently demonstrated lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemia compared with other basal insulins [22–24].…”

A European, multicentre, retrospective, non‐interventional study (EU‐TREAT) of the effectiveness of insulin degludec after switching basal insulin in a population with type 1 or type 2 diabetes

“…Insulin degludec (IDeg) is a basal insulin with a unique mode of protraction that provides an ultra‐long duration of action, exceeding 42 hours, and low day‐to‐day variability in blood glucose‐lowering effect compared with insulin glargine U100 and U300 . Randomized controlled trials (RCTs) in adults, using a treat‐to‐target approach, have demonstrated that IDeg is associated with a reduced risk of hypoglycaemia, vs other insulin analogues, at equivalent levels of glycaemic control …”