Insulin degludec (IDeg) is an ultra-long-acting basal insulin that forms soluble multi-hexamers after injection. These release monomers slowly and continuously to produce a flat and stable glucose-lowering effect. We describe the pharmacokinetic and pharmacodynamic properties of IDeg compared with insulin glargine (IGlar) under steady-state conditions in patients with type 1 diabetes (T1D). This was a randomised, double-blind, two-period crossover study in 66 patients with T1D. Patients (mean, 37 years old, BMI 24.9 kg/m2, HbA1c 8.1%) received one of three fixed doses (0.4, 0.6, 0.8 U/kg) of IDeg and IGlar once daily for 8 days with a 721 day wash-out period. A euglycaemic glucose clamp (glucose level: 5.5 mmol/L) was performed at the end of each treatment period with PK sampling throughout and for 120 h after last dose. Total exposure to IDeg at steady state was stable and increased proportionally with increasing dose. The serum exposure to IDeg was equally distributed between the first and second 12 hours post-dosing (AUC[IDeg, 0-12h]/AUC[IDeg, total] = 0.5) whereas 60% of exposure to IGlar occurred during the first 12 hours (AUC[IGlar,0-12h]/AUC[IGlar, total] = 0.6) for all doses. Likewise, the cumulated AUC below and above the average glucose infusion rate (AUCF[GIR]) was considerably lower for all doses of IDeg (0.25, 0.37, 0.38 mg/kg/min) than with IGlar (0.39, 0.54, 0.73 mg/kg/min). The estimated molar dose ratio (AUC[GIR, total]) was 1.03 [95% CI: 0.95; 1.12]. IDeg was detectable in the serum for at least 120 h post-dosing, whereas IGlar fell below the lower limit of quantification 3648 h post-dosing. Mean terminal half-lives were 25.4 and 12.5 h for IDeg and IGlar, respectively. Both treatments were well tolerated with no safety concerns. IDeg has a half-life that is twice as long as IGlar with a more evenly distributed and stable pharmacokinetic exposure and glucose-lowering effect, over 24 hours at steady state in patients with T1D.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.