A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir

OBJECTIVE - To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin determir (0. 1, 0.2, 0.4, 0.8, and 1.6 units/kg; 1 unit = 24 nmol) and one subcutaneous close of NPH insulin (0.3 IU/kg; 1 IU = 6 nmol). RESEARCH DESIGN AND METHODS- This single-center, randomized, double-blind, six-period, crossover study was carried Out as a 24-h isoglycernic clamp (7.2 mmol/1) in 12 type 1 diabetic patients. RESULTS - Duration of action for insulin detemir was dose dependent and varied from 5.7, to 12.1. to 19.9, to 22.7, to 23.2 h for 0.1, 0.2, 0.4, 0.8, and 1.6 units/kg, respectively. Interpolation Of the dose-response relationships for AUC(GIR) (area under the glucose infusion rate curve) revealed that a detemir dose of 0.29 units/kg would provide the same effect as 0.3 IU/kg NPH but has a longer duration of action (16.9 vs. 12.7 h, respectively). Lower between-subject variability was observed for insulin detemir on duration of action (0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, P < 0.05) and GIRmax (maximal glucose infusion rate) (0.2 and 0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, both P < 0.05). Assessment of endogenous glucose production (EGP) and peripheral glucose uptake (PGU) resulted in an AOCEGP (area over the EGP curve) of 636 mg/kg (95% CI 279-879) vs. 584 (323-846) and an AUCPGU (area under the PGU curve) of 173 (47-316) vs. 328 (39-617) for 0.29 units/kg deteinir vs. 0.3 IU/kg NPH, respectively. CONCLUSIONS - This study shows that insulin detemir provides a flat and protracted pharmacodynamic profile.