A Double-Blind, Randomized, Dose-Response Study Investigating the Pharmacodynamic and Pharmacokinetic Properties of the Long-Acting Insulin Analog Detemir

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Abstract
OBJECTIVE—To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin detemir (0.1, 0.2, 0.4, 0.8, and 1.6 units/kg; 1 unit = 24 nmol) and one subcutaneous dose 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 isoglycemic clamp (7.2 mmol/l) 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 AUCGIR (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 detemir vs. 0.3 IU/kg NPH, respectively. CONCLUSIONS—This study shows that insulin detemir provides a flat and protracted pharmacodynamic profile.