original article Diabetes, Obesity and Metabolism 15: 241 – 245, 2013. © 2012 Blackwell Publishing Ltd original article A direct comparison of the pharmacodynamic properties of insulin detemir and neutral protamine lispro insulin in patients with type 1 diabetes S. Korsatko 1 , K. Glettler 1 , K. J. Olsen 2 , A. Wutte 1 , G. Bock 1 , G. Koehler 1 , J. K. Mader 1 , B. Semlitsch 1 & T. R. Pieber 1 1 Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Larix ApS, Ballerup, Denmark Aims: To compare the pharmacodynamic properties of insulin detemir (detemir) and neutral protamine lispro (NPL) insulin using a euglycaemic glucose clamp. Methods: In a double-blind, crossover study, 30 patients with C-peptide negative type 1 diabetes were randomly assigned to a single dose (0.4 U/kg) of detemir and NPL. Plasma glucose (PG) was normalized with a variable insulin infusion and then decreased stepwise, followed by a euglycaemic clamp at 5.5 mmol/l over 32 h. Duration of action was defined as time from dosing until PG exceeded 8.3 mmol/l for at least 30 min. Results: Duration of action was similar for detemir [23.0 (range 2.25–32) h] and NPL [22.0 (9.5–32) h], p = 0.55. Using glucose infusion rate (GIR) parameters, detemir showed a flatter pharmacodynamic profile versus NPL: area under the curve, AUC GIR(0–32) = 1326 vs. 1841 mg/kg, p < 0.01 (detemir vs. NPL, respectively); AUC GIR(0–12) = 784 vs. 1392 mg/kg, p < 0.05; AUC GIR(12–32) = 455 vs. 274 mg/kg, p = 0.051; GIR late (12–32)/GIR early (0–12) ratio = 0.33 vs. 0.04, p < 0.001. Detemir also showed a lower and later peak of action than NPL [GIR max 2.0 vs. 3.2 mg/kg/min, p < 0.01; T max 9.1 (95% confidence interval: 3.0–14.7) vs. 7.0 h (1.8–15.2)]. Conclusions: Detemir and NPL had similar duration of action of approximately 24 h in patients with type 1 diabetes. Compared with NPL, detemir had a flatter profile with a more even distribution of metabolic effect over 24 h. Keywords: insulin analogues, insulin therapy, pharmacodynamics, randomized trial, type 1 diabetes Date submitted 11 July 2012; date of first decision 17 August 2012; date of final acceptance 22 September 2012 Introduction Basal insulin preparations attempt to mimic the low and con- stant plasma insulin levels seen between meals and overnight in normal physiology [1]. The first available intermediate-acting insulin, neutral protamine Hagedorn (NPH), represented a tremendous improvement from unmodified insulin as its pro- longed duration of action and allowed patients to reduce the daily number of insulin injections [1]. However, NPH insulin has a peak of action 4 – 6 h after injection, followed by a marked decrease in activity. As a result, when NPH insulin is admin- istered at bedtime, insulin levels peak between midnight and 2 am, when less insulin is required, increasing the risk of noc- turnal hypoglycaemia [2 – 4]. In addition, the insulin levels are often not sufficient to cover the increased requirements at dawn [2 – 4]. To overcome these shortcomings, long-acting insulin analogues that better mimic physiological basal insulin secre- tion – such as insulin glargine and insulin detemir (detemir) – have been developed [1]. For the insulin analogues detemir and Correspondence to: Thomas R. Pieber, MD, Department of Internal Medicine, Division of Diabetes and Metabolism, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: thomas.pieber@medunigraz.at glargine, flat time–action profiles with duration of action of up to 24 h have been described in patients with type 1 and type 2 diabetes [5 – 8]. Another relatively recent intermediate-acting analogue insulin is neutral protamine lispro (NPL) insulin – a protamine-based insulin formulation of the analogue insulin lispro. Single-dose time – action profiles for NPL are available in healthy subjects and patients with type 2 diabetes [9,10]. However, there are no data available comparing the pharma- cokinetic (PK) and pharmacodynamic (PD) properties of NPL with another insulin within the basal insulin analogue family in patients with type 1 diabetes. Therefore, detemir was chosen as a comparator in our study. The gold standard to elucidate the PD properties of new insulin analogues is to perform a glucose clamp. In fact, regulatory bodies such as the European Medicines Agency consider results of time – action profiles using euglycaemic clamps of primary importance to show therapeutic equivalence or differences between insulin prepa- rations [11]. Moreover, as patients with C-peptide negative type 1 diabetes lack endogenous insulin, euglycaemic clamp studies performed in this population are likely to provide accurate time – action profiles because the results are not confounded by endogenous insulin secretion [12]. This study aimed to