T he long-acting insulin analog insulin glargine (HOE901) is produced by substituting asparagine with glycine in position A21 of the A-chain of the human insulin molecule and by adding 2 arginine-molecules on positions B31 and B32 of the B-chain of the human insulin molecule. These modifications of the insulin molecule led to a shift of the isoelectric point from pH 5.4 in native insulin to 6.7 ± 0.2, making HOE901 a soluble insulin preparation at a slightly acidic pH and a less soluble insulin preparation at physiological pH levels. After subcutaneous injection, HOE901 precipitates in the subcutaneous tissue, which delays its absorption and thereby prolongs its duration of action. Moreover, HOE901 forms hexamers that are more stable and more dense than those of human insulin (1).Up to now, the protracted time-action profile of HOE901 in comparison with that of NPH insulin has never been described in published clinical pharmacology studies. Only abstracts or review articles describing investigations of the time-action profile are available (2-4). Furthermore, these studies investigated HOE901 with the addition of 15 and 80 µg/ml zinc, which is different than the zinc content of HOE901 that is used in phase II and phase III clinical trials (30 µg/ml). Even more importantly, one of these studies (2) conducted in healthy volunteers suffers from a problematic study design that uses somatostatin for suppression of the endogenous insulin production. Somatostatin is well known to influence subcutaneous blood flow and insulin clearance (5), which makes pharmacodynamic results difficult to interpret.A continuous intravenous insulin infusion allows the establishment of comparable baseline insulin levels and suppression of endogenous insulin secretion. Nevertheless, the infused insulin induces a metabolic effect on its own, which might vary over time, especially over a study duration of Ͼ12 h. To correct for this metabolic effect of the intravenous insulin infusion and the prolonged fasting, a control experiment with application of placebo must be included.The aim of our study was to evaluate the pharmacodynamic properties of HOE901 (with a zinc concentration of 30 µg/ml) in comparison with those of NPH insulin after subcutaneous injection in healthy volunteers, taking into account the metabolic effect of the continuous intravenous insulin infusion.
RESEARCH DESIGN ANDMETHODS -This euglycemic glucose clamp study was designed as a single-dose randomized double-blind placebo-conFrom the Department of Metabolic Diseases and Nutrition, the World Health Organization Collaborating Centre for Diabetes, Heinrich-Heine University, Düsseldorf, Germany.Address correspondence and reprint requests to Lutz Heinemann, PhD, Profil Institute for Metabolic Research, Stresemannallee 6, 41460 Neuss, Germany. E-mail: lutz.heinemann@profil-research.de.Abbreviations: AUC, area under the curve; C max , maximal serum insulin concentration; C min , minimal serum insulin concentration; CV, coefficient of variation; GIR, glucose infusion rate; GIR ma...
