OBJECTIVE: To study the pharmacodynamic properties of the subcutaneously injected long-acting insulin analog HOE901 (30 microg/ml zinc) in comparison with those of NPH insulin and placebo. RESEARCH DESIGN AND METHODS: In this single-center double-blind euglycemic glucose clamp study, 15 healthy male volunteers (aged 27 +/- 4 years, BMI 22.2 +/- 1.8 kg/m2) received single subcutaneous injections of 0.4 U/kg body wt of HOE901, NPH insulin, or placebo on 3 study days in a randomized order. The necessary glucose infusion rates (GIRs) to keep blood glucose concentrations constant at 5.0 mmol/l were determined over a 30-h period after administration. RESULTS: The injection of HOE901 did not induce the pronounced peak in metabolic activity observed with NPH insulin (GIRmax 5.3 +/- 1.1 vs. 7.7 +/- 1.3 mg x kg(-1) x min(-1)) (P < 0.05); after an initial rise, metabolic activity was rather constant over the study period. This lack of peak was confirmed by a lower glucose consumption in the first 4 h after injection (area under the curve from 0 to 4 h [AUC(0-4 h)] 1.02 +/- 0.34 vs. 1.48 +/- 0.34 g/kg) (P < 0.001) with HOE901, as compared with NPH insulin. In this single-dose study, the metabolic effect measured over a period of 30 h was lower with HOE901 than with NPH insulin (AUC(0-30 h) 7.93 +/- 1.82 vs. 9.24 +/- 1.29 g/kg) (P < 0.05). CONCLUSIONS: This study shows that the soluble long-acting insulin analog HOE901 induces a smoother metabolic effect than NPH insulin, from which a better substitution of basal insulin requirements may follow.