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Discussion of criteria for evaluating the quality of glucose clamp studies

Andreas V. Groth, Mikael S. Thomsen, Morten Colding-Jørgensen & Erik Mosekilde

Technical University of Denmark & Novo Nordisk A/S

The pharmacodynamic (PD) action of insulin and insulin analogues is the lowering of the blood glucose concentration (BG) by increased glucose uptake into the body tissues. The “golden standard” test of the PD time profile of any insulin analogue is a glucose clamp, in which the insulin analogue is administered to the test subject by the same route as intended for clinical use and BG is subsequently clamped, i.e. maintained approximately constant. This occurs by means of a variable Glucose Infusion Rate (GIR), by which one attempts to compensate as exactly as possible for the glucose disappearance from the blood induced by the insulin (analogue). If the compensation succeeds well, the GIR time profile may be interpreted as the analogue PD time profile and this is standard procedure.

However, practical glucose clamping is imperfect: Some variation in BG occurs, and criteria for when circumstances may have deviated so much from the ideal clamping conditions that the PD time profile cannot be considered identical to the experimental GIR time profile are not well defined. In this study we discuss what deviations from ideal may significantly affect the pharmacological endpoints, i.e. the conclusions about the drug action that are drawn from the clamp study. We use the GIR-AUC (total amount of infused glucose) as our “case end-point” since GIR-AUC is generally a key end-point in glucose clamp studies. Based on these considerations, we propose criteria for evaluating “glucose clamp quality”, i.e. measures that we should attempt to minimise when doing a glucose clamp. Finally, we compare the performance of an automatic glucose clamp control system (the BIOSTATOR system) with that of a manual glucose clamp control system, both of them evaluated by the proposed criteria.