How to Improve the Quality of Euglycemic Glucose Clamp Tests in Long-Acting Insulin Studies

Abstract

Background The euglycemic clamp test stands as the gold standard for assessing the pharmacokinetic and pharmacodynamic properties of long-acting insulin. However, despite its widespread use, there remains a notable absence of an established gold standard for evaluating the test’s quality. Existing recommendations from regulatory agencies lack specific threshold values, particularly concerning long-acting insulin. This study aimed to determine the evaluation criteria for assessing the quality of the long-acting insulin euglycemic glucose clamp test and to improve the overall quality of this testing method. Methods Fifty-three healthy volunteers were administered a single dose of insulin degludec (0.4 IU/kg) and underwent a 24-h euglycemic clamp test. Blood samples were collected to evaluate the pharmacokinetics and pharmacodynamics of insulin degludec. Volunteers were separated into Group A (coefficient of variation in blood glucose [CVBG] ≤ 3.5%) and Group B (CVBG > 3.5%). The quality difference of the clamp test between the groups was assessed using various quality control indices. Volunteers were also categorized into Group C (C-peptide reduction rate < 50%) and Group D (C-peptide reduction rate ≥ 50%). The clamp test quality, pharmacokinetics, and pharmacodynamics of Groups C and D were compared. Results Group A (2.95%) had significantly lower CVBG than Group B (4.15%), and Group D (63.22%) had significantly higher C-peptide reduction than Group C (35.23%). CVBG was positively correlated with other quality control indicators, such as the percentage of glucose excursion from the target range (GEFTR), duration of GEFTR, and area under the curve (AUC) of GEFTR. Groups C and D had CVBG < 3.5%; however, the area under the curve of GEFTR was significantly lower in Group C. Conclusions CVBG could be used as a standard for evaluating the quality of long-acting insulin euglycemic glucose clamp test, and the test quality was superior with a CVBG ≤ 3.5%. A C-peptide reduction ratio ≥ 50% indicated sufficient endogenous insulin inhibition; however, it cannot be inhibited when the CVBG level is low.