Impact of setting distinct target blood glucose levels on endogenous insulin suppression and pharmacodynamics of insulin preparations

Abstract

BACKGROUND

Insulin therapy plays a crucial role in managing diabetes. Regulatory guidelines mandate assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of new insulin formulations with euglycemic clamp techniques before entry into the market. Typically, blood glucose (BG) levels are maintained at 5% below baseline to suppress endogenous insulin secretion in healthy volunteers. However, in scenarios where BG baseline is relatively low, maintaining it at 5% below baseline can increase hypoglycemic risk. Consequently, we adjusted to maintain it at 2.5% below a baseline of < 4.00 mmol/L. It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin.

AIM

To evaluate and compare the PD and C-peptide status using two different target BG setting methods.

METHODS

Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart (IAsp) in healthy participants. Target BG was set at 2.5% below baseline for those with a basal BG of < 4.00 mmol/L (group A), and at 5% below baseline for others (group B). The area under the curve (AUC) of IAsp (AUC_{IAsp, 0-8 h}) and GIR from 0 to 8 hours (AUC_{GIR, 0-8 h}) was used to characterize the PK and PD of IAsp, respectively. The C-peptide reduction and PK/PD of IAsp were compared between the two groups.

RESULTS

Out of 135 subjects, 15 were assigned to group A and 120 to group B; however, group B exhibited higher basal C-peptide (1.59 ± 0.36 vs 1.32 ± 0.42 ng/mL, P = 0.006). Following propensity score matching to adjust for basal C-peptide differences, 71 subjects (15 in group A and 56 in group B) were analyzed. No significant differences were observed in demographics, IAsp dosage, or clamp quality. Group B showed significantly higher baseline (4.35 ± 0.21 vs 3.91 ± 0.09 mmol/L, P < 0.001), target (4.13 ± 0.20 vs 3.81 ± 0.08 mmol/L, P < 0.001), and clamped (4.10 ± 0.17 vs 3.80 ± 0.06 mmol/L, P < 0.001) BG levels. Both groups exhibited comparable C-peptide suppression (32.5% ± 10.0% vs 35.6% ± 12.1%, P = 0.370) and similar IAsp activity (AUC_{GIR, 0-8 h}: 1433 ± 400 vs 1440 ± 397 mg/kg, P = 0.952) under nearly equivalent IAsp exposure (AUC_{IAsp, 0-8 h}: 566 ± 51 vs 571 ± 85 ng/mL × h, P = 0.840).

CONCLUSION

Maintaining BG at 2.5% below a baseline of < 4.00 mmol/L did not compromise the endogenous insulin suppression nor alter the observed pharmacodynamic effects of the study insulin.

Keywords: Euglycemic clamp; Target glucose setting; Healthy subject; C-peptide; Pharmacodynamics; Endogenous insulin secretion

Core Tip: Insulin therapy is of great importance in anti-diabetes treatment. This study focuses on the preclinical assessment of insulin preparation using the euglycemic clamp technique in healthy subjects. Typically, blood glucose is usually maintained below the individual’s baseline throughout the clamp to inhibit endogenous insulin secretion. The hypoglycemic risk would increase if the BG baseline is relatively low. This retrospective cohort study enrolled euglycemic clamp trials evaluating the pharmacokinetics and pharmacodynamics of insulin aspart to explore optimal methodologies for conducting euglycemic clamps under these circumstances.