{"title":"Impact of setting distinct target blood glucose levels on endogenous insulin suppression and pharmacodynamics of insulin preparations.","authors":"Hui Liu, Ting Li, Xin-Lei Chen, Hong-Ling Yu, Ye-Rong Yu","doi":"10.4239/wjd.v16.i2.101779","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Aim: </strong>To evaluate and compare the PD and C-peptide status using two different target BG setting methods.</p><p><strong>Methods: </strong>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<sub>IAsp, 0-8 h</sub>) and GIR from 0 to 8 hours (AUC<sub>GIR, 0-8 h</sub>) 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.</p><p><strong>Results: </strong>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 <i>vs</i> 1.32 ± 0.42 ng/mL, <i>P</i> = 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 <i>vs</i> 3.91 ± 0.09 mmol/L, <i>P</i> < 0.001), target (4.13 ± 0.20 <i>vs</i> 3.81 ± 0.08 mmol/L, <i>P</i> < 0.001), and clamped (4.10 ± 0.17 <i>vs</i> 3.80 ± 0.06 mmol/L, <i>P</i> < 0.001) BG levels. Both groups exhibited comparable C-peptide suppression (32.5% ± 10.0% <i>vs</i> 35.6% ± 12.1%, <i>P</i> = 0.370) and similar IAsp activity (AUC<sub>GIR, 0-8 h</sub>: 1433 ± 400 <i>vs</i> 1440 ± 397 mg/kg, <i>P</i> = 0.952) under nearly equivalent IAsp exposure (AUC<sub>IAsp, 0-8 h</sub>: 566 ± 51 <i>vs</i> 571 ± 85 ng/mL × h, <i>P</i> = 0.840).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":48607,"journal":{"name":"World Journal of Diabetes","volume":"16 2","pages":"101779"},"PeriodicalIF":4.2000,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11718471/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"World Journal of Diabetes","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4239/wjd.v16.i2.101779","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
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 (AUCIAsp, 0-8 h) and GIR from 0 to 8 hours (AUCGIR, 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 (AUCGIR, 0-8 h: 1433 ± 400 vs 1440 ± 397 mg/kg, P = 0.952) under nearly equivalent IAsp exposure (AUCIAsp, 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.
期刊介绍:
The WJD is a high-quality, peer reviewed, open-access journal. The primary task of WJD is to rapidly publish high-quality original articles, reviews, editorials, and case reports in the field of diabetes. In order to promote productive academic communication, the peer review process for the WJD is transparent; to this end, all published manuscripts are accompanied by the anonymized reviewers’ comments as well as the authors’ responses. The primary aims of the WJD are to improve diagnostic, therapeutic and preventive modalities and the skills of clinicians and to guide clinical practice in diabetes. Scope: Diabetes Complications, Experimental Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Diabetes, Gestational, Diabetic Angiopathies, Diabetic Cardiomyopathies, Diabetic Coma, Diabetic Ketoacidosis, Diabetic Nephropathies, Diabetic Neuropathies, Donohue Syndrome, Fetal Macrosomia, and Prediabetic State.