Effectiveness of dapagliflozin as an insulin adjunct in type 1 diabetes: a semi-mechanistic exposure-response model

Frontiers in Pharmacology

Pharmacology

Weifeng Tang¹  David W. Boulton¹  Robert C. Penland²  Tatiana Yakovleva³  Victor Sokolov⁴ 

[1] Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States;Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, MA, United States;M&S Decisions LLC, Moscow, Russia;M&S Decisions LLC, Moscow, Russia;STU “Sirius”, Sochi, Russia;

关键词: continuous glucose monitoring;    dapagliflozin;    insulin;    exposure-response model;    SGLT-2 inhibitor;    HbA1c;    type 1 diabetes;   

DOI  :  10.3389/fphar.2023.1229255

 received in 2023-05-26, accepted in 2023-10-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Dapagliflozin-induced improvement of glycemic control in patients with inadequately controlled type 1 diabetes (T1D) is complicated by the delicate balance between blood glucose and exogenous insulin. In this work, we developed a semi-mechanistic population exposure-response model using pooled patient-level data to characterize the joint effect of dapagliflozin and insulin on average daily glucose concentrations and glycated hemoglobin (HbA1c) levels in patients with T1D.Methods: A non-linear mixed-effects model was developed in Monolix (Lixoft, France) and R software (R Project, www.r-project.org) using pooled patient-level data from phase 2 and phase 3 trials (NCT01498185, NCT02460978, NCT02268214).Results: Because of the apparent lack of association between bolus insulin dose and glucose concentrations measured by continuous glucose monitoring the model was able to capture the quantitative link between basal, but not bolus, insulin dose and plasma glucose. Even so, this association remained flat, with a 50% decrease in the basal insulin dose from pretreatment level, resulting in ∼5% increase in glucose exposure. Therefore, dapagliflozin efficacy was not significantly affected by the insulin dose adjustment, with 24-week HbA1c reduction on 10-mg dapagliflozin treatment changing from −0.5 [95% CI: −0.55, −0.45] to −0.42 [95%CI: −0.48, −0.36] after adjustment. At the same time, the analysis revealed ∼2-fold steeper slope of glucose-HbA1c relationship in dapagliflozin-treated patients vs. control group, suggesting the presence of additional dapagliflozin treatment–related benefits, not explained by the dapagliflozin-mediated ∼4% increase in plasma hemoglobin levels. Finally, the efficacy of 5 and 10-mg doses, represented by the mean HbA1c reduction at week 24 of dapagliflozin treatment, was shown to be notably greater than the 1- and 2.5-mg doses.Discussion: This research is an attempt to deconvolute and reconstruct dapagliflozin-HbA1c dose-response relationship in T1D by accounting for the drug’s action on both daily insulin dose and plasma glucose on a subject-level. While the model is able to adequately capture the observed data, it also revealed that the variability in CGM is poorly approximated by the variability in insulin dose alone. Furthermore, the slope of CGM/HbA1c relationship may differ depending on the population and treatment scenarios. As such, a deeper dive into the physiological mechanisms is required to better quantify the intricate network of glycemic response under dapagliflozin treatment.

【 授权许可】

Unknown   
Copyright © 2023 Sokolov, Yakovleva, Penland, Boulton and Tang.