AUTHOR=Sokolov Victor , Yakovleva Tatiana , Penland Robert C. , Boulton David W. , Tang Weifeng 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1229255

DOI=10.3389/fphar.2023.1229255

ISSN=1663-9812

ABSTRACT=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 from phase 2 and phase 3 trials (NCT01498185, NCT02460978, NCT02268214) to characterize the joint effect of dapagliflozin and insulin on average daily glucose concentrations and glycated hemoglobin (HbA1c) levels in patients with T1D. Because of the apparent lack of association between bolus insulin dose and glucose concentrations measured by continuous glucose monitoring (CGM), 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-mg 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.