A model-based approach to investigating the relationship between glucose-insulin dynamics and dapagliflozin treatment effect in patients with type 2 diabetes.

Aims We developed a quantitative systems pharmacology model to describe the effect of dapagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on glucose-insulin dynamics in type 2 diabetes mellitus (T2DM) patients and identified key determinants of treatment-mediated glycated hemoglobin (HbA1c) reduction. Materials and methods Glycemic control during dapagliflozin treatment was mechanistically characterized by integrating components representing pharmacokinetics (PK), glucose-insulin homeostasis, renal glucose reabsorption, and HbA1c formation. The model was developed using PK, glucose, plasma insulin, and urinary glucose excretion (UGE) from a phase IIa dapagliflozin trial in patients with T2DM (NCT00162305). The model was used to predict dapagliflozin-induced HbA1c reduction; model predictions were compared to actual data from phase III trials (NCT00528879, NCT00683878, NCT00680745, and NCT00673231). Results The integrated glucose-insulin-dapagliflozin (IGID) model successfully described plasma glucose and insulin levels, as well as UGE in response to oral glucose tolerance tests and meal intake. HbA1c reduction was also well predicted. The results show that dapagliflozin-mediated glycemic control is anticorrelated to steady-state insulin concentration and insulin sensitivity. Conclusions The developed model framework is the first to integrate SGLT2 inhibitor mechanism of action with both short-term glucose-insulin dynamics and long-term glucose control (HbA1c). The results suggest that dapagliflozin treatment is beneficial in patients with inadequate glycemic control from insulin alone and this benefit increases as insulin control diminishes. NCT00162305, NCT00528879, NCT00683878, NCT00680745, and NCT00673231. This article is protected by copyright. All rights reserved.