Pharmacometric analysis of dapagliflozin for triglyceride-lowering effects in Japanese patients with type 2 diabetes mellitus based on long-term real-world data and experimental analysis of dyslipidemia model rats.

Abstract

Although dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown potential triglyceride-lowering effects, the clinical evidence remains inconsistent. This study aimed to determine whether the triglyceride-lowering effect observed in patients receiving dapagliflozin was associated with dapagliflozin exposure using a pharmacometric approach integrating clinical data and a preclinical model.Clinical data were retrieved from 85 Japanese patients with type 2 diabetes mellitus who received dapagliflozin 5 mg/day for 12 months. Serum triglyceride levels and plasma concentrations of dapagliflozin were analysed using a population pharmacokinetic-pharmacodynamic (PK-PD) model. In addition, dapagliflozin (0.1 or 0.2 mg/kg) was administered to poloxamer-407-induced dyslipidemia model rats to examine exposure-dependent triglyceride-lowering effects.Among the 18 patients with elevated serum triglyceride levels (≥150 mg/dL) at baseline, dapagliflozin significantly reduced triglyceride levels, with a mean reduction of 47 mg/dL at 12 months. The population PK-PD model captured 103 triglyceride measurements and revealed an exposure-dependent triglyceride-lowering effect. Consistently, a dose-dependent reduction in triglyceride levels was observed in the dyslipidemia model rats.These findings suggest that dapagliflozin exposure is associated with triglyceride-lowering effects, demonstrating an exposure-response relationship supported by pharmacometric analysis of long-term real-world data and a dyslipidemia model.