# LC-MS-Based Untargeted Metabolic Profiling in Plasma Following Dapagliflozin Administration in Healthy Volunteers

## TL;DR

This study used untargeted metabolomics to explore how dapagliflozin affects metabolism in healthy people, revealing changes in several metabolic pathways.

## Contribution

The study provides new insights into dapagliflozin's metabolic effects in healthy individuals, beyond its known glucose-lowering mechanism.

## Key findings

- Eight metabolites increased significantly, including phosphatidylcholine and phosphatidylserine species.
- Dehydroepiandrosterone sulfate and bilirubin were found to decrease after dapagliflozin administration.
- The affected metabolites are linked to glycerophospholipid, amino acid, pyrimidine, and steroid-hormone metabolism.

## Abstract

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well documented in patients with diabetes, their magnitude and underlying mechanisms in healthy individuals remain poorly understood. Background/Objectives: We investigated metabolic alterations after a single 10 mg dose of dapagliflozin in healthy adults with normal body-mass indices (BMIs) using untargeted metabolomics. Methods: Thirteen healthy volunteers completed this study. Plasma was collected before and 24 h after dosing. Untargeted metabolic profiling was performed with ultra-high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry. Results: Twenty-five endogenous metabolites were annotated; ten were putatively identified. Eight metabolites increased significantly, whereas two decreased. Up-regulated metabolites included phosphatidylcholine (PC) species (PC O-36:5, PC 36:3), phosphatidylserine (PS) species (PS 40:2, PS 40:3, PS 36:1, PS 40:4), lysophosphatidylserine 22:1, and uridine. Dehydroepiandrosterone sulfate and bilirubin were down-regulated. According to the Human Metabolome Database, these metabolites participate in glycerophospholipid, branched-chain amino acid, pyrimidine, and steroid-hormone metabolism. Conclusions: Dapagliflozin may affect pathways related to energy metabolism and homeostasis beyond glucose regulation. These data provide a reference for future investigations into energy balance and metabolic flexibility in metabolic disorders.