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Effect of dapagliflozin on urine metabolome in patients with type 2 diabetes

Bletsa, Evdoxia1; Filippas-Dekouan, Sebastien2; Kostara, Christina2; Dafopoulos, Panagiotis2; Dimou, Aikaterini2; Pappa, Eleni2; Chasapi, Styliani3; Spyroulias, Georgios3; Koutsovasilis, Anastasios1; Bairaktari, Eleni2; Ferrannini, Ele4; Tsimihodimos, Vasilis2

Published Mar 09, 2021 on Dryad. https://doi.org/10.5061/dryad.3n5tb2rg9

Data files

Mar 09, 2021 version files 1.41 MB

Abstract

Abstract   

Context

Inhibitors of sodium-glucose cotransporters-2 have cardio- and renoprotective properties. However, the underlying mechanisms remain indeterminate.

Objective

To evaluate the effect of dapagliflozin on renal metabolism assessed by urine metabolome analysis in patients with type 2 diabetes.

Design

Prospective cohort study.

Setting

Outpatient diabetes clinic of a tertiary academic centre.

Patients

Eighty patients with HbA1c> 7% on metformin monotherapy were prospectively enrolled. 

Intervention

Fifty patients were treated with dapagliflozin for 3 months.  To exclude that the changes observed in urine metabolome were merely the result of the improvement in glycemia, 30 patients treated with insulin degludec were used for comparison.

Main Outcome Measure

Changes in urine metabolic profile before and after the administration of dapagliflozin and insulin degludec were assessed by Proton-Nuclear Magnetic Resonance spectroscopy (1H-NMR).

Results

In multivariate analysis urine metabolome was significantly altered by dapagliflozin (R2X=0.819, R2Y=0.627, Q2Y=0.362, and CV-ANOVA, p<0.001) but not insulin. After dapagliflozin the urine concentrations of ketone bodies, lactate, branched chain amino acids (p<0.001), betaine, myo-inositol (p<0001) and N-Methylhydantoin (p< 0.005) were significantly increased. Additionally, the urine levels of alanine, creatine, sarcosine and citrate were also increased (p<0001, <0.0001 and <0.0005, respectively) whereas anserine decreased (p<0005).

Conclusions

Dapagliflozin significantly affects urine metabolome in patients with type 2 diabetes in a glucose lowering-independent way. Most of the observed changes can be considered beneficial and may contribute to the renoprotective properties of dapagliflozin.