Inhibitors of sodium-glucose cotransporters-2 have cardio- and renoprotective properties. However, the underlying mechanisms remain indeterminate.To evaluate the effect of dapagliflozin on renal metabolism assessed by urine metabolome analysis in patients with type 2 diabetes.Prospective cohort study.Outpatient diabetes clinic of a tertiary academic centre.Eighty patients with HbA1c> 7% on metformin monotherapy were prospectively enrolled.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).In multivariate analysis urine metabolome was significantly altered by dapagliflozin (R 2X=0.819, R 2Y=0.627, Q 2Y=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).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.
Evdoxia Bletsa, Sebastien Filippas-Dekouan, Christina Kostara, Panagiotis Dafopoulos, Aikaterini Dimou, Eleni Pappa, Styliani Chasapi, Georgios Spyroulias, Anastasios Koutsovasilis, Eleni Bairaktari, Ele Ferrannini, Vasilis Tsimihodimos