Empagliflozin increases plasma levels of citrulline, histidine, and α-aminobutyric acid in patients with type 2 diabetes: effects of a sodium-glucose co-transporter 2 inhibitor on the plasma amino acid profile

To investigate effects of empagliflozin on plasma amino acids in people with type 2 diabetes. In a randomized, active-controlled, open-label trial, 58 patients with type 2 diabetes were randomized to 10 mg/day empagliflozin (<i>n</i> = 29) or standard treatment without empagliflozin (control group, <i>n</i> = 29) and treated for 12 weeks. We obtained blood samples at baseline and 12 weeks and assessed the plasma amino acid profile by liquid chromatography-mass spectrometry liquid chromatography. We also calculated the Fischer ratio (the ratio of branched-chain to aromatic amino acids). In the empagliflozin group but not in the control group, plasma levels of citrulline, histidine, and α-aminobutyric acid (AABA), the Fischer ratio, and serum high-molecular weight (HMW) adiponectin increased significantly (<i>p</i> = 0.0099, 0.0277, 0.0318, 0.0135, and 0.0304, respectively) and plasma plasminogen activator inhibitor-1 (PAI-1) decreased significantly (<i>p</i> = 0.0014). In the empagliflozin group, the change in plasma citrulline was positively correlated with the changes in HMW adiponectin (<i>r</i> = 0.488, <i>p</i> = 0.0084) and the Fischer ratio (<i>r</i> = 0.393, <i>p</i> = 0.0353) but negatively correlated with the change in ferritin (<i>r</i>= −0.533,<i>p</i> = 0.0051); the change in plasma histidine was negatively correlated with the change in PAI-1 (<i>r</i>= –0.398, <i>p</i> = 0.0397) and urinary albumin creatinine ratio (<i>r</i>= −0.478, <i>p</i> = 0.0088). Empagliflozin significantly increases plasma citrulline, histidine, and AABA in people with type 2 diabetes. www.umin.ac.jp identifier is UMIN000025418.