SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function

Background and objectives: Sodium glucose transporter 2 (SGLT2)-inhibitor-induced uric acid lowering may contribute to kidney protective effects of the drug-class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2-inhibitors in people with type 2 diabetes with a focus on urate transporter (URAT)1. Methods: We conducted an analysis of two randomized, clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED) study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion and hemodynamic kidney function were measured in the fasted state and during clamped eu- or hyperglycemia. Second, in the Uric Acid Excretion study (UREX) study, 10 people with type 2 diabetes received 1-week empagliflozin, benzbromarone and their combination in a cross-over design and effects on plasma uric acid, fractional uric acid excretion and 24-hr uric acid excretion were measured. Results: In the RED study, compared to the fasted state (5.3±1.1mg/dL), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dL (both p<0.001), while increasing fractional uric acid excretion (by 3.2±3.1% and 8.9±4.5% respectively (both p<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8mg/dL, 1.0±1.0mg/dL and by 0.8±0.7mg/dL during fasting, hyperinsulinemic-euglycemic and hyperglycemic conditions (p<0.001), whereas fractional uric acid excretion in 24-hr urine increased by 3.0±2.1% (p<0.001) and 2.6±4.5% during hyperinsulinemic-euglycemic conditions (p=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r= 0.35, p=0.02). In the UREX study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy. Conclusion: In conclusion, SGLT2-inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and which is attenuated during concomitant pharmacological blockade of URAT1.