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 1. Design, setting, participants, & measurements We conducted an analysis of two randomized clinical trials. First,in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes 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 euglycemia orhyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effectson plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured. Results In the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with 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 <.001) while increasing fractional uric acid excretion (by 3.2%+/- 3.1% and 8.9%+/- 4.5%,respectively; bothP,0.001). Dapagliflozin reduced plasma uric acid by 0.8 +/- 0.8 during fasting, 1.0 +/- 1.0 in hyperinsulinemic-euglycemic state, and 0.8 +/- 0.7 mg/dl during hyperglycemic conditions (P < 0.001), respectively, where as fractional uric acid excretion in 24-hour 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 Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination the rapydid not differ from benzbromarone monotherapy. Conclusions In conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinaryglucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1.

Automated summary

This study investigates the mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes, and finds that it is strongly linked to urate transporter 1 and urinary glucose excretion.