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Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.

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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.