Abstract
Clinical trials have found that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce serum urate levels by 0.6-1.5 mg/dL, which might contribute to cardiovascular protection. Urate is the final degradation product of purine nucleotides in humans who lack uricase, unlike most mammals. Thus, the processes of urate handling differ. This review aims to address the handling of urate in humans and the mechanisms through which SGLT2 inhibitors reduce serum urate levels. The kidneys and intestines are respectively responsible for excreting 70% and 30% of urate in humans. Medications that inhibit urate excretion, as well as increased purine intake or production, can cause hyperuricemia and decrease kidney function, which plays a key role in urate excretion. Hyperuricemia is significantly associated with gout, renal stones, mortality, and cardiovascular and chronic kidney diseases. SGLT2 inhibitors lower serum urate by inhibiting its reabsorption through urate anion exchanger 1 in apical membranes of renal proximal tubules and promoting urate excretion through ATP-binding cassette subfamily G member 2 (ABCG2) located in the apical membrane of the proximal tubule and ABCG2 in the intestinal membrane. Further mechanistic studies are needed to elucidate how SGLT2 inhibitors lower serum urate levels. Although the clinical benefits of SGLT2 inhibitors probably do not arise solely from urate reduction, they decrease serum urate levels, suggesting that they could serve as adjunctive therapy for patients with hyperuricemia.