Hyperuricemia and Gout Reduction by SGLT2 Inhibitors in Diabetes and Heart Failure: JACC Review Topic of the Week.

Abstract

Gout is characterized by increased production of purines (through the pentose phosphate pathway), which is coupled with reduced renal or intestinal excretion of urate. Concurrent upregulation of nutrient surplus signaling (mammalian target of rapamycin and hypoxia-inducible factor-1a) and downregulation of nutrient deprivation signaling (sirtuin-1 and adenosine monophosphate-activated protein kinase) redirects glucose toward anabolic pathways (rather than adenosine triphosphate production), thus promoting heightened oxidative stress and cardiomyocyte and proximal tubular dysfunction, leading to cardiomyopathy and kidney disease. Hyperuricemia is a marker (rather than a driver) of these cellular stresses. By inducing a state of starvation mimicry in a state of nutrient surplus, sodium-glucose cotransporter-2 inhibitors decrease flux through the pentose phosphate pathway (thereby attenuating purine and urate synthesis) while promoting renal urate excretion. These convergent actions exert a meaningful effect to lower serum uric acid by ≈0.6 to 1.5 mg/dL and to reduce the risk of gout by 30% to 50% in large-scale clinical trials.