Baylor Heart and Vascular Institute, Dallas, Texas, USA; Imperial College, London, United Kingdom.
J Am Coll Cardiol. 2024 Jan 16;83(2):371-381. doi: 10.1016/j.jacc.2023.10.030.
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.
痛风的特征是嘌呤产量增加（通过戊糖磷酸途径），同时尿酸的肾脏或肠道排泄减少。营养过剩信号（雷帕霉素靶蛋白和缺氧诱导因子-1a）的同时上调和营养缺乏信号（沉默调节蛋白-1 和单磷酸腺苷激活蛋白激酶）的下调将葡萄糖重新导向合成代谢途径（而不是三磷酸腺苷生成），从而促进氧化应激和心肌细胞和近端肾小管功能障碍，导致心肌病和肾病。高尿酸血症是这些细胞应激的标志物（而不是驱动因素）。钠-葡萄糖共转运蛋白-2 抑制剂通过诱导营养过剩状态下的饥饿模拟状态，减少戊糖磷酸途径的通量（从而减少嘌呤和尿酸的合成），同时促进肾脏尿酸排泄。这些收敛作用在大规模临床试验中可显著降低血清尿酸约 0.6 至 1.5mg/dL，并降低 30%至 50%的痛风风险。
