Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
Curr Opin Nephrol Hypertens. 2020 Sep;29(5):523-530. doi: 10.1097/MNH.0000000000000632.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic drugs that act by inhibiting renal sodium-glucose cotransport. Here we present new insights into 'off target', or indirect, effects of SGLT2 inhibitors.
SGLT2 inhibition causes an acute increase in urinary glucose excretion. In addition to lowering blood glucose, there are several other effects that contribute to the overall beneficial renal and cardiovascular effects. Reabsorption of about 66% of sodium is accomplished in the proximal tubule and dependent on the sodium-hydrogen exchanger isoform 3 (NHE3). SGLT2 colocalizes with NHE3, and high glucose levels reduce NHE3 activity. The proximal tubule is also responsible for the majority of phosphate (Pi) reabsorption. SGLT2 inhibition is associated with increases in plasma Pi, fibroblast growth factor 23 and parathyroid hormone levels in nondiabetics and type 2 diabetes mellitus. Studies in humans identified a urate-lowering effect by SGLT2 inhibition which is possibly mediated by urate transporter 1 (URAT1) and/or glucose transporter member 9 in the proximal tubule. Of note, magnesium levels were also found to increase under SGLT2 inhibition, an effect that was preserved in nondiabetic patients with hypomagnesemia.
Cardiorenal effects of SGLT2 inhibition might involve, in addition to direct effects on glucose homeostasis, effects on NHE3, phosphate, urate, and magnesium homeostasis.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂是通过抑制肾脏钠-葡萄糖共转运而起作用的抗高血糖药物。在这里，我们提出了 SGLT2 抑制剂的“非靶点”或间接作用的新见解。
SGLT2 抑制会导致尿糖排泄的急性增加。除了降低血糖外，还有其他几种作用有助于整体有益的肾脏和心血管作用。大约 66%的钠在近端小管中被重吸收，并且依赖于钠-氢交换体同工型 3（NHE3）。SGLT2 与 NHE3 共定位，并且高葡萄糖水平降低 NHE3 活性。近端小管还负责大部分磷酸盐（Pi）的重吸收。SGLT2 抑制与非糖尿病和 2 型糖尿病患者的血浆 Pi、成纤维细胞生长因子 23 和甲状旁腺激素水平的增加相关。在人类中的研究发现 SGLT2 抑制具有降低尿酸的作用，这可能是通过近端小管中的尿酸转运蛋白 1（URAT1）和/或葡萄糖转运体成员 9 介导的。值得注意的是，还发现镁水平在 SGLT2 抑制下增加，在非糖尿病伴低镁血症的患者中这种作用得以保留。
SGLT2 抑制的心脏肾脏作用除了对葡萄糖稳态的直接作用外，还可能涉及 NHE3、磷酸盐、尿酸和镁稳态的作用。
