a Department of Internal Medicine, School of Medicine , University of Crete, University Hospital of Heraklion , Heraklion , Greece.
b Department of Internal Medicine, School of Medicine , University of Ioannina , Ioannina , Greece.
Postgrad Med. 2019 Mar;131(2):82-88. doi: 10.1080/00325481.2019.1581971.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a 'superfuel' in the cardiac and renal tissue (the 'thrifty substrate' hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na-H exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂抑制近端肾小管中的葡萄糖重吸收。两项试验表明，恩格列净和卡格列净可显著减少心血管（CV）事件，而这些作用不能仅归因于它们的降糖作用。本综述的目的是批判性地介绍 SGLT2 抑制剂心脏保护作用的建议机制/假说。文献检索揭示了许多可能的心脏保护机制，因为 SGLT2 抑制剂（i）增加尿钠排泄，并具有独特的利尿作用，导致前负荷和心肌拉伸减少（利尿假说）；（ii）降低血压和后负荷（降压假说）；（iii）有利于酮体的产生，酮体可以作为心脏和肾脏组织中的“超级燃料”（“节俭底物”假说）；（iv）改善许多代谢变量（代谢效应假说）；（v）发挥许多抗炎作用（抗炎作用假说）；（vi）可以通过血管紧张素 II 型 2 受体在同时抑制肾素-血管紧张素-醛固酮系统（RAAS）的情况下发挥作用，导致血管舒张和正性肌力作用（RAAS 假说）；（vii）直接降低心力衰竭时心肌细胞中上调的 Na-H 交换器的活性，导致心肌细胞中线粒体钙处理的恢复（钠假说）。此外，一些 SGLT2 抑制剂还具有抑制 SGLT1 的作用，可能减轻缺血心肌中的氧化应激（SGLT1 抑制假说）。因此，已经提出了许多机制（可能累积作用）来解释 SGLT2 抑制剂的心脏保护作用。
