In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1α/2α. The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1α/2α to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.

中文翻译：

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自噬刺激和细胞内钠减少作为钠-葡萄糖共转运蛋白2抑制剂的心脏保护作用的介质。

在涉及> 40 000名患者的五项大规模试验中，钠-葡萄糖共转运蛋白2（SGLT2）抑制剂可将发生严重心力衰竭事件的风险降低25-40％。这种作用不能通过控制高血糖来解释，因为用降糖作用更大的抗糖尿病药物没有观察到这种作用。它不能归因于生酮作用，因为它与酮体的产生没有因果关系，并且对糖尿病患者的益处并未增强。该作用不能归因于利钠药作用，因为SGLT2抑制剂仅适度降低利钠肽，并且它们降低了心血管死亡，这是利尿剂所没有的益处。尽管SGLT2抑制剂会增加红细胞的数量，但促红细胞生成的增强并不会对心力衰竭的进程产生有利的影响。相比之下，实验研究表明，SGLT2抑制剂可减少细胞内钠，从而防止氧化应激和心肌细胞死亡。此外，SGLT2抑制剂诱导模仿营养和氧气剥夺的转录范例，其中包括单磷酸腺苷活化蛋白激酶，sirtuin-1和/或低氧诱导因子-1α/2α的活化。这些介体的相互作用会刺激自噬，这是一种溶酶体介导的降解途径，可维持细胞稳态。自噬介导的清除受损细胞器的清除减少了炎性体的活化，从而减轻了心肌细胞功能障碍和冠状动脉微血管损伤。有趣的是 缺氧诱导因子-1α/2α既刺激促红细胞生成素又诱导自噬的作用可能解释了为什么红细胞增多与心力衰竭事件的减少密切相关。因此，SGLT2抑制剂对心力衰竭的益处可通过与负责心肌细胞稳态的途径调节有关的直接心脏保护作用来介导。