An increasing number of individuals is at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and premature death. The sodium-glucose cotransporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption, and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated view on the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With robust trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (ie, at cardiac, vascular, renal, and systemic levels), we provide insights into key mechanisms that may underlie their beneficial effects, including gliflozins’ role in the modulation of vascular inflammation, oxidative stress, cellular energy metabolism and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrythmias are presented, and potential implications for future research and clinical practice are comprehensively reviewed.

中文翻译：

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SGLT2 抑制剂：从降糖到心血管益处

越来越多的人面临 2 型糖尿病 (T2D) 及其心血管并发症的高风险，包括心力衰竭 (HF)、慢性肾病 (CKD) 和过早死亡。钠-葡萄糖协同转运蛋白 2 (SGLT2) 蛋白位于人肾单位的近端小管中，调节葡萄糖重吸收，格列净对其的抑制代表了当代 T2D 和 HF 治疗的基石。在此，我们的目标是提供格列净多效性的最新观点，提供机制见解并描述相关的心血管（CV）益处。通过讨论在临床前模型和具有里程碑意义的随机对照试验中获得的当代证据，我们在广泛的心脑血管疾病领域从实验室转向临床。稳健的试验证实主要不良心血管事件（MACE；心血管死亡、非致命性心肌梗死和非致命性中风的复合终点）减少，SGLT2 抑制剂可显着降低糖尿病患者和非糖尿病患者因心力衰竭住院的风险同时为特定患者群体提供肾脏保护。沿着四个主要病理生理轴（即心脏、血管、肾脏和全身水平），我们深入了解可能构成其有益作用的关键机制，包括格列净在调节血管炎症、氧化应激、细胞能量代谢中的作用和内务管理机制。我们还讨论了此类药物如何控制高血糖、生酮、尿钠排泄和高尿酸血症，从而发挥其多效性。最后，介绍了脑血管疾病和心律失常的不断变化的数据，并全面回顾了对未来研究和临床实践的潜在影响。