Preda Alberto, Montecucco Fabrizio, Carbone Federico, Camici Giovanni G, Lüscher Thomas F, Kraler Simon, Liberale Luca
Department of Clinical Cardiology, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.
Cardiovasc Res. 2024 Apr 30;120(5):443-460. doi: 10.1093/cvr/cvae047.
An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-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 overview of 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 landmark randomized controlled 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 (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.
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，这些并发症包括心力衰竭（HF）、慢性肾脏病（CKD），最终导致过早死亡。钠-葡萄糖协同转运蛋白2（SGLT2）位于人类肾单位的近端小管中，以调节葡萄糖重吸收，而格列净类药物对其的抑制作用是当代T2D和HF管理的基石。在此，我们旨在提供格列净类药物多效性的最新概述，提供机制性见解，并阐述相关的心血管（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，我们跨越广泛的心血管和脑血管疾病领域，从实验室走向临床。具有里程碑意义的随机对照试验证实，主要不良心血管事件（MACE；CV死亡、非致命性心肌梗死和非致命性中风的复合终点）有所减少，SGLT2抑制剂在糖尿病患者和非糖尿病患者中均能显著降低心力衰竭住院风险，同时在特定患者群体中具有肾脏保护作用。沿着四个主要的病理生理轴（即全身、血管、心脏和肾脏水平），我们深入探讨了可能是其有益作用基础的关键机制，包括格列净类药物在调节炎症、氧化应激、细胞能量代谢和看家机制中的作用。我们还讨论了这类药物如何控制高血糖、生酮、利钠和高尿酸血症，这些共同促成了它们的多效性作用。最后，介绍了脑血管疾病和心律失常方面不断发展的数据，并对未来研究和临床实践的潜在影响进行了全面综述。
