Martens Pieter, Mathieu Chantal, Verbrugge Frederik H
Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600, Genk, Belgium.
Doctoral School for Medicine and Life Sciences, Hasselt University, Agoralaan gebouw D, 3590, Diepenbeek, Belgium.
Curr Treat Options Cardiovasc Med. 2017 Mar;19(3):23. doi: 10.1007/s11936-017-0522-x.
This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3-6 mmHg) and body weight (∼2-4 kg/m). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubuloglomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover, SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering β-hydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.
本综述深入探讨了钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂的多效性作用机制，尤其关注其与心力衰竭病理生理学的关系。SGLT-2抑制剂恩格列净最近已证实可使糖尿病患者的心血管死亡率史无前例地降低38%。尽管其对长期血糖控制的作用较为温和，但却显著降低了心力衰竭住院率和终末期肾病的发生率。SGLT-2抑制剂是最新获批的一类降糖药物。通过阻断肾单位近端小管对钠/葡萄糖的重吸收，它们可诱导糖尿。糖尿病患者使用SGLT-2抑制剂治疗可使糖化血红蛋白水平持续降低约1%，同时动脉血压（约3 - 6 mmHg）和体重（约2 - 4 kg/m）也有良好下降。然而，这些作用并不能完全解释其在心血管死亡率、心力衰竭再入院率和终末期肾病方面的显著降低。SGLT-2抑制剂独特的药理特性使其处于影响心脏和肾脏疾病的重要血流动力学、神经体液、代谢及血管内皮途径的交叉点。SGLT-2抑制剂可减少近端小管钠和氯的重吸收，从而重置管球反馈。这会引起血浆容量收缩而不激活交感神经系统，减少有害的肾小球高滤过，从而实现更好的长期肾脏保护，并改善对其他利尿剂的利尿和排钠反应。此外，SGLT-2抑制剂可能通过提供β-羟基丁酸作为一种有吸引力的氧化燃料来提高心肌能量代谢效率，并增加血细胞比容以改善氧运输。最后，糖尿病患者使用SGLT-2抑制剂可观察到血管僵硬度降低和内皮功能改善。这些多种非降糖作用进一步巩固了SGLT-2抑制剂作为治疗心力衰竭糖尿病患者首选降糖药物的地位。未来，甚至可能会考虑将其用于无糖尿病的心力衰竭或慢性肾病患者。
