Lytvyn Yuliya, Bjornstad Petter, Udell Jacob A, Lovshin Julie A, Cherney David Z I
From Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Ontario, Canada (Y.L., J.A.L., D.Z.I.C.); Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, Aurora (P.B.); Women's College Research Institute and Department of Medicine, Division of Cardiology, Women's College Hospital, University of Toronto, Ontario, Canada (J.A.U.); Peter Munk Cardiac Centre, University Health Network, University of Toronto, Ontario, Canada (J.A.U.); and Department of Medicine, Division of Endocrinology and Metabolism, University Health Network and Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada (J.A.L.).
Circulation. 2017 Oct 24;136(17):1643-1658. doi: 10.1161/CIRCULATIONAHA.117.030012.
Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor. The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular events and HF hospitalization risk. Although SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, and decreases in blood pressure, arterial stiffness, and afterload as well, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients who have HF with and without T2D. Accordingly, in this review, we summarize the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of SGLT2 inhibitors in patients with HF who have T2D. Because these favorable effects presumably occur independent of blood glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.
尽管目前已有既定的治疗方法，但心力衰竭（HF）仍是全球范围内住院和死亡的主要原因。因此，需要新的治疗靶点来改善HF患者的预后。EMPA-REG OUTCOME试验（[恩格列净]2型糖尿病患者心血管结局事件试验）表明，使用抗高血糖药物恩格列净（一种钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂）可显著降低2型糖尿病（T2D）合并心血管疾病患者的死亡率和HF住院风险。CANVAS试验（卡格列净心血管评估研究）随后报告了3点主要不良心血管事件和HF住院风险的降低。尽管SGLT2抑制可能在T2D之外有潜在应用，包括HF，但SGLT2抑制剂心脏保护作用的机制仍未完全了解。SGLT2抑制促进尿钠排泄和渗透性利尿，导致血浆容量收缩和前负荷降低，同时血压、动脉僵硬度和后负荷也降低，从而改善HF患者的心内膜下血流。SGLT2抑制还与肾功能的保留有关。基于机制研究和临床试验的数据，目前使用SGLT2抑制剂的大型临床试验正在研究SGLT2抑制在有或无T2D的HF患者中的潜在用途。因此，在本综述中，我们总结了SGLT2抑制剂的关键药效学作用以及支持在合并T2D的HF患者中使用SGLT2抑制剂的临床证据。由于这些有益作用可能独立于血糖降低而发生，我们还探讨了SGLT2抑制在无T2D但有HF或有HF风险的患者中的潜在用途，例如冠状动脉疾病或高血压患者。最后，我们详细概述并总结了正在进行的使用SGLT2抑制剂的心血管结局试验。
