Packer Milton, Anker Stefan D, Butler Javed, Filippatos Gerasimos, Ferreira Joao Pedro, Pocock Stuart J, Sattar Naveed, Brueckmann Martina, Jamal Waheed, Cotton Daniel, Iwata Tomoko, Zannad Faiez
Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; Imperial College, London, United Kingdom.
Department of Cardiology, Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany.
J Am Coll Cardiol. 2021 Mar 23;77(11):1381-1392. doi: 10.1016/j.jacc.2021.01.033.
Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.
This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.
This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.
Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.
Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).
研究人员推测，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂具有利尿作用，这有助于其降低严重心力衰竭事件的发生风险，且这一作用在有液体潴留的患者中尤为重要。
本研究旨在评估SGLT2抑制剂恩格列净对有或无近期容量超负荷的患者的症状、健康状况及主要心力衰竭结局的影响。
这项双盲随机试验比较了恩格列净和安慰剂对3730例射血分数降低的心力衰竭患者（无论是否患有糖尿病）的影响。约40%的患者在研究入组前4周内存在容量超负荷。
近期有容量超负荷的患者在过去12个月内因心力衰竭住院以及在门诊接受静脉利尿剂治疗的可能性更大，且在随机分组后发生心力衰竭事件的可能性也更大，尽管他们作为门诊患者更有可能接受高剂量的袢利尿剂治疗（所有p<0.001）。与安慰剂相比，恩格列净降低了心血管死亡或因心力衰竭住院的复合风险，减少了因心力衰竭的总住院次数，并改善了健康状况和心功能分级。然而，尽管近期有容量超负荷的患者易发生液体潴留，但这些益处的程度（即使在治疗1个月后）在近期有容量超负荷的患者中并不更显著（交互作用p值>0.05）。体重、血细胞比容和利钠肽的变化（每一项都可能提示SGLT2抑制剂的利尿作用）在时间进程或个体患者中彼此之间并未紧密相关。
综合来看，研究结果不支持利尿作用在介导SGLT2抑制剂对射血分数降低的心力衰竭患者心力衰竭病程的生理变化或临床益处方面起主要作用。（射血分数降低的慢性心力衰竭患者恩格列净结局试验[EMPEROR-Reduced]；NCT03057977）
