Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF From the EMPA-TROPISM Study
Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF From the EMPA-TROPISM Study
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DOI：
10.1016/j.jchf.2021.04.014
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发表时间：
2021-07-26
影响因子：
13
通讯作者：
Badimon, Juan Jose
中科院分区：
文献类型：
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作者：
Requena-Ibanez, Juan Antonio;Santos-Gallego, Carlos G.;Badimon, Juan Jose
本研究的目的是评价恩格列净在最佳药物治疗基础上对心外膜脂肪组织（EAT）、间质性心肌纤维化，背景几项随机临床试验已经确定了钠-葡萄糖协同转运蛋白2受体（SGLT 2-i）抑制剂的益处，在HFrEF中，独立于其降血糖作用。SGLT 2-i在HFrEF中获益的机制尚未明确。方法本研究是对EMPA-TROPISM [ATRU-4]（恩格列净的心脏获益是否独立于其降糖活性？）入组患者的次要分析。临床试验这是一项双盲、安慰剂对照、随机临床试验，研究恩格列净在非糖尿病HFrEF患者中的作用。患者在基线和6个月后接受心脏磁共振检查。采用T-1标测（细胞外容积）计算间质心肌纤维化。主动脉僵硬度通过脉冲波速度计算，EAT通过电影序列测量。结果恩格列净与EAT体积显著减少相关（-5.14 mL; 95% CI：-8.36至-1.92）与安慰剂相比（-0.75 mL; 95% CI：-3.57至2.06; P < 0.05）;皮下脂肪组织面积减少证实了这一发现（-5.33 cm（2）[95% CI：-12.61至1.95] vs 9.13 cm（2）[95% CI：-2.72至20.99]; P < 0.05）。恩格列净治疗患者报告细胞外容量减少（-1.25% [+/- 0.56 95% CI] vs 0.24% [+/- 0.57 95% CI];（P < 0.01）];具体而言，恩格列净降低了两种基质体积（-7.24 mL [95% CI：-11.59至-2.91] vs 0.70 mL [95% CI：-0.89至2.29]; P < 0.001）和心肌细胞体积（-11.08 mL [95% CI：-19.62至-2.55] vs 0.80 mL [95% CI：-1.96至3.55]; P < 0.05）。恩格列净组的脉搏波速度也显著降低（-0.58 cm/s [95% CI：-0.92至-0.25] vs 0.60 cm/s [95% CI：0.14至1.06]; P < 0.01）。使用蛋白质组学，恩格列净与炎症生物标志物显着减少。结论恩格列净显着改善肥胖，间质性心肌纤维化，主动脉僵硬度，炎症标志物在非糖尿病患者HFrEF。这些结果揭示了SGLT 2-i的作用机制。(C)2021年由美国心脏病学会基金会。
OBJECTIVES The goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF).BACKGROUND Several randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined.METHODS This study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T-1 mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences.RESULTS Empagliflozin is associated with significant reductions in EAT volume (-5.14 mL; 95% CI: -8.36 to -1.92) compared with placebo (-0.75 mL; 95% CI: -3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (-5.33 cm(2) [95% CI: -12.61 to 1.95] vs 9.13 cm(2) [95% CI: -2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (-1.25% [+/- 0.56 95% CI] vs 0.24% [+/- 0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (-7.24 mL [95% CI: -11.59 to -2.91] vs 0.70 mL [95% CI: -0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (-11.08 mL [95% CI: -19.62 to -2.55] vs 0.80 mL [95% CI: -1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (-0.58 cm/s [95% CI: -0.92 to -0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers.CONCLUSIONS Empagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (C) 2021 by the American College of Cardiology Foundation.