Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF,JACC: Heart Failure

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Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF
JACC: Heart Failure ( IF 10.3 ) Pub Date : 2021-07-26 , DOI: 10.1016/j.jchf.2021.04.014
Juan Antonio Requena-Ibáñez ₁ , Carlos G Santos-Gallego ₁ , Anderly Rodriguez-Cordero ₁ , Ariana P Vargas-Delgado ₁ , Donna Mancini ₂ , Samantha Sartori ₂ , Farah Atallah-Lajam ₂ , Chiara Giannarelli ₂ , Frank Macaluso ₂ , Anuradha Lala ₂ , Javier Sanz ₂ , Valentin Fuster ₂ , Juan José Badimon ₁

Affiliation

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 T₁ 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 cm² [95% CI: –12.61 to 1.95] vs 9.13 cm² [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. (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222)

中文翻译：

Empagliflozin 在 HFrEF 非糖尿病患者中的作用机制

目标

本研究的目的是评估除最佳药物治疗外，恩格列净对射血分数降低的非糖尿病性心力衰竭 (HFrEF) 患者的心外膜脂肪组织 (EAT)、间质心肌纤维化和主动脉僵硬度的影响。

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 (SGLT2-i) 抑制剂在 HFrEF 中的益处，与它们的降血糖作用无关。SGLT2-i 在 HFrEF 中的获益机制尚未明确。

方法

本研究是对参加 EMPA-TROPISM [ATRU-4]（恩格列净的心脏益处是否与其降血糖活性无关？）临床试验的患者进行的二次分析。这是一项双盲、安慰剂对照的随机临床试验，研究恩格列净对非糖尿病 HFrEF 患者的影响。患者在基线和 6 个月后接受了心脏磁共振检查。间质心肌纤维化通过使用T ₁映射（细胞外体积）计算。通过使用脉冲波速度计算主动脉僵硬度，并根据电影序列测量 EAT。

结果

与安慰剂（–0.75 mL；95% CI：–3.57 至 2.06；P < 0.05）相比，恩格列净与 EAT 体积显着减少（–5.14 mL；95% CI：–8.36 至 –1.92 ）相关；这一发现同时伴随着皮下脂肪组织面积的减少（–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）。Empagliflozin 治疗的患者报告细胞外体积减少（–1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]；（P < 0.01）]；具体而言，empagliflozin 减少了两种基质体积（–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] 与 0.80 mL [95% CI：–1.96 至 3.55]；P < 0.05）。恩格列净组的脉冲波速度也显着降低（–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）。使用蛋白质组学，恩格列净与炎症生物标志物的显着减少有关。