Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study

Juan Antonio Requena-Ibáñez, Carlos G. Santos-Gallego, Anderly Rodriguez-Cordero, Ariana P. Vargas-Delgado, Donna Mancini, Samantha Sartori, Farah Atallah-Lajam, Chiara Giannarelli, Frank Macaluso, Anuradha Lala, Javier Sanz, Valentin Fuster, Juan José Badimon

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128 Scopus citations


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.

Original languageEnglish
Pages (from-to)578-589
Number of pages12
JournalJACC: Heart Failure
Issue number8
StatePublished - Aug 2021


  • CMR
  • SGLT2-inhibitors
  • epicardial adipose tissue
  • heart failure
  • myocardial fibrosis


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