Original Investigation
Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction

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Abstract

Background

Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.

Objectives

The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.

Methods

In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.

Results

Empagliflozin was associated with a significant reduction of LV end-diastolic volume (−25.1 ± 26.0 ml vs. −1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (−26.6 ± 20.5 ml vs. −0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (−17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. −0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. −0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. −145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. −35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001).

Conclusions

Empagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222)

Key Words

cardiac magnetic resonance
clinical trial
heart failure
LV remodeling
SGLT2-inhibitors

Abbreviations and Acronyms

6MWT
6-min walk test
CMR
cardiac magnetic resonance
CPET
cardiopulmonary exercise test
HFrEF
heart failure with reduced ejection fraction
KCCQ-12
Kansas City Cardiomyopathy Questionnaire
LV
left ventricle/ventricular
LVEDV
left ventricular end-diastolic volume
LVEF
left ventricle ejection fraction
LVESV
left ventricular end-systolic volume
OUES
oxygen uptake efficiency slope
SGLT2i
sodium-glucose cotransporter 2 inhibitors
VO2
oxygen consumption

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Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

Lee R. Goldberg, MD, MPH, served as Guest Associate Editor for this paper. Athena Poppas, MD, served as Guest Editor-in-Chief for this paper.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Drs. Santos-Gallego and Vargas-Delgado contributed equally to this work.