Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial

Abstract

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness.

Methods: EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated.

Results: Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed.

Conclusions: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT03332212.

Keywords: empagliflozin; heart failure; magnetic resonance spectroscopy; sodium-glucose transporter proteins.

Figure 1.

Patient flow diagram for the EMPA-VISION double-blind, phase-III randomized controlled trial. Patients (n=1008) were assessed for eligibility; 101 patients were consented and underwent a screening visit. Of those, 72 were eventually eligible and randomly allocated to either 10 mg of empagliflozin (n=35) or matching placebo (n=37) once daily, stratified in their respective cohorts (HFrEF and HFpEF). One participant with HFrEF in the placebo group withdrew from further participation before the individual end of treatment (visit 4). In the HFpEF cohort, 5 patients in the empagliflozin arm and 5 in the placebo arm were excluded due to missing data because of COVID-19 lockdown restrictions. Two patients in the placebo group withdrew from treatment due to serious adverse events. CMR indicates cardiovascular magnetic resonance; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and SAE, serious adverse event.

Figure 2.

Cardiac energetics (PCr/ATP). Cardiac energetics (PCr/ATP) defined by phosphorus-31 (³¹P) magnetic resonance spectroscopy violin plots (including median and interquartile range) for the placebo and the empagliflozin treatment groups at baseline and 12 weeks after the respective treatment. PCr/ATP remained unchanged in both HFrEF (A) and HFpEF (B) after 12 weeks of empagliflozin treatment at rest (top row) and during dobutamine stress (middle row), with 65% of age-maximum heart rate (ie, 220-age). Furthermore, the difference of PCr/ATP at rest minus dobutamine stress (ΔPCr/ATP) from baseline to week 12 was equally unchanged (bottom row). Subgroup analyses in HFrEF (C) and HFpEF (D), including the overall presence or absence of T2D, AF, and eGFR, were consistent with the overall neutral results. AF indicates atrial fibrillation; eGFR, estimated glomerular filtration rate; Empa, empagliflozin; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; PBO, placebo; and PCr/ATP, phosphocreatine/ATP ratio.

Figure 3.

Targeted serum metabolomics. A, Principal component analysis showed no significant differences in clustering Euclidean distance by either condition (HFpEF or HFrEF; P=0.23) or group (empagliflozin vs placebo; P=0.38). Top (right and left), empagliflozin. Bottom (right and left), placebo. Red indicates HFpEF; blue indicates HFrEF. B, Volcano plot visualizing the degree of statistical significance (Wilcoxon rank-sum test) on the y axis vs the magnitude of change (fold change of medians) on the x axis, with a P value <0.05 considered statistically significant. Data points represent the difference of treatment from baseline to week 12 (between empagliflozin and placebo) in the HFpEF and HFrEF groups, respectively. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; GABA, γ-aminobutyric acid; and SAH, S-adenosyl-L-homocysteine.

Figure 4.

Changes in Kansas City Cardiomyopathy Questionnaire (baseline to week 12). Boxplot showing unadjusted mean change from baseline to week 12 in the overall summary score (OSS) and clinical summary score (CSS) of the Kansas City Cardiomyopathy Questionnaire for the placebo (blue) and empagliflozin (red) groups in patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Whiskers indicate SD.