Design and rationale of the EMPA-VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure

Abstract

Aims: Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR).

Methods and results: The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by ³¹ Phosphorus-MRS.

Conclusions: EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).

Trial registration: ClinicalTrials.gov NCT03332212.

Keywords: 31P-MRS; Diabetes; Empagliflozin; Heart failure; SGLT2 inhibitors; Trial design.

Figure 1

Schematic overview of the EMPA‐VISION study design. After screening (Visit 1; Day 0) and randomization, participants will be invited for dedicated assessment before randomization and treatment (Visit 2; Day 1). A safety assessment will be conducted after 2 weeks of treatment (Visit 3; Day 15 ± 1). Following treatment for 12 weeks, assessment will be repeated as described before (Visit 4; Day 84 ± 4). A final follow‐up will be carried out via telephone (Visit 5; Day 91 ± 7). HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Figure 2

Overview of the cardiovascular magnetic resonance (CMR) techniques used in the EMPA‐VISION trial. All CMR sequences will be performed at a field strength of 3 Tesla (Siemens Healthineers, Erlangen, Germany). The CMR protocol is estimated to last approximately 2 h in total, split in two 1 h slots. After resting spectroscopy, dobutamine will be infused to target 65% of age maximal heart rate and stress spectroscopy will be acquired. ¹H‐MRS, proton magnetic resonance spectroscopy; ³¹P‐MRS, phosphorus magnetic resonance spectroscopy; ECV, extracellular volume.

Figure 3

Postulated mechanisms by which empagliflozin might exert beneficial effects on patients with heart failure via manipulation of cardiac energy metabolism. Empagliflozin may enhance oxidative phosphorylation by inhibiting the cardiac isoform of the sodium/hydrogen‐exchanger 1 (NHE 1), promoting branched chain amino acid metabolism, and/or increasing ketone body oxidation. All of these effects would result in a measurable increase in cardiac energy production and storage, which in turn results in an increase in PCr/ATP as well as myocardial function. ATP, adenosine triphosphate; BCAA, branched chain amino acids; PCr, phosphocreatine.