Within recent years, attention to heart failure (HF) care in patients with type 2 diabetes (T2D) has increased markedly after results from three randomized clinical trials (RCT) evaluating the effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors [
1‐
3]. In these safety trials, it was observed that three different SGLT2 inhibitors could prevent development of HF and prolong life in patients with T2D. Recently, the results have been replicated in real life [
4,
5]. The mechanism behind these observations are poorly understood and while several hypotheses have been proposed, data are lacking [
6‐
9].
In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, the Canagliflozin Cardiovascular Assessment Study (CANVAS) program, and the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, 10–14% of the included patients had a reported history of HF at baseline and a significant subgroup effect was observed with a reduction in the composite endpoint of hospitalization for HF or cardiovascular death in patients treated with empagliflozin, canagliflozin, and dapagliflozin, respectively [
3,
10,
11]. However, HF was neither well-defined nor described in these trials; central information such as whether the patients with reported HF had preserved (HFpEF) or reduced (HFrEF) ejection fraction is unknown. The possible beneficial effects of SGLT2 inhibitors are unknown in patients without T2D but the primary action in the kidneys – induction of glucosuria and natriuresis – have been demonstrated in individuals without T2D [
12]. Proposed derived mechanisms potentially explaining the observed cardiovascular benefits of SGLT2 inhibitors include a proportionally larger reduction in the extracellular volume (ECV) than in the plasma volume (PV) [
13,
14], leading to a reduced preload, left ventricular (LV) filling pressure, and LV wall stress, the latter being the primary driver for N-terminal pro-brain natriuretic peptide (NT-proBNP) production. Thereby, a net effect of decreased NT-proBNP levels, which is associated with a decreased mortality risk in HF populations, is plausible [
15,
16] and a decrease of 30% in NT-proBNP has previously been shown to be clinically significant in this population [
17]. Other proposed derived mechanisms of SGLT2 inhibitors supporting beneficial cardiovascular effects in HF patients include a favorable shift in glucose and fat metabolism towards increased ketone substrate use [
18,
19], renoprotective effects with changes in intrarenal hemodynamics, uricosuria and reduced albuminuria [
7], and direct cardiac effects with remodeling of the myocardium ultimately leading to an improvement in the ventricular systolic function [
9].
To increase the understanding of the cardiovascular effects of SGLT2 inhibitors, we are evaluating the effect of the SGLT2 inhibitor empagliflozin in HFrEF patients with a left ventricular ejection fraction (LVEF) ≤ 40% on cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, and daily activity level and quality of life. The results of the Empire HF trial will complement the results from ongoing event-driven trials and may provide pathophysiological insight into the effect of this new group of drugs in HFrEF patients. Here, we present the protocol for the Empire HF trial. A checklist in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) for the reporting of the protocol is available (Additional file
1).