EMPAGUM: Effects of Empagliflozin on Gut Microbiota in Heart Failure With a Preserved Ejection Fraction

Overview

Empagliflozin was recommended for patients with heart failure with reduced ejection fraction (HFrEF) in 2021 European Society of Cardiology (ESC) guidelines (Class of Recommendation Ia) and patients with heart failure with preserved ejection fraction (HFpEF) in 2022 American Heart Association (AHA) guidelines (Class of Recommendation IIa). However, the physiopathologic mechanisms in its effects on HFpEF are not clear. Studies illustrate that gut microbiota plays an essential role in the progress of the heart failure. Studies on mice found that sodium-glucose cotransporter-2 inhibitors (sglt-2i) could affect the intestinal microbiota in mice. The purpose of this study is to clarify the changes of gut microbiota in the patients with HFpEF taking Empagliflozin and explore the role of gut microbiota in this process.

As one of the most important cardiovascular diseases, heart failure is characterized by high incidence and high fatality rate. Heart failure with reduced ejection fraction (HFrEF) has been widely researched for decades and its clinical treatments have been improved remarkably. However, patients with non-reduced ejection fraction accounts for more than 50% of the whole group, especially patients with HFpEF. As for its complicated mechanism as well as normally less serious symptoms, its clinical treatments were not detailed enough before. Patients with heart failure often have decreased cardiac output combined with peripheral circulation congestion, leading to intestinal ischemia and edema. In this case, the intestinal barrier function is weakened, the intestinal wall permeability increases, the bacterial flora is displaced, and more harmful metabolites would also enter the blood circulation through the weakened intestinal mucosal barrier, inspiring more inflammatory substances and aggravating the states of heart failure. Empagliflozin is a sodium-glucose transporter 2 (sglt-2) inhibitor, which can inhibit the reabsorption of glucose in the kidney, discharge excessive glucose from the urine, and reduce blood glucose. It is a new type of hypoglycemic drugs. However, as the study progressed, the effect of sglt-2 inhibitors extends. In fundamental and animal trials, sglt-2 inhibitors were found to reduce sodium uptake, inhibit NO synthesis, improve cardiac energy metabolism, and inhibit cardiac inflammation. In the 2021 ESC heart failure guidelines, sglt-2 inhibitors have been included in the "new quadruple" therapy to target patients with HFrEF. Moreover, in the newly published EMPEROR-preserved study, Empagliflozin still achieved very good efficacy in ejection fraction-preserved heart failure, reducing the composite endpoint event by 21%. The mechanisms by which sglt-2 inhibitors act on heart failure have not been fully resolved, and in basic studies, sglt-2 inhibitors were found to affect the intestinal microbiota in mice. Based on the emerging importance of intestinal microbiota in the process of heart failure, and the impacts of sglt-2 inhibitors on intestinal microbiota and heart failure. It is necessary to clarify the changes of gut microbiota in the patients with non-reduced ejection fraction taking Empagliflozin and explore the role of gut microbiota in this process.