Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Effects of Enavogliflozin on Outcomes in Patients With Functional Tricuspid Regurgitation and Heart Failure With Preserved Left Ventricular Ejection Fraction

Functional tricuspid regurgitation (TR) develops due to functional and structural alterations related to heart failure (HF), mitral valve disease and atrial fibrillation. An increase in cardiac filling pressure due to left ventricular (LV) systolic or diastolic dysfunction leads to left atrial, right atrial (RA) and right ventricular (RV) remodeling, which causes tricuspid annular dilatation and TR. The development of significant functional TR causes RV dysfunction and further dilation of RV, which deteriorates TR. Functional TR may occur with HF with preserved or reduced ejection fraction (EF), and the prevalence of moderate-to-severe functional TR is around 19% in patients with HF. Regardless of LVEF or pulmonary artery pressure, presence of moderate or severe functional TR is associated with more symptoms, reduced cardiac output, and worse renal function. A vicious cycle of significant TR, RV volume overload, adverse remodeling of RA, RV, and tricuspid annulus, and consequent aggravation of TR is suggested as a pathophysiologic mechanism of the poor clinical outcomes of patients with TR, and the presence of moderate or severe functional TR is a strong independent determinant of mortality in patients with HF. Because functional TR has a strong prognostic impact and plays an important pathophysiologic role in patients with HF, functional TR is suggested as a therapeutic target in HF. However, there have been no proven medical therapies for TR and only loop diuretics are cautiously recommended for relief of congestive symptoms in patients with severe TR and signs of RV failure. In patients with functional TR associated with systolic dysfunction, medical therapy for HF with a reduced EF may diminish functional TR by improving LV systolic function. Otherwise, the morbidity and mortality of patients with functional TR remain high and a novel therapeutic agent is needed to improve clinical outcomes of HF patients with functional TR and a preserved LV ejection fraction.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors induce urinary excretion of glucose and sodium by blocking the SGLT2 transporter in the proximal tubule (8). SGLT2 inhibitor-induced natriuresis lower cardiac preload and reduce pulmonary congestion and systemic edema. SGLT2 inhibitors also restore tubuloglomerular feedback and lower the intraglomerular pressure by vasoconstriction of the afferent arterioles and consequently reduce hyperfiltration-related renal damage. The beneficial effects of SGLT2 inhibitors on the heart and kidneys may halt the vicious cardiorenal cycle in patients with functional TR (9), which results in deterioration of renal function, hospitalization for heart failure, and cardiovascular mortality.

Accordingly, the Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT) will test the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor enavogliflozin for 18 months would improve clinical and echocardiographic outcomes in HF patients with functional TR and preserved LVEF.