Ertugliflozin for Functional Mitral Regurgitation

Overview

In patients with heart failure (HF) and left ventricular (LV) dilation, adverse LV remodeling causes tethering of mitral valve (MV) preventing sufficient coaptation of normal leaflets and resulting in functional MR. Because secondary functional MR usually develops as a result of LV dysfunction, guideline-directed medical therapy for HF forms the mainstay of therapy. However, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) fail to reverse adverse LV remodeling and functional MR, and the morbidity and mortality of patients with functional MR remain high despite standard medical therapy. Randomized trials to explore cardiovascular (CV) benefit of the sodium-glucose co-transporter-2 (SGLT2) inhibitor have been performed and showed a significant reduction on the risk of CV death or hospitalization for HF. However, its effect on cardiac structure and function was not evaluated and further mechanistic studies are needed to interpret beneficial clinical effects of the SGLT2 inhibitors. Based on studies demonstrating SGLT2 inhibitors' favorable effects on LV modeling, investigators hypothesize that SGLT2 inhibitor, ertugliflozin, is effective on improving MR in patients with functional MR secondary to LV dysfunction and try to examine this hypothesis in a multicenter, double-blind, randomized comparison study using echocardiography.

In patients with heart failure (HF) and left ventricular (LV) dilation, adverse LV remodeling causes tethering of mitral valve (MV) preventing sufficient coaptation of normal leaflets and resulting in functional MR. Because secondary functional MR usually develops as a result of LV dysfunction, guideline-directed medical therapy (GDMT) for HF forms the mainstay of therapy. However, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) fail to reverse adverse LV remodeling and functional MR, and the morbidity and mortality of patients with functional MR remain high despite standard medical therapy. A recent randomized trial (COAPT) proved that reduction of functional MR by transcatheter MV repair resulted in a lower rate of hospitalization for HF and lower mortality in patients with HF and significant secondary MR, but more than two-thirds of such patients either died or were hospitalized for HF within 5 years. Thus, optimization of GDMT for timely reduction of functional MR is important, because the persistence of severe functional MR despite GDMT contributes to a vicious cycle of deterioration and leads to irreversible LV dysfunction and a poorer prognosis. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce cardiac preload and afterload by natriuresis and lowering arterial stiffness, similar to the neprilysin inhibitor that facilitates sodium excretion and has vasodilating effects. Randomized trials to explore cardiovascular (CV) benefit of the SGLT2 inhibitor have been performed and showed a significant reduction on the risk of CV death or hospitalization for HF. Based on remarkable outcomes of recent clinical trials, SGLT2 inhibitors are recommended for HF with reduced EF and can be beneficial in HF with preserved EF. These outcome trials of SGLT2 inhibitors did not examine their effects on cardiac structure and function, and small imaging trials reported conflicting results in terms of the effect of a SGLT2 inhibitor on LV remodeling in patients with HFrEF and diabetes. Despite current recommendations of SGLT2 inhibitors for HF, SGLT2 inhibitors are rarely used in patients with HF with functional MR, as shown in the COAPT trial, because their effects on cardiac remodeling and functional MR are uncertain. The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was designed to evaluate the therapeutic efficacy of the SGLT2 inhibitor, ertugliflozin, on functional MR. The major hypothesis of this trial was that ertugliflozin would be superior to placebo in reducing functional MR associated with HF with mildly or moderately reduced EF.