1/2 Empagliflozin to Improve Right Ventricular Function in Pulmonary Arterial Hypertension

Project Summary/Abstract Despite advances in medical therapy for pulmonary arterial hypertension (PAH), mortality rates are still unacceptably high. This may be partly due to the lack of therapy that specifically addresses right ventricular (RV) dysfunction, the primary cause of death in PAH. In the failing RV glucose and fatty acid oxidation are decreased, leading to deficient ATP production and accumulation of cytotoxic glucose and lipid by-products. Previous work and preliminary data show that (1) lipid-related insulin resistance is common and RV glucose uptake is increased in PAH and associated with worse outcomes; (2) a high plasma palmitate to acetylcarnitine ratio, suggestive of incomplete fatty acid oxidation, is associated with poor survival; and (3) metformin and diet and exercise can improve RV function. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that reduce the development and progression of left heart failure with an excellent safety profile. Empagliflozin promotes cardiac glucose and fatty acid oxidation, improves left ventricular ejection fraction, lowers pulmonary pressures in heart failure, and attenuates experimental PAH. Our central hypothesis is that treatment with empagliflozin will improve RV function and other key outcomes in patients with PAH. To test our hypothesis, we propose three specific aims: 1. To determine if empagliflozin improves RV function in PAH. We propose a randomized, triple- masked, parallel arm phase II clinical trial of empagliflozin versus placebo in PAH patients on stable approved PAH-targeted medical therapy. The primary endpoint will be change in RV ejection fraction measured by cardiac magnetic resonance imaging (CMR) after 24 weeks of treatment. 2. To determine if empagliflozin affects patient-reported and other clinical outcomes in PAH. This aim will assess whether empagliflozin improves secondary endpoints including tricuspid annular systolic excursion (TAPSE) measured by echocardiography, 6-minute walk distance, N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, the composite endpoints of time to clinical worsening, multicomponent improvement and French risk score, and general- and disease-specific quality of life. 3. To determine if empagliflozin affects metabolic and other cardiac imaging parameters and to identify responders to empagliflozin therapy. This aim will assess effects of empagliflozin on exploratory endpoints related to metabolism and cardiac function including left and right heart interactions. We will assess the effects of empagliflozin on plasma HDL-C, a strong predictor of outcomes in PAH. We will determine the effects of empagliflozin on left and right ventricular mass, RV volumes and stroke volume, interventricular dyssynchrony and RV-arterial coupling. In addition, we will investigate clinical, biomarker, and cardiac imaging phenotypes associated with response to empagliflozin therapy, defined as an improvement in RV ejection fraction ≥ 11 percentage points.