Exenatide infusion acutely improves hemodynamics and right ventricular function in pulmonary arterial hypertension patients and rats

Pulmonary Arterial Hypertension (PAH) is a severe, progressive lung disease characterized by elevated pulmonary artery pressure, leading to right ventricular (RV) failure and premature death. Current therapies primarily target vasodilation but often fail to fully reverse disease progression or improve RV function, leaving a significant unmet need. Glucagon-like peptide-1 (GLP-1) agonists, traditionally used for type 2 diabetes and obesity, have shown promising cardiovascular benefits, including vasodilation and cardioprotection, in preclinical models, suggesting a potential role in treating PAH by addressing both vascular and cardiac dysfunction.

This first-in-disease study evaluated the acute effects of exenatide in 17 patients (9 idiopathic PAH, 8 chronic thromboembolic pulmonary hypertension or CTEPH) and in a rodent model. Patients received an exenatide intravenous infusion during right heart catheterization, with multisite blood sampling for metabolomics. Hemodynamic parameters were measured before and after infusion. In parallel, monocrotaline (MCT) PAH rats and control rats were assessed for acute exenatide effects on RV function using cardiac magnetic resonance imaging (CMR). The study aimed to identify acute hemodynamic changes and explore metabolomic shifts.

Exenatide infusion was well tolerated in all patients. It significantly improved key hemodynamic parameters across the patient cohort. Mean pulmonary artery pressure (mPAP) decreased from 45 ± 15 mmHg to 40 ± 18 mmHg, representing an 11% reduction. Cardiac index (CI) improved from 2.1 ± 0.6 L/min to 2.4 ± 0.9 L/min/m2, a 14% increase. Pulmonary vascular resistance (PVR) also decreased from 7.8 ± 8.0 WU to 5.9 ± 5.0 WU, a 24% improvement. In a subset of patients undergoing pressure-volume measurements, both right ventricular (RV) contractility and afterload showed improvement. An exploratory metabolomics analysis revealed that 47 metabolite levels changed after exenatide infusion, with a predominant impact on free fatty acid pathways. Notably, six metabolites with known prognostic relevance in PAH, involved in myocardial glycolytic and lipid oxidation pathways, were also favorably altered by exenatide. In the MCT rat model of PAH, exenatide acutely improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling, further supporting its beneficial cardiac effects. The most significant finding was the acute reduction in mean pulmonary artery pressure by 11% and pulmonary vascular resistance by 24% in human PAH patients, alongside improved cardiac index, demonstrating immediate hemodynamic benefits.