Exploring the Therapeutic Potential of GLP-1 Receptor Agonists in Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is a progressive and multifactorial disease marked by elevated pulmonary arterial pressure and right ventricular (RV) dysfunction. Among its subtypes, pulmonary arterial hypertension (PAH) is characterized by profound vascular remodeling, inflammation, and fibrosis. Despite therapeutic advances targeting the endothelin, nitric oxide, prostacyclin, and, more recently, the activin signaling pathway via sotatercept, outcomes in PAH remain suboptimal, particularly in patients with cardiovascular comorbidities. This has prompted growing interest in novel metabolic-based interventions, such as Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs). GLP-1RAs, initially developed for type 2 diabetes and obesity, exhibit pleiotropic properties including vasodilation, anti-inflammatory, anti-fibrotic, and endothelial-protective effects. In experimental models of PAH GLP-1RAs administration attenuate the severity of PH. Additional studies highlight their ability to protect against lung fibrosis and preserve endothelial function. Indirect enhancement of GLP-1 signaling through dipeptidyl peptidase-4 (DPP-4) inhibition similarly improves pulmonary hemodynamics and mitigates fibrosis and inflammation, underscoring the relevance of this pathway. Although no clinical trials have specifically evaluated GLP-1RAs in PH, observational studies in patients with heart failure with preserved ejection fraction suggest potential cardiopulmonary benefits. GLP-1RAs emerge as promising candidates bridging metabolic, vascular, and cardiac domains in pulmonary hypertension, warranting rigorous clinical validation. These findings support further translational research and randomized clinical trials to evaluate GLP-1RAs as a disease-modifying therapy in PAH.