GLP-1 Receptor Agonists Show Promising Pleiotropic Effects for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by elevated pulmonary arterial pressure and right ventricular (RV) dysfunction, driven by vascular remodeling, inflammation, and fibrosis. Current therapies targeting endothelin, nitric oxide, prostacyclin, and activin signaling (e.g., sotatercept) offer suboptimal outcomes, especially for patients with cardiovascular comorbidities. This gap highlights the need for novel metabolic-based interventions, making glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) a compelling area of study due to their established pleiotropic benefits beyond diabetes and obesity.

This comprehensive review synthesized existing preclinical and observational evidence regarding glucagon-like peptide-1 receptor agonists (GLP-1RAs) in pulmonary arterial hypertension (PAH). The authors examined studies on GLP-1RA administration in various experimental PAH models, along with research exploring indirect GLP-1 signaling enhancement via dipeptidyl peptidase-4 (DPP-4) inhibition. The review also considered observational data from patients with heart failure with preserved ejection fraction, where GLP-1RAs have shown potential cardiopulmonary benefits, thereby building a case for their therapeutic potential in PAH.

The review identified consistent evidence from experimental PAH models demonstrating that GLP-1RA administration significantly attenuates the severity of pulmonary hypertension. These agonists exhibit a range of beneficial pleiotropic properties, including direct vasodilation, potent anti-inflammatory, and antifibrotic effects. Furthermore, GLP-1RAs were found to provide significant endothelial-protective effects, crucial for mitigating the vascular remodeling characteristic of PAH. Indirect enhancement of GLP-1 signaling through DPP-4 inhibition similarly improved pulmonary hemodynamics and mitigated both fibrosis and inflammation in preclinical settings. Observational studies in patients with heart failure with preserved ejection fraction further suggested broader cardiopulmonary benefits, reinforcing the potential of GLP-1RAs to bridge metabolic, vascular, and cardiac domains in PAH.

GLP-1RAs consistently attenuated PH severity in experimental models, demonstrating vasodilation, anti-inflammatory, antifibrotic, and endothelial-protective effects.