GLP-1 Receptor Agonists in Pulmonary Hypertension: Mechanistic Rationale, Preclinical Evidence, and Clinical...

Pulmonary hypertension (PH) frequently coexists with type 2 diabetes mellitus, obesity, and heart failure with preserved ejection fraction (HFpEF), particularly in World Symposium on Pulmonary Hypertension (WSPH) Group 2 disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists improve several cardiometabolic conditions and have anti-inflammatory and vascular effects. Whether these agents directly modify pulmonary haemodynamics or clinical outcomes in PH remains unknown.

A structured narrative review was conducted using PubMed/MEDLINE and Google Scholar from database inception through March 2026, with additional studies identified by reference-list screening. Search terms encompassed GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, pulmonary hypertension, pulmonary vascular remodelling, endothelial dysfunction, inflammation, and HFpEF. The structured search yielded 491 unique PubMed/MEDLINE records. Of these, 189 were assessed at full-text level alongside 40 additional articles identified through reference-list screening; 67 publications were included in the final synthesis. Evidence was organized by mechanism, experimental model, WSPH group, and whether PH evidence was direct or indirect.

GLP-1 receptor expression has been demonstrated in pulmonary arterial smooth muscle in human and non-human primate tissue and in selected alveolar cell populations in rodent studies; however, available studies do not establish greater expression in pulmonary than systemic vascular smooth muscle. GLP-1 receptor signalling modulates inflammatory, endothelial nitric oxide, endothelin-1, and mitochondrial pathways relevant to PH. In monocrotaline- and hypoxia-induced models that primarily resemble Group 1 pre-capillary pulmonary arterial hypertension (PAH), liraglutide reduced right ventricular pressures or hypertrophy and pulmonary vascular remodelling, while semaglutide improved right ventricular mitochondrial and functional measures in an experimental pressure-overload model. By contrast, available human evidence is observational or derived indirectly from HFpEF studies, involves populations likely enriched for Group 2 or unclassified PH, and lacks prespecified, catheterization-confirmed PH endpoints. Consequently, these studies do not establish that GLP-1-based therapy prevents or treats PH.

Current evidence supports a mechanistic hypothesis and a preclinical signal, not clinical efficacy in PH. Future cardiometabolic and HFpEF trials should incorporate standardized PH and right ventricular measures, and dedicated prospective studies with haemodynamic classification are required before GLP-1-based therapies can be considered for PH.