Glucagon-like peptide-1 receptor agonists (GLP-1RAs), a drug class widely used to treat type 2 diabetes and obesity, may have therapeutic potential in pulmonary arterial hypertension (PAH), according to a recent review published in ERJ Open Research.1 The evidence remains preliminary, however, and the authors said dedicated clinical trials are needed before these agents can be considered a treatment option for patients with PAH.
The review, led by Benoît Aguado, MD, from the Department of Respiratory Medicine at the University Hospital of Limoges, examined experimental and clinical evidence linking GLP-1 signaling to pulmonary vascular disease. Interest in the drug class stems from growing recognition that metabolic dysfunction contributes to key features of PAH, including endothelial dysfunction, vascular remodeling, inflammation, fibrosis, and maladaptive right ventricular (RV) remodeling.1
“The strongest evidence supporting GLP-1RAs in PAH remains preclinical,” Dr. Aguado said.
For example, studies in monocrotaline-exposed rats show that liraglutide both prevented and reversed pulmonary hypertension, reducing pulmonary arterial remodeling and RV hypertrophy. Dr. Aguado also highlighted an early human signal from a small 2026 study in which intravenous exenatide acutely reduced pulmonary vascular resistance and improved cardiac output in patients with PAH and chronic thromboembolic pulmonary hypertension.
“The available data provide a sound rationale for clinical investigation but do not establish GLP-1 RAs as a treatment for PAH,” he said.
The new review details several mechanisms that could make GLP-1RAs relevant to pulmonary vascular disease. Results from experimental studies suggest the drugs may offer more beyond lowering glucose, including improving endothelial function, enhancing nitric oxide signaling, reducing oxidative stress, suppressing inflammatory pathways, and limiting fibrosis. GLP-1Ras have also been identified in cardiopulmonary tissues, supporting the possibility of direct vascular effects.
Among the preclinical findings, Dr. Aguado said, “we were particularly struck by the benefits observed when liraglutide was initiated after pulmonary hypertension had already developed rather than only before disease onset.”
The associated reductions in pulmonary vascular remodeling and RV hypertrophy suggest the drug may influence established disease, although it remains unclear whether those changes reflect direct myocardial effects or simply reduced RV afterload, he said.
Additional animal studies cited in the review found that liraglutide reduced pulmonary artery smooth muscle cell proliferation, oxidative stress, inflammation, and fibrotic remodeling. Similar benefits have been reported in chronic hypoxia and bleomycin-induced models of pulmonary hypertension and lung injury.
Despite these encouraging findings, significant barriers remain before large-scale clinical testing can begin.
“A major challenge is designing trials that can distinguish direct pulmonary vascular or right ventricular effects from the consequences of weight loss and improved metabolic health,” Dr. Aguado said.
Because PAH is a rare and heterogeneous disease, the investigators believe future studies will require careful patient phenotyping, multicenter recruitment, invasive hemodynamic assessment, RV imaging, and close monitoring for adverse effects such as gastrointestinal symptoms, volume depletion, hypotension, and loss of lean body mass.
If future trials are successful, patients with well-characterized Group 1 PAH and cardiometabolic comorbidities such as obesity or type 2 diabetes may be among the most appropriate candidates for this approach.
References
1. Aguado B, Lacoste-Palasset T, Ruffenach G, et al. Exploring the therapeutic potential of GLP-1 receptor agonists in pulmonary arterial hypertension. ERJ Open Res. 2026;12(3):01479-2025. doi:10.1183/23120541.01479-2025
