S28 Semaglutide added to anticoagulation in acute intermediate-risk pulmonary embolism is safe and downregulates immunometabolic glycoproteins

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Background Up to 50% of patients suffering acute pulmonary embolism (PE) demonstrate impaired pulmonary vascular recovery at follow up despite optimal anticoagulation, impacting negatively on long-term outcomes. Multiple inflammatory and immune factors may contribute to aberrant thrombus remodelling during PE recovery and in rare cases, chronic thromboembolic pulmonary hypertension may develop. Glucagon-like peptide-1 agonists have prominent anti-inflammatory and vasorelaxant properties supporting their use in higher risk patients with PE at risk of worse outcome. Methods We undertook a proof-of-concept open-label controlled study evaluating the safety and tolerability of the GLP-1 agonist Semaglutide administered as an add-on therapy to standard of care anticoagulation for four weeks in adult patients with acute PE of at least intermediate risk severity. In addition to clinical assessments, we evaluated the effect of Semaglutide on plasma proteomics including markers of vascular inflammation and endothelial dysfunction. CT-based metrics of RV dysfunction were measured at baseline and follow-up to determine exploratory clinical effects on RV recovery. Results After four weeks, open-label treatment with GLP-1 agonist, Semaglutide, added to anticoagulation in patients with intermediate high-risk PE was well tolerated with no relevant safety signals. Examining all well detected proteins in response to Semaglutide, a total of 44 proteins were nominally significantly altered during the study period (p<0.05) although none individually met significance for multiple testing. Enrichment testing of these 44 proteins (p<0.05) identified significant enrichment of glycoproteins (40/44 proteins, FDR q<0.05), and the expression of these glycoproteins showed a clear down-regulation pattern post-treatment. Downregulated proteins included regulators of metabolic stress and key complement intermediates (C3 - C5) with reduction in complement glycoproteins and plasma MMP-9 validated by ELISA. Glycopeptide analysis demonstrated deglycosylation of highly abundant candidate glycoproteins in response to Semaglutide as the plausible mechanism for glycoprotein downregulation. Exploratory CT markers of right ventricular dysfunction improved between baseline and follow up only in those patients who received Semaglutide. Conclusion This study contributes to the growing evidence base for GLP-1 agonist-mediated metabolic modulation in cardiovascular disease and suggests GLP-1 agonists warrant further clinical evaluation as a potential therapeutic add-on in selected acute PE populations.

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