Semaglutide promotes bone marrow-derived progenitor cell flux toward an anti-inflammatory and pro-regenerative profile in high-risk patients: the SEMA-VR CardioLink-15 trial

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major atherosclerotic cardiovascular events in individuals living with either diabetes or obesity. Since the turnover of vascular regenerative (VR) stem and progenitor cells has been demonstrated to modulate vessel repair and atherothrombotic risk, this study aimed to determine the effect of the GLP-1RA semaglutide on the levels of circulating VR cells. SEMA-VR CardioLink-15 was a randomized translational trial of usual care vs. semaglutide for 6 months in 46 participants with either type 2 diabetes and/or obesity plus atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors. VR cells were enumerated using multi-parametric flow cytometry for high aldehyde dehydrogenase activity (ALDHhi) and lineage-specific cell surface marker expression. The primary endpoint was the 6-month change in VR cell content. Compared to usual care (n = 24), semaglutide (n = 22) led to a greater increase in the number of VR cells (ALDHhiSSClow: +0.8% vs. +34.8%, P = .036), pan-haematopoietic myeloid progenitors (ALDHhiSSClowCD45+: +2.8% vs. +40.1%, P = .017), and endothelial precursors (ALDHhiSSClowCD34+CD133+CD45-: -2.3% vs. +66.2%; P = .037) from baseline. Semaglutide also decreased granulocyte precursors (ALDHhiSSChi: +0.3% vs. -50.8%, P = .002), particularly those expressing the neutrophil activation marker CD66b and chemokine receptor CXCR2. Semaglutide downregulated serum proteins over-represented in pro-inflammatory tumor necrosis factor and interleukin signalling pathways. In people living with either type 2 diabetes or obesity plus ASCVD risk, semaglutide increased circulating VR cell content while reducing pro-inflammatory granulocyte precursors and cytokine production. Collectively, these findings suggest that semaglutide may improve endogenous progenitor cell-mediated blood vessel repair processes.