Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are known to reduce major atherosclerotic cardiovascular events, but the full extent of their mechanisms is still being explored. The SEMA-VR CardioLink-15 trial investigated whether semaglutide affects the levels of circulating vascular regenerative (VR) cells, which are involved in vessel repair and may modulate atherothrombotic risk.¹˒²
Methodology
The SEMA-VR CardioLink-15 trial was a 6-month, open-label, randomised translational study conducted in Canada. It enrolled 46 participants with either type 2 diabetes and/or obesity, alongside established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors.
Participants were randomised 1:1 to receive either usual care (n=24) or once-weekly subcutaneous semaglutide (n=22) for 6 months. The semaglutide dose was initiated at 0.25 mg and titrated to a target of 1.0 mg. The primary endpoint was the 6-month change in the content of VR cells, identified by high aldehyde dehydrogenase 1A1 activity and low side scatter (ALDHhiSSClow).
Results
After 6 months, the semaglutide group demonstrated a significantly greater increase in the primary endpoint of VR cell content compared with the usual care group (+34.8% vs +0.8%; p=0.036).¹
Further analysis of cell subsets revealed that semaglutide treatment also led to a greater increase from baseline in:
- Pan-haematopoietic myeloid progenitors (ALDHhiSSClowCD45+): +40.1% vs +2.8% (p=0.017)
- Endothelial precursors (ALDHhiSSClowCD34+ CD133+ CD45−): +66.2% vs -2.3% (p=0.037)
Conversely, semaglutide was associated with a significant decrease in pro-inflammatory granulocyte precursors (ALDHhiSSChi) compared to usual care (-50.8% vs +0.3%; p=0.002). Proteomic analysis also showed that semaglutide down-regulated serum proteins involved in pro-inflammatory tumour necrosis factor and interleukin signalling pathways. Five adverse events were reported in the semaglutide group, including two cases of gastrointestinal disturbances.
In Practice
These findings suggest a novel biological action for semaglutide beyond its established metabolic benefits. The study authors concluded, “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.”¹ This shift towards a more anti-inflammatory and pro-regenerative profile may contribute to the cardiovascular protection observed with GLP-1RA therapy.
Next Steps
The trial was not powered for clinical outcomes, and the authors note that further research is needed to explore how these changes in VR cell content may translate into a reduction in cardiovascular events.
This study was funded by the Canadian Institutes of Health Research.
References
1. Park B, Dennis F, He AZ, et al. Semaglutide promotes bone marrow–derived progenitor cell flux towards an anti-inflammatory and pro-regenerative profile in high-risk patients: the SEMA-VR CardioLink-15 trial. _Eur Heart J_. 2026;47(10):1171–1182. https://doi.org/10.1093/eurheartj/ehaf690
2. Hess DA, Verma S, Bhatt D, et al. Vascular repair and regeneration in cardiometabolic diseases. _Eur Heart J_. 2022;43:450–9. https://doi.org/10.1093/eurheartj/ehab758
Disclaimer
The information presented in this article is for educational purposes only. Any quotes included reflect the opinions of the individual quoted, and do not necessarily reflect the views of the publisher. The publisher does not guarantee the accuracy or completeness of the content and accepts no responsibility for any errors, or any consequences arising from its use.