Rebooting blood vessel repair: implications of the SEMA-VR CardioLink-15 trial

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE), heart failure, and mortality through undetermined mechanisms independent of glycemic control. This review examines emerging evidence that GLP-1RAs overcome vascular regenerative cell exhaustion (VRCE), a pathological depletion of bone marrow-derived progenitor cells that mediate vessel repair. RECENT FINDINGS: VRCE, the progressive loss of circulating progenitor cells that mediate vessel regeneration, has recently emerged as an underappreciated driver of MACE risk in individuals living with type 2 diabetes (T2D), obesity or atherosclerotic cardiovascular disease. In a recent randomized translational trial of semaglutide vs. usual care, SEMA-VR CardioLink-15 provided the direct evidence that 6-month semaglutide administration could reverse VRCE profile associated with longstanding cardiometabolic disease (34.8% increase in VR myeloid progenitor cells, 66.2% expansion of endothelial precursor cells). Semaglutide additionally reduced circulating granulocyte content and suppressed pro-inflammatory TNF and interleukin family cytokines in sera. SUMMARY: GLP-1RAs can restore bone marrow progenitor cell output towards a more vessel regenerative profile. Reversal of VRCE may partially explain early event curve separation in cardiovascular outcome trials with multiple GLP-1RAs. Therefore, circulating VR cell content could serve as a measure of compromised vascular regenerative capacity and elevated cardiovascular disease risk.