Glucagon-like peptide-1 receptor agonists reduce experimental atherosclerosis progression, inflammatory biomarkers and cardiovascular events, irrespective of hyperglycaemia and obesity

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular events. However, their impact on atherosclerosis and inflammation, regardless of diabetes or obesity, is unknown. Here, GLP-1 RA effects were investigated on (i) atherosclerosis burden and inflammation in vivo in rabbits and (ii) inflammatory biomarkers and major adverse cardiovascular events (MACE) in clinical subjects, adjusted for glycaemic and obesity status. METHODS: Rabbits with atherosclerosis received liraglutide (0.1 mg/kg/day) or saline for 4 weeks. Serial intravascular ultrasound (IVUS) and near-infrared fluorescence-optical coherence tomography (NIRF-OCT) assessed plaque burden and cathepsin activity. Histological, plasma, and in vitro analyses assessed GLP-1 RA effects on atheroinflammation. A clinical study of 47,324 participants from the Mass General Brigham Biobank evaluated the association between GLP-1 RA prescription and inflammatory biomarkers [lymphocyte-based ratios and C-reactive protein (CRP)], and MACE. Analyses included multivariable regression, propensity score matching (PSM), and mediation analysis. RESULTS: In 28 normoglycaemic, non-obese rabbits, liraglutide significantly inhibited atherosclerosis progression compared with controls [IVUS Δ percent atheroma volume: -7.8%, 95% confidence interval (CI) -11.3 to -4.2; P < .001], and reduced NIRF-OCT plaque cathepsin activity (-9.8 nM, 95% CI -18.5 to -1.1; P = .028). Liraglutide further reduced plaque cathepsin S, macrophage content, and plasma CRP levels. In vitro, multiple GLP-1 RAs suppressed cathepsin activity and inflammatory mediators in macrophages. In biobank patients, GLP-1 RA prescription associated with significantly lower levels of inflammatory biomarkers and MACE in regression and PSM analyses, with benefits persisting in subgroups stratified by body mass index or glycated haemoglobin. Mediation analysis showed inflammatory biomarkers partly contributed to this effect. CONCLUSIONS: This integrative preclinical-clinical study demonstrates that GLP-1 RAs reduce atherosclerosis progression, inflammatory biomarkers and MACE, irrespective of hyperglycaemia or obesity.