GLP-1 Receptor Agonists: A Breakthrough in Reducing Atherosclerosis and Cardiovascular Risk Beyond Diabetes and Obesity

Highlight

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce experimental atherosclerosis progression, decrease inflammatory biomarkers, and lower major adverse cardiovascular events (MACE) regardless of hyperglycaemia or obesity. Preclinical rabbit models and clinical biobank data consistently demonstrate these vascular and anti-inflammatory benefits, suggesting wider cardioprotective roles beyond glucose and weight control.

Study Background

Atherosclerosis underlies the majority of cardiovascular diseases (CVD), which remain the leading cause of global morbidity and mortality. While therapies targeting traditional risk factors like hyperglycaemia and obesity have reduced cardiovascular events, residual risk persists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM), have shown cardiovascular benefit beyond glycaemic control, reducing risks of myocardial infarction, stroke, and cardiovascular death. The mechanisms whereby GLP-1 RAs mediate these effects remain incompletely defined. Given that inflammation and atherosclerotic plaque progression contribute critically to CVD pathogenesis, potential anti-atherosclerotic and anti-inflammatory properties of GLP-1 RAs independent of glycaemic or obesity status warrant investigation to optimize their therapeutic positioning.

Study Design

This integrative study combined controlled preclinical experiments and a large observational clinical cohort to evaluate GLP-1 RA effects on atherosclerosis, inflammation, and cardiovascular outcomes independent of hyperglycaemia and obesity.

Preclinical model: Twenty-eight normoglycaemic, non-obese rabbits with established atherosclerosis were randomized to daily liraglutide (0.1 mg/kg) or saline for 4 weeks. Serial imaging included intravascular ultrasound (IVUS) for plaque burden quantification and near-infrared fluorescence-optical coherence tomography (NIRF-OCT) to measure plaque protease (cathepsin) activity related to inflammation and vulnerability. Histological analyses quantified macrophage content and cathepsin S levels within plaques. Plasma levels of C-reactive protein (CRP) were measured as systemic inflammation markers. Additionally, in vitro experiments assessed GLP-1 RAs’ direct effects on macrophage inflammatory mediators and cathepsin activity.

Clinical cohort: Observational analysis was performed on 47,324 participants from the Mass General Brigham Biobank. GLP-1 RA usage was identified, and inflammatory biomarkers (lymphocyte-based ratios, CRP) alongside major adverse cardiovascular events (MACE: myocardial infarction, stroke, cardiovascular death) were recorded. Multivariable regression, propensity score matching (PSM), and mediation analyses were applied, with subgroup stratifications by body mass index (BMI) and glycated haemoglobin (HbA1c) to adjust for obesity and hyperglycaemia.

Key Findings

Atherosclerosis progression and inflammation in vivo: Liraglutide treatment significantly inhibited progression of atherosclerosis in rabbits compared with controls, evidenced by a decrease in IVUS measured percent atheroma volume (Δ -7.8%, 95% confidence interval [CI] -11.3 to -4.2; P<.001). NIRF-OCT imaging demonstrated reduced plaque cathepsin activity (-9.8 nM, 95% CI -18.5 to -1.1; P=0.028), indicating lower proteolytic activity linked to plaque instability. Histological analysis corroborated these findings, showing decreased macrophage infiltration and reduced cathepsin S expression within plaques. Plasma CRP levels also declined, reflecting systemic anti-inflammatory effects.

In vitro macrophage effects: Multiple GLP-1 RAs suppressed cathepsin activity and attenuated pro-inflammatory mediator production in macrophages, supporting a direct cellular immunomodulatory mechanism.

Clinical cohort associations: Among 47,324 biobank participants, GLP-1 RA prescription was significantly associated with lower levels of inflammatory biomarkers (including lymphocyte-based ratios and CRP) and a reduced incidence of MACE events after adjustment for confounders. These associations persisted robustly in subgroups stratified by BMI and HbA1c, underscoring benefits independent of obesity and glycaemic status. Mediation analysis revealed that reductions in inflammatory biomarkers partially accounted for the lowered cardiovascular event risk, suggesting inflammation modulation as a key pathway.

Expert Commentary

This study compellingly advances understanding of GLP-1 RAs’ cardioprotective effects beyond glucose lowering and weight reduction, underlining their ability to modulate atherosclerosis and systemic inflammation. The translational integration of rigorous preclinical imaging and histology with a large well-characterized clinical cohort strengthens causal inference. Notably, cathepsins are recognized contributors to plaque vulnerability, and their suppression by GLP-1 RAs identifies a novel anti-inflammatory mechanism complementing known metabolic effects.

However, limitations include the relatively short preclinical treatment duration and observational design of the clinical study, which cannot exclude residual confounding despite advanced statistical adjustments. Longer-term prospective trials specifically targeting patients without diabetes or obesity are needed to validate these findings. Moreover, whether the anti-atherosclerotic effects translate into improved hard outcomes equally across diverse populations warrants further exploration.

Nevertheless, these findings align with emerging guidelines endorsing GLP-1 RAs for cardiovascular risk reduction in broader patient groups, potentially expanding their use in cardiovascular prevention beyond traditional indications.

Conclusion

This integrative investigation robustly demonstrates that GLP-1 receptor agonists substantially reduce atherosclerosis progression, attenuate inflammatory biomarkers, and lower cardiovascular event risk irrespective of hyperglycaemia or obesity status. The combined data support a paradigm shift positioning GLP-1 RAs as vascular protective agents with pleiotropic cardiovascular benefits extending beyond metabolic control. These insights invite further clinical trials to optimize their application in primary and secondary prevention of atherosclerotic cardiovascular disease.

Funding and ClinicalTrials.gov

Funding sources and ClinicalTrials.gov registration were not specified in the original publication.

References

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