What is the clinical evidence from this study?

Study design: Review. Population: Cardiovascular diseases. Intervention: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs).

What question did this study set out to answer?

This review aims to summarize the mechanisms by which GLP-1 receptor agonists exert antiatherosclerotic effects.

May 16, 2026Open Access

Direct or Indirect Action? Mechanisms of the Antiatherosclerotic Effects of Glucagon‐Like Peptide‐1 Receptor Agonists

Key Result

Glucagon-like peptide-1 receptor agonists reduce cardiovascular risk through multifactorial indirect and direct antiatherogenic mechanisms, including plaque stabilization.

Key Points

This review aims to summarize the mechanisms by which GLP-1 receptor agonists exert antiatherosclerotic effects.
Review of literature regarding GLP-1 receptor agonists and cardiovascular effects.
Categorized mechanisms into direct and indirect actions.
Discussion of preclinical evidence alongside clinical findings.
GLP-1 RAs improve lipid metabolism, insulin sensitivity, and blood pressure.
Direct actions include anti-inflammatory effects and enhanced endothelial function.
Evidence supports plaque stabilization and reduced atherothrombotic risk through various mechanisms.

Structured PICO

What are the direct and indirect mechanisms underlying the antiatherosclerotic effects of GLP-1 RAs?

Population

Patients with and without Type 2 diabetes, as well as preclinical/animal models

Intervention

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)

Outcome

Mechanisms of antiatherosclerotic effects (indirect and direct pathways)

GLP-1 RAs reduce cardiovascular risk through a combination of indirect systemic benefits and direct vascular antiatherogenic actions, though human mechanistic data remains limited.

Limitations

Mechanistic insights are predominantly derived from preclinical or animal models.

Abstract

Cardiovascular diseases (CVD) remain the leading cause of global mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduce major adverse cardiovascular events in patients with and without Type 2 diabetes, offering benefits that extend beyond glycemic control. This review summarizes proposed multifactorial mechanisms underlying these effects, categorizing them into indirect and direct pathways. Indirect mechanisms include, among others, improvements in lipid metabolism, insulin sensitivity, blood pressure, and renal protection. In addition to the previously described effects, GLP-1 RAs may exert direct vascular actions, including anti-inflammatory actions, suppression of oxidative stress, improved endothelial function, modulation of macrophage polarization, reduction of adhesion molecule expression, and inhibition of vascular smooth muscle cell proliferation and migration, as well as downregulation of matrix metalloproteinases and plasminogen activator inhibitor-1. Collectively, these processes contribute to plaque stabilization and reduced atherothrombotic risk. Although clinical evidence for cardiovascular risk reduction of GLP-1 RAs is robust, mechanistic insights are predominantly derived from preclinical or animal models. Therefore, further functional studies in humans are warranted to clarify the direct antiatherogenic actions of GLP-1 RAs.