# Targeting inflammation in cardiometabolic disease: Icosapent ethyl modulates monocyte‐derived macrophages isolated from patients with cardiovascular disease with or without type 2 diabetes

## TL;DR

This study explores how icosapent ethyl reduces inflammation in macrophages from patients with heart disease and type 2 diabetes, potentially lowering cardiovascular risk.

## Contribution

The study investigates the direct anti-inflammatory effects of icosapent ethyl on patient-derived macrophages, distinguishing drug effects from therapy changes.

## Key findings

- Icosapent ethyl may reduce NLRP3 inflammasome activation in macrophages.
- The study will compare EPA effects in healthy and diseased macrophages.
- Findings could inform strategies to target residual inflammation in cardiometabolic disease.

## Abstract

Despite intensive lipid‐lowering therapy, individuals with atherosclerotic cardiovascular disease (ASCVD) exhibit residual inflammatory risk, which drives recurrent cardiovascular events. This risk is amplified in type 2 diabetes mellitus (T2DM), where a pro‐inflammatory milieu accelerates atherogenesis. Monocyte‐derived macrophages (MDMs), key mediators of vascular inflammation, contribute significantly to this process. Icosapent ethyl (IPE), a highly purified ethyl ester of eicosapentaenoic acid (EPA), reduces major adverse cardiovascular events (MACE) beyond triglyceride lowering, yet its cellular mechanisms remain unclear. This study aims to determine whether IPE modulates inflammatory pathways in patient‐derived MDMs and to distinguish direct EPA effects from therapy‐mediated changes.

This single‐centre, open‐label, randomised observational cohort study will recruit ASCVD patients, stratified by T2DM status, who are prescribed IPE (Vazkepa®). MDMs and plasma/serum samples will be collected from patients, either IPE‐naïve or following 6 months of therapy. In parallel, direct EPA effects will be assessed by treating MDMs from healthy donors and ASCVD patients with physiologically relevant concentrations of EPA. We will evaluate NOD‐like receptor protein 3 (NLRP3) inflammasome priming and activation, inflammatory cytokine profiles, and markers of cellular senescence.

The study will investigate mechanisms that potentially underlie the cardiovascular benefits of IPE, focusing on the modulation of inflammatory pathways. We hypothesise that IPE attenuates priming and activation of the NLRP3 inflammasome in monocyte‐derived macrophages, thereby reducing cellular inflammation and senescence.

This study will provide mechanistic insight into how IPE influences macrophage‐driven inflammation in ASCVD and T2DM, informing strategies to target residual inflammatory risk in high‐risk cardiometabolic populations.