Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.

Background: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia.

Methods: Seventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDH) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The primary endpoint was the change in frequency of pro-vascular ALDHside scatter (SSC)CD133 progenitor cells. Change in frequencies of ALDHSSC monocyte and ALDHSSC granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated.

Findings: Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDHSSCCD133 cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDHSSC cell frequency. IPE assignment also reduced oxidative stress in ALDHSSC progenitors and increased ALDHSSC granulocyte precursor cell content.

Conclusions: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE can modulate VR cell content and suggests a novel mechanism that may underlie the cardioprotective effects observed with IPE in REDUCE-IT.

Funding: HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.