(P236) EFFECTS OF ICOSAPENT ETHYL ON VASCULAR REGENERATIVE CELLS IN INDIVIDUALS WITH ELEVATED TRIGLYCERIDES: INSIGHTS FROM THE IPE-PREVENTION CARDIOLINK-14 TRIAL

Background: The mechanistic basis for why icosapent ethyl (IPE) reduced MACE by 25% in the REDUCE-IT trial remains elusive. The IPE-PREVENTION CardioLink-14 trial sought to determine if IPE modulates vascular regenerative (VR) cell content, a critical component of vessel repair and regeneration, in high-risk people with elevated triglycerides (TG).

METHODS AND RESULTS: We randomized 70 statin-treated individuals with moderately elevated TG (≥132 mg/dL and < 495 mg/dL) and either a history of ASCVD or T2D with additional ASCVD risk factors (1:1) to IPE 2g BID or usual care for 3 months. People with eGFR < 30 mL/min/1.73 m2, persistent atrial fibrillation, or a history of major bleeding events were excluded. Mononuclear cells were isolated from peripheral blood collected at baseline and at 3 months. VR cells with high aldehyde dehydrogenase-activity (ALDHhi)) were characterized alongside lineage-specific cell surface markers using flow cytometry. The primary endpoint was the change in the frequency of pro-vascular ALDHhiSSClowCD133+ progenitor cells. Baseline characteristics of the usual care- and IPE-assigned groups were comparable – age 66 vs. 67 years old; BMI 28.9 vs. 28.9 kg/m2; LDL-C 77.0 vs. 70.8 mgl/L; TG 212.6 vs. 204.6 mgl/L; HbA1c 7.1 vs 7.1%; eGFR 76.6 vs. 69.5 mL/min/1.73 m2; with diabetes 71 vs. 71%; with ASCVD 63 vs. 69%, respectively. Relative to usual care, IPE assignment caused a marked 6-fold increase in the frequency of ALDHhiSSClowCD133+ cells despite a decrease in the frequency of the ALDHhiSSClow population. IPE was associated with reduced oxidative stress in ALDHhiSSClow progenitors, an increase in ALDHhiSSChi granulocyte cell content, and elevated EPA metabolites.

Conclusion: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE-mediated changes in VR cell content may in part underlie the CV benefits observed in REDUCE-IT.