Reduced postprandial lipid accumulation in circulating monocytes by olezarsen attenuates pro-inflammatory changes in hypertriglyceridemic patients

Abstract The pathophysiological mechanisms linking hypertriglyceridemia to atherosclerotic cardiovascular disease (ASCVD) remain incompletely understood. Accumulating evidence implicates postprandial triglyceride-rich lipoproteins (TRLs) in lipid accumulation and activation of monocytes, thereby exacerbating arterial wall inflammation. Olezarsen lowers fasting and postprandial triglycerides, but its effect on monocyte activation in hypertriglyceridemia remains unclear. In this double-blind, randomized, placebo-controlled trial, 28 patients with hypertriglyceridemia (fasting triglycerides ≥350 mg/dL) received two 80 mg doses of subcutaneous olezarsen or placebo (2:1) at 4-weekly intervals. Peripheral blood mononuclear cells (PBMCs) and CD14⁺ monocytes were isolated 4 h after a standardized oral fat load (OFL) for phenotyping. OFL induced a marked triglyceride increase, accompanied by a 49.0% [95% CI: 30.2%, 71.0%] (p=0.0001) increase in lipid droplets per monocyte. Olezarsen reduced postprandial triglyceride area under the curve (AUC) by 55%, which was associated with a 25.0% decrease [95% CI: 7.9%, 40.5%] (p=0.0049) in intracellular lipid droplets. Mass cytometry-based profiling of PBMCs revealed a decrease of CD11c (p=0.006), CD11b (p=0.049) and CD16 (p=0.039) while CD14 remained unchanged. Postprandial monocyte interleukin-1beta gene expression (IL1B) was reduced in olezarsen-treated patients (p=0.0024). Functionally, monocytes from olezarsen treated patients exhibited a 14.4% decrease (p=0.036) in monocyte adhesion in an ex vivo transendothelial migration assay compared to baseline. In conclusion, olezarsen reduced postprandial lipid droplet accumulation in monocytes, and was associated with decreased expression of activation markers and reduced monocyte adhesion and transendothelial migration of monocytes ex vivo. These findings support an olezarsen-induced reduction in lipid-driven immune-cell activation, an effect associated with a reduced postprandial triglyceride burden.