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

Abstract Aims The pathophysiological mechanisms linking hypertriglyceridaemia to atherosclerotic cardiovascular disease remain incompletely understood. Accumulating evidence implicates postprandial triglyceride-rich lipoproteins 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 hypertriglyceridaemia remains unclear. Methods and results In this double-blind, randomized, placebo-controlled trial, 28 patients with hypertriglyceridaemia (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 and CD14⁺ monocytes were isolated 4 h after a standardized oral fat load for phenotyping. Oral fat load 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 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 peripheral blood mononuclear cells revealed a decrease of CD11c (P = 0.006), CD11b (P = 0.049), and CD16 (P = 0.039) whilst CD14 remained unchanged. Postprandial monocyte interleukin-1beta gene expression 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. 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.