PURPOSE OF REVIEW: Apolipoprotein CIII (ApoCIII) is now recognized as a key 
regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of 
triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of 
lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic 
reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the 
liver. ApoCIII gain-of-function mutations are associated with atherosclerosis 
and coronary heart disease (CHD), and contribute to the development of 
cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus. 
Conversely, loss-of-function mutations in ApoCIII are associated with lower 
levels of plasma triglycerides (TG), attenuation of vascular inflammatory 
processes such as monocyte adhesion and endothelial dysfunction, and 
potentially, a reduction in the incidence and progression of atherosclerosis and 
cardioprotection.
RECENT FINDINGS: Evidence is now emerging that volanesorsen, a second-generation 
antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in 
decreases in TG in patients with familial chylomicronemia syndrome, severe 
hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving 
support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when 
reduced, endogenous clearance of TRLs can result in substantial reductions in TG 
levels. Discovery of the ApoCIII inhibitor volanesorsen opens a new era of 
lipid-lowering drugs for reduction in TG and potentially for reduction in LDL-C. 
Herein, this review will provide an update on the pathophysiology of 
ApoCIII-linked atherosclerosis and the development of the first drug to target 
ApoCIII, volanesorsen, as a promising lipid-lowering agent.