Targeting Apolipoprotein C-III in Hypertriglyceridemia: Implications for Pancreatitis and Cardiovascular risk

Apolipoprotein C-III (apoC-III) has emerged as a validated target for lowering triglycerides, triglyceride-rich lipoproteins, and remnant cholesterol. This review summarizes the biology of apoC-III, the genetic and clinical trial evidence supporting its inhibition, and remaining questions.

Loss-of-function variants in APOC3 are associated with lower levels of triglycerides and reduced cardiovascular risk. Pharmacologic inhibition of apoC-III with RNA-based agents has led to substantial reductions in apoC-III and triglycerides across familial chylomicronemia syndrome (FCS), severe hypertriglyceridemia (sHTG), and moderate hypertriglyceridemia (mHTG). In FCS, agents volanesorsen, olezarsen, and plozasiran have demonstrated reductions in triglycerides and acute pancreatitis. In sHTG, olezarsen has extended this benefit to a larger, multifactorial population. In mHTG, olezarsen and plozasiran lower triglycerides, remnant cholesterol, non-HDL-cholesterol, and apolipoprotein B, but an imaging study with olezarsen demonstrated neutral findings on coronary plaque composition, and cardiovascular event reduction has not been demonstrated. ApoC-III inhibition provides a potent strategy for lowering triglycerides and triglyceride-rich lipoproteins. Its most immediate clinical role is in FCS and sHTG, where prevention of acute pancreatitis is the main objective. Its future as a cardiovascular therapy will depend on whether reductions in remnant cholesterol and apolipoprotein B translate into fewer atherosclerotic events in a dedicated cardiovascular outcomes trial.