Severe hypertriglyceridemia (>500 mg/dL) markedly increases the risk of pancreatitis. Olezarsen is a GalNAc-conjugated antisense oligonucleotide that lowers triglycerides by targeting APOC3 mRNA and thereby reducing apolipoprotein C-III (ApoC-III) production in the liver. Lower ApoC-III levels enhance lipoprotein lipase activity and hepatic clearance of triglyceride-rich lipoprotein remnants, leading to a strong reduction in VLDL and triglycerides.

In two randomized, double-blind trials, olezarsen (50 mg or 80 mg) reduced triglyceride levels by about 50% versus placebo at 6 months and significantly lowered pancreatitis events. Adverse events were similar across groups, although higher liver enzymes and thrombocytopenia occurred more often with the 80-mg dose.