Targeting Apolipoprotein C-III with Olezarsen to Reduce Triglycerides and Prevent Acute Pancreatitis
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on March 6th, 2026
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Severe hypertriglyceridemia is a well-established risk factor for acute pancreatitis, a condition associated with substantial morbidity and mortality. Consequently, therapies that lower serum triglyceride levels, such as fibrates, are commonly used to reduce pancreatic complications. A recent study published in the New England Journal of Medicine evaluated the efficacy and safety of olezarsen, a novel agent targeting apolipoprotein C-III, in lowering triglyceride levels and preventing pancreatitis.
Funding Source(s): Ionis Pharmaceuticals
The clinical trial enrolled 1,061 participants with a mean age of approximately 54 years and a median baseline triglyceride level of about 800 mg/dL. Median apolipoprotein C-III concentrations were approximately 130 mg/dL at baseline. Nearly all participants were receiving background lipid-lowering therapy, including statins (70%), ezetimibe (20%), fibrates (70%), and omega-3 fatty acids (30%). Participants were randomly assigned to receive subcutaneous injections every four weeks of either placebo or olezarsen at doses of 50 mg or 80 mg. Olezarsen is an antisense oligonucleotide that binds to apolipoprotein C-III mRNA, thereby reducing its expression and enhancing triglyceride clearance.
After 12 months of treatment, both olezarsen dose groups achieved triglyceride reductions exceeding 50%, whereas no meaningful reduction was observed in the placebo group. These effects were driven by an approximately 50% reduction in circulating apolipoprotein C-III levels. Importantly, treatment with olezarsen was associated with an 85% reduction in the risk of acute pancreatitis.
However, olezarsen therapy-particularly at the 80 mg dose-was linked to a higher incidence of adverse events, including elevated liver enzymes, thrombocytopenia, and increased hepatic fat fraction. The rise in liver fat may reflect enhanced triglyceride uptake by hepatocytes, potentially contributing to hepatocellular injury and elevations in ALT and AST. Future studies should include a more balanced sex distribution, as only 25% of participants were female, and extend follow-up duration to better assess long-term efficacy, safety, and treatment durability.
Funding Source(s): Ionis Pharmaceuticals
The clinical trial enrolled 1,061 participants with a mean age of approximately 54 years and a median baseline triglyceride level of about 800 mg/dL. Median apolipoprotein C-III concentrations were approximately 130 mg/dL at baseline. Nearly all participants were receiving background lipid-lowering therapy, including statins (70%), ezetimibe (20%), fibrates (70%), and omega-3 fatty acids (30%). Participants were randomly assigned to receive subcutaneous injections every four weeks of either placebo or olezarsen at doses of 50 mg or 80 mg. Olezarsen is an antisense oligonucleotide that binds to apolipoprotein C-III mRNA, thereby reducing its expression and enhancing triglyceride clearance.
After 12 months of treatment, both olezarsen dose groups achieved triglyceride reductions exceeding 50%, whereas no meaningful reduction was observed in the placebo group. These effects were driven by an approximately 50% reduction in circulating apolipoprotein C-III levels. Importantly, treatment with olezarsen was associated with an 85% reduction in the risk of acute pancreatitis.
However, olezarsen therapy-particularly at the 80 mg dose-was linked to a higher incidence of adverse events, including elevated liver enzymes, thrombocytopenia, and increased hepatic fat fraction. The rise in liver fat may reflect enhanced triglyceride uptake by hepatocytes, potentially contributing to hepatocellular injury and elevations in ALT and AST. Future studies should include a more balanced sex distribution, as only 25% of participants were female, and extend follow-up duration to better assess long-term efficacy, safety, and treatment durability.