Monthly Olezarsen Significantly Lowers Triglycerides in High-Risk Patients: NEJM

A new study published in The New England Journal of Medicine found that a once-monthly injection of olezarsen reduced triglyceride levels by up to 60% in adults with moderate hypertriglyceridemia and elevated cardiovascular risk, with over 80% achieving normal triglyceride levels at 6 months. Olezarsen, an experimental N-acetylgalactosamine–conjugated antisense oligonucleotide, targets messenger RNA of apolipoprotein C-III, which is a protein that impairs the clearance of triglycerides from the bloodstream. By blocking this protein, olezarsen facilitates faster removal of triglycerides, addressing a core mechanism of the disorder. The phase 3 trial enrolled 1,349 participants who had either moderate hypertriglyceridemia, defined as triglyceride levels between 150 and 499 milligrams per deciliter, combined with elevated cardiovascular risk, or severe hypertriglyceridemia with levels exceeding 500 mg/dL. The participants were randomly assigned to receive monthly subcutaneous injections of olezarsen at either 50 milligrams or 80 milligrams, or to receive a placebo. The primary outcome was the percent change in triglyceride levels after 6 months of treatment. These results found triglyceride levels fell by 58.4% with the 50-mg dose and 60.6% with the 80-mg dose when compared to placebo. Both results were statistically highly significant, with confidence intervals confirming consistency across the patient groups. The study population was diverse, with a median age of 64 years and 40% women. The baseline median triglyceride level was 238.5 mg/dL, with most patients falling between 190.5 and 307.5 mg/dL. Also, reductions were consistent across both olezarsen dosage groups, highlighting the robust efficacy of the drug. The incidence of serious adverse events was similar between the drug-treated groups and the placebo group, indicating that the therapy does not appear to introduce new risks despite its powerful lipid-lowering effects. Overall, the results position olezarsen as a promising new option for patients struggling with high triglycerides, particularly those at elevated risk for heart attacks, strokes, or pancreatitis. By achieving reductions of more than half in triglyceride levels, the effect of olezarsen size surpasses most current therapies, like fibrates or omega-3 fatty acids, which typically deliver more modest improvements. Source: Bergmark, B. A., Marston, N. A., Prohaska, T. A., Alexander, V. J., Zimerman, A., Moura, F. A., Kang, Y. M., Weinland, J., Murphy, S. A., Goodrich, E. L., Zhang, S., Li, D., Banach, M., Stroes, E., Lu, M. T., Tsimikas, S., Giugliano, R. P., & Sabatine, M. S. (2025). Targeting APOC3 with olezarsen in moderate hypertriglyceridemia. The New England Journal of Medicine,. https://doi.org/10.1056/nejmoa2507227