Olezarsen in Hypertriglyceridemia With High Cardiac Risk: A <scp>GRADE</scp> ‐Assessed Meta‐Analysis of Randomized Trials With Trial Sequential Evidence

Abstract

ABSTRACT Background Hypertriglyceridemia is a widely prevalent disorder of lipid metabolism that increases the risk of cardiovascular disease and pancreatitis, and it often remains difficult to control even with standard treatments. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C‐III (ApoC‐III), offers a new and promising option for lowering triglyceride levels. Methods A systematic search of PubMed, Scopus, Web of Science, and Cochrane was conducted through September 2025 to identify randomized controlled trials (RCTs) comparing olezarsen with placebo in adults with hypertriglyceridemia at high cardiovascular risk. Dichotomous outcomes were analysed as risk ratios (RRs) and continuous outcomes as percentage mean differences (MDs), both with 95% confidence intervals (CIs). Results Four RCTs ( n = 1615 patients) were included. Olezarsen significantly reduced triglycerides (MD −47.71%, 95% CI −56.78 to −38.64, p &lt; 0.0001), non‐HDL‐C (MD −22.11%, 95% CI −28.48 to −15.75, p &lt; 0.0001), ApoC‐III (MD −68.93%, 95% CI −77.54 to −60.31, p &lt; 0.0001), VLDL‐C (MD −48.52%, 95% CI −57.16 to −39.87, p &lt; 0.0001), and ApoB (MD −10.67%, 95% CI −16.83 to −4.51, p = 0.0007), while increasing HDL‐C (MD 35.13%, 95% CI –27.30 to –42.96, p &lt; 0.0001). LDL‐C showed no significant change. The risks of any or serious adverse events were comparable to placebo. Olezarsen was associated with fewer acute pancreatitis events ( p = 0.035) but higher rates of liver enzyme elevations ≥ 3× ULN ( p = 0.046). Conclusions Olezarsen demonstrated consistent improvements in triglycerides and other atherogenic lipid parameters with an overall acceptable safety profile. These findings suggest that olezarsen may be a useful adjunct option for patients with persistent hypertriglyceridemia despite standard therapy. Further large‐scale and long‐term studies are needed to confirm its cardiovascular and safety outcomes.