Advancing the treatment of hypertriglyceridemia: a systematic review and meta-analysis of olezarsen

Hypertriglyceridemia is a metabolic disorder associated with acute pancreatitis and atherosclerotic cardiovascular disease. This meta-analysis evaluated the efficacy and safety of olezarsen in adults with hypertriglyceridemia. We conducted a systematic review and meta-analysis of randomized controlled trials comparing olezarsen with placebo. MEDLINE via PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception to August 15, 2026. The primary outcome was the placebo-adjusted mean difference in percentage change from baseline in triglycerides. Secondary outcomes included lipid parameters, achievement of triglycerides < 150 mg/dL, and safety. Risk of bias was assessed using Cochrane RoB 2.0, and random-effects models were applied. Six randomized controlled trials ( n = 2,744) were included. Olezarsen significantly reduced the placebo-adjusted mean percentage change from baseline in triglycerides (MD -54.93%; 95% CI -61.93 to -47.93; p < 0.01; I²=73.6%). Achievement of triglycerides < 150 mg/dL was greater with olezarsen at 6 months (RR 6.99; 95% CI 6.38–7.66) and 12 months (RR 10.70; 95% CI 3.60-31.81), although the 12-month estimate was accompanied by substantial heterogeneity (I²=75.8%) and a wide prediction interval (95% PI 1.41–80.93), indicating considerable uncertainty regarding the magnitude of the effect. Olezarsen significantly increased the placebo-adjusted mean percentage change from baseline in HDL-C and reduced ApoB, ApoC-III, VLDL-C, non-HDL-C, remnant cholesterol, and total cholesterol. Although the primary analyses showed increases in ApoA1 and LDL-C, these effects were not statistically significant in sensitivity analyses accounting for assumed within-trial correlations of 0.5 and 0.8 between active treatment estimates sharing a common placebo group, indicating sensitivity to the analytical assumptions. No statistically detectable differences were observed in overall or serious adverse events compared with placebo. Injection-site reactions were more frequent with olezarsen (RR 5.37), while the primary analysis showed a lower relative risk of acute pancreatitis (RR 0.15) and of experiencing a ≥ 30% decrease in eGFR (RR 0.74); however, these findings should be interpreted cautiously given the limited number of events and studies contributing to these outcomes, and the acute pancreatitis finding did not demonstrate a statistically significant absolute risk reduction. Olezarsen was associated with substantial improvements in triglyceride levels and several secondary lipid parameters compared with placebo, while no statistically detectable differences were observed for several overall safety outcomes during the available follow-up. However, the effects on ApoA1 and LDL-C were sensitive to assumptions regarding within-trial correlations arising from shared placebo groups, and substantial heterogeneity was present across several lipid outcomes. The increased risk of injection-site reactions, uncertainty surrounding uncommon clinical and laboratory safety outcomes, and limited long-term evidence warrant cautious interpretation.