Dose-related effects of olezarsen in hypertriglyceridaemia: a systematic review and meta-analysis of 2,610 patients

Abstract

Hypertriglyceridaemia is characterised by accumulation of triglyceride-rich lipoproteins (TRLs) contributing to residual atherosclerotic cardiovascular risk. Olezarsen is a GalNAc-conjugated antisense oligonucleotide targeting hepatic ApoC-III mRNA, thereby lowering ApoC-III and accelerating TRL clearance. We performed a systematic review and meta-analysis to assess the dose-specific benefit–risk profile relative to placebo. To quantify dose-related effects of olezarsen (50 mg and 80 mg) versus placebo on triglycerides and TRL-related biomarkers, and to assess key safety outcomes. PubMed and Embase were searched through 1 February 2026 for randomised controlled trials comparing olezarsen with placebo in patients with hypertriglyceridaemia. The primary outcome was triglyceride change. Secondary outcomes included ApoC-III, remnant cholesterol, non-HDL cholesterol, apolipoprotein B, HDL cholesterol, and LDL cholesterol. Safety outcomes included platelet count <100,000/µL, >25% decline in estimated glomerular filtration rate (eGFR) by CKD-EPI, and major cardiovascular events. Random-effects models pooled mean differences (MD) with 95% confidence intervals (CI) for continuous data, and risk ratios (RR) with 95% CI for dichotomous data. Effect estimates were derived from placebo-adjusted least-squares mean (LSM) changes and corresponding standard errors at 12 months. Heterogeneity was assessed using the Chi-squared test and I² statistic. Five trials, including 2,610 patients (olezarsen n=1,862; placebo n=748) were included. Olezarsen reduced triglyceride levels with both doses (50 mg: MD −50.52 [−55.92, −45.12]; 80 mg: MD −54.55 [−59.54, −49.56]). Marked improvements were also seen in ApoC-III and remnant cholesterol. Non-HDL cholesterol and ApoB decreased significantly in both doses. HDL-C increased with both doses. In severe hypertriglyceridaemia, LDL-C levels increased. Major cardiovascular events were infrequent with no clear between-group differences. Thrombocytopenia only increased with 80 mg (RR 2.24 [1.27, 3.96]; p=0.005); 50 mg showed no clear association. Olezarsen 50 mg reduced the risk of >25% eGFR decline (RR 0.71 [0.51, 0.98]; p=0.04). At 12 months, olezarsen produced robust reductions in triglycerides and TRL-related biomarkers, with consistent improvements in ApoC-III and remnant cholesterol across both doses. Clinically, dose selection should be guided by safety: 80 mg was associated with increased thrombocytopenia, whereas 50 mg maintained substantial lipid efficacy and was associated with a lower risk of >25% eGFR decline. These findings support phenotype-guided individualised dosing and underscore the need for longer, adequately powered trials to determine cardiovascular and renal outcomes.Central IllustrationForest Plots