Key result
Olezarsen reduces triglyceride levels by up to ~55% vs placebo at 12 months.
Why the study?
Olezarsen targets hepatic ApoC-III mRNA to lower ApoC-III and accelerate triglyceride-rich lipoprotein clearance in hypertriglyceridaemia. This study sought to quantify the dose-specific benefit-risk profile of olezarsen 50 mg and 80 mg relative to placebo on triglycerides, related biomarkers, and safety outcomes.
Does olezarsen (50 mg and 80 mg) reduce triglyceride levels and improve triglyceride-rich lipoprotein-related biomarkers compared to placebo in patients with hypertriglyceridaemia?
Meta-Analysis (n=2,610)
Randomized controlled trials
Does olezarsen (50 mg and 80 mg) reduce triglyceride levels and improve triglyceride-rich lipoprotein-related biomarkers compared to placebo in patients with hypertriglyceridaemia?
Olezarsen 50 mg and 80 mg both produce robust 12-month reductions in triglycerides and TRL-related biomarkers, though the 50 mg dose offers a superior safety profile by avoiding the increased risk of thrombocytopenia seen with 80 mg while reducing the risk of eGFR decline.
Olezarsen substantially lowers triglycerides; confirms efficacy across randomized trials in this meta-analysis.
Background 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. Purpose 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. Methods 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. Results 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). Conclusion 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.
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Fernandez et al. (2026) conducted a meta-analysis in Hypertriglyceridaemia (n=2,610). Olezarsen vs. Placebo was evaluated on Triglyceride change at 12 months (MD -54.55 (80 mg); MD -50.52 (50 mg), 95% CI -59.54 to -49.56 (80 mg); -55.92 to -45.12 (50 mg)). Olezarsen significantly reduced triglyceride levels vs placebo at 12 months with both 50 mg (MD -50.52; 95% CI -55.92 to -45.12) and 80 mg (MD -54.55; 95% CI -59.54 to -49.56).
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