This updated systematic review and meta-analysis evaluated the efficacy and safety of olezarsen in patients with dyslipidemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing olezarsen with placebo. Seven trials ( n = 2,121) were included. Olezarsen significantly reduced triglycerides (mean difference [MD] −59.20 mg/dL), very-low-density lipoprotein cholesterol (MD −52.68 mg/dL), apolipoprotein B (MD −10.74 mg/dL), non-HDL cholesterol (MD −17.06 mg/dL), and apolipoprotein C-III (MD −64.16 mg/dL), and increased HDL cholesterol (MD 30.97 mg/dL), with no significant effect on LDL cholesterol. Injection site reactions (risk ratio [RR] 3.93) and platelet counts <140,000/µL (RR 4.76) were increased, whereas serious adverse events and significant liver enzyme elevations were comparable to placebo. Certainty of evidence ranged from moderate to low. In conclusion, olezarsen produces substantial improvements in triglyceride-rich lipoproteins with an acceptable safety profile; long-term cardiovascular outcome trials are warranted.
Graphical abstract
Cardiovascular diseases (CVDs) are a major global health problem because of their significant contribution to morbidity and mortality. They involve a complex interaction between genetic, environmental, and lifestyle variables. Among these factors, dyslipidemia, which is defined as abnormal levels of blood lipids including elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), or decreased high-density lipoprotein cholesterol (HDL-C) plays a significant role. Dyslipidemia affects millions of individuals worldwide, with prevalence estimates ranging from 20% to 80%. , Despite the widespread use of statin therapy, considerable residual cardiovascular risk due to persistent hypertriglyceridemia has remained a potent contributor to CVDs. However, the link between triglyceride lowering and a reduction in major adverse cardiovascular events (MACE) remains a subject of debate. Previous trials with other agents, such as the PROMINENT trial (Das Pradhan et al.), failed to show a reduction in cardiovascular outcomes despite significant triglyceride lowering, highlighting the need for further evidence in this area.
Apolipoprotein C3 (APOC3) which is mainly expressed in hepatocytes encodes apoC-III, a smaller apolipoprotein of 79 amino acid residues. , ApoC-III plays a significant role in triglyceride metabolism. It interferes with the activation of lipoprotein lipase (LPL) by apoC-II, reduces the binding of apoE to hepatic lipoprotein receptors, and also inhibits hepatic lipase, which plays an important role in the conversion of dense VLDL to IDL and LDL. Hypertriglyceridemic individuals have increased plasma apoC-III concentrations and production rates compared with normolipidemic individuals. Therefore, elevated apoC-III levels directly influence atherosclerosis formation through multiple mechanisms, including facilitating subendothelial accumulation of atherogenic lipoproteins and enhancing their affinity for arterial wall proteoglycans. Pollin et al. reported in 2008 that carriers of the APOC3 null mutation (R19X) had about 40% lower plasma apoC-III levels, significantly lower postprandial triglycerides, and higher HDL-cholesterol levels than noncarriers. This evidence highlights APOC3 as a novel therapeutic target for managing dyslipidemia, particularly in patients with hypertriglyceridemia.
This concept was supported by a small pilot study involving 3 patients with familial chylomicronemia syndrome, where antisense inhibition of hepatic APOC3 mRNA using volanesorsen reduced plasma apoC-III by 56% to 86% and led to marked decreases in triglyceride levels. Interestingly, these reductions appeared to involve not only LPL-dependent but also LPL-independent pathways, suggesting broader mechanisms contributing to triglyceride clearance. However, the clinical use of volanesorsen was limited due to adverse events, such as thrombocytopenia and injection site reactions, highlighting the need for safer alternatives.
Recently, olezarsen has emerged as a next-generation, hepatocyte targeted antisense oligonucleotide (ASO) specifically designed to suppress hepatic production of ApoC-III which is a key regulator that inhibits lipolysis of triglyceriderich lipoproteins. Compared to volanesorsen, olezarsen is a hepatocyte-targeted, N-acetyl-galactosamine (GalNAc)-conjugated ASO that binds the asialoglycoprotein receptor to enhance liver-specific delivery. This targeted approach enhances therapeutic potency while improving safety and tolerability. Like volanesorsen, olezarsen is administered subcutaneously, but it achieves similar triglyceride reduction and HDL-C elevation with lower doses and less frequent administration. Each dose of olezarsen has been shown to significantly lower apoC-III, apolipoprotein B, and non-HDL cholesterol levels, with minimal effect on LDL cholesterol. Recent findings from 2024 suggest that olezarsen can reduce TG levels by nearly 50% although the optimal therapeutic dose remains to be determined.
A recent meta-analysis by Tristan et al. provided valuable insights into the efficacy and safety of olezarsen in treating dyslipidemia. However, its conclusions were constrained by the limited number of randomized controlled trials available at the time, along with short follow-up durations and small sample sizes. Moreover, key clinical outcomes such as dose–response relationships, durability of triglyceride reduction, and long-term safety were not comprehensively evaluated. Since its publication, several pivotal studies have been published, demonstrating significant improvements in the lipid profile with olezarsen. These new data, particularly those exploring dose response and evaluating optimal therapeutic dosing, necessitate an updated meta-analysis to accurately reflect the current evidence base. Such analysis will address existing knowledge gaps, incorporate recent findings, and provide clinicians with the most current and comprehensive information regarding the efficacy and safety of olezarsen.
Material and Methods
Protocol registration
This systematic review and meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) with the reference number CRD420251157130.
Data sources and search strategy
A systematic and comprehensive search of electronic databases, including PubMed/MEDLINE, Cochrane CENTRAL, Embase, and Scopus, was performed to identify all relevant studies from inception to September 2025. The reference lists of included articles and relevant reviews were also manually screened to find any additional studies. The search was conducted without limitations on language or publication date.
The search strategy was designed to be broad and included a combination of MeSH terms and related keywords including: (“Dyslipidemia” OR “Hypertriglyceridemia” OR “Hyperlipidemia” OR “Familial Chylomicronemia Syndrome” OR “Atherosclerosis”) AND (“Olezarsen” OR “ISIS 678354” OR “APOC3 antisense oligonucleotide”). The detailed search strategy for each database is provided in Supplementary Table 1 .
Study selection and eligibility criteria
All identified records were imported into a Rayyan.AI, and duplicates were removed. Two authors independently screened the titles and abstracts of the remaining records for potential eligibility. The full texts of the selected articles were then retrieved and assessed against the predefined inclusion criteria. Any disagreements between the reviewers were resolved by consensus or by consulting a third author.
Studies were selected according to the Population, Intervention, Control, Outcomes, and Study design (PICOS) framework. The eligible population (P) included patients with dyslipidemia, particularly those with elevated triglyceride levels (e.g., hypertriglyceridemia, severe hypertriglyceridemia, or familial chylomicronemia syndrome). The intervention (I) consisted of treatment with olezarsen at any dose or regimen, compared to a control (C) group receiving placebo or standard-of-care therapy. Key outcomes (O) were assessed for both efficacy and safety. Efficacy outcomes included the percent change from baseline in lipid and lipoprotein parameters, such as triglycerides (TG), apolipoprotein C-III (ApoC-III), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and apolipoprotein B (ApoB). Safety outcomes encompassed all-cause mortality, serious adverse events (SAEs), adverse events leading to treatment discontinuation, injection site reactions, thrombocytopenia, and elevated liver enzymes (ALT/AST). Regarding study design (S), only randomized controlled trials (RCTs) were considered for inclusion. Exclusion criteria included nonrandomized studies, observational studies, case reports, reviews, and studies lacking a relevant comparator or outcome data.
Data extraction
Two authors independently extracted data from the included studies using a standardized Microsoft Excel sheet. The extracted information included (1) study identifiers (author, year), (2) baseline characteristics of the study populations (age, sex, baseline lipid levels), (3) primary outcomes, such as the percent change in triglycerides, ApoC-III, and (4) secondary outcomes, such as the incidence of SAEs and adverse events leading to discontinuation.
Quality assessment
The methodological quality of the included RCTs was assessed using the Cochrane Risk of Bias 2 (RoB-2) tool. This tool evaluates the risk of bias across 5 domains: the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Studies were categorized as having a “low risk,” “some concerns,” or “high risk” of bias.
Statistical analysis
All statistical analyses will be performed using the R programming language (version 4.3.1), primarily with the “meta” and “metaphor” packages. Risk ratios (RRs) with 95% confidence intervals (CIs) will be calculated for dichotomous outcomes (e.g., SAEs, treatment discontinuation), while mean differences (MDs) with 95% CIs will be calculated for continuous outcomes (e.g., percent change in triglyceride levels). For all analyses, results will be reported with 95% CIs, and a p-value of ≤0.05 will be considered statistically significant.
Statistical heterogeneity will be assessed using the I2 statistic, with thresholds of <25%, 25% to 50%, and >50% indicating low, moderate, and high heterogeneity, respectively. A random-effects model (DerSimonian and Laird) was used for all pooled analyses given the anticipated clinical and methodological diversity across studies. A sensitivity analysis using a leave-one-out approach is planned to identify studies contributing to significant heterogeneity. Publication bias will be evaluated by visually inspecting funnel plots for asymmetry.
Certainty of evidence (GRADE assessment)
The certainty of the evidence for each primary outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. The GRADE approach evaluates the quality of evidence based on 5 domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The final certainty of evidence was rated as high, moderate, low, or very low. The GRADE assessment is provided in Supplementary Table 2 .
Results
Study selection
A comprehensive search across various electronic databases (PubMed, Embase, Cochrane, and Scopus) initially identified 721 records. After the removal of 221 duplicate records, 500 unique articles remained. A preliminary screening of titles and abstracts was conducted based on predefined exclusion criteria, leading to the elimination of 460 studies. Subsequently, 40 studies were sought for retrieval, all of which were accessed. A rigorous full-text evaluation was then conducted on these 40 studies by 2 independent authors, applying both inclusion and exclusion criteria. This process led to the exclusion of 37 studies (due to wrong population, intervention, or outcome), reducing the number of relevant studies to 3 new studies, which met all requirements for inclusion. These 3 new studies, combined with 4 studies from the previous review, resulted in a total of 7 studies included in the final review. The PRISMA flow chart outlines the systematic screening process as shown in Figure 1 .
PRISMA flow diagram illustrating the systematic study selection process.
Study characteristics
A total of 7 randomized controlled trials (RCTs) were included in this meta-analysis, evaluating the efficacy and safety of Olezarsen, an apolipoprotein C-III (apoC-III) inhibitor, in patients with hypertriglyceridemia. The studies collectively enrolled 2,121 participants, with sample sizes ranging from 28 to 1,349 individuals. All trials were randomized, double-blind, and placebo controlled. Geographically, the trials were conducted primarily in North America (United States and Canada), with 1 multicenter international study (Bergmark et al. 2025).
The intervention consisted of subcutaneous Olezarsen administered at varying doses (ranging from 10 mg to 120 mg) across the studies, compared against a matched placebo. The follow-up duration for efficacy outcomes ranged from 3 to 7 months, with most trials reporting a 6-month endpoint.
Participants were adults with a mean age ranging from approximately 42 to 65 years. The populations exhibited a mix of gender distributions, with most studies enrolling a higher percentage of male participants (ranging from 39.5% to 83.3% male). At baseline, patients presented with characteristic dyslipidemia. Mean triglyceride levels were elevated across all studies, with 1 study (Stroes et al. ) specifically enrolling patients with severe hypertriglyceridemia (mean TG > 2,500 mg/dL). Baseline levels of other lipid parameters, including LDL cholesterol, non-HDL cholesterol, and apolipoprotein B, varied across the trials, reflecting differences in the enrolled patient populations. The baseline characteristics were generally well-balanced between the Olezarsen and placebo groups within each study. A detailed overview of the study and patient characteristics is provided in Table 1 .
Table 1
Baseline characteristics of the included studies and patient populations
| Baseline characteristics | Alexander et al. 2019 | Bergmark et al. 2024 | Bergmark et al. 2025 | Karwatowska et al. 2024 | Karwatowska et al. 2022 | Stroes et al. 2024 | Tardiff et al. 2022 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Olezarsen | Placebo | Olezarsen | Placebo | Olezarsen | Placebo | Olezarsen | Placebo | Olezarsen | Placebo | Olezarsen | Placebo | Olezarsen | Placebo | |
| Study design | RCT | RCT | RCT | RCT | RCT | RCT | RCT | |||||||
| Country | Canada | US and Canada | Multi-center | USA | USA | USA | USA | |||||||
| Doses of olezersen (mg) | 10, 30, 60, 90, 120 | 50, 80 | 50,80 | 30, 60, 90 | 30, 50 | 50, 80 | 10, 30, 40, 50, | |||||||
| Follow up duration, months | 3 | 6 | 6 | 7 | NR | 6 | 6 | |||||||
| Sample size | 49 | 18 | 115 | 39 | 1020 | 329 | 22 | 6 | 90 | 24 | 43 | 23 | 90 | 24 |
| Age (yrs), mean ± SD | 50.6 ± 10.3 | 54.3 ± 8.9 | 61.8 ± 4.8 | 63.8 ± 4.0 | 63.4 ± 4.0 | 63.0 ± 4.0 | 41.7 ± 10.6 | 49.8 ± 11.95 | NR | NR | 45.5 ± 12.8 | 44.0 ± 14.7 | 65.49 ± 8.17 | 64.6 ± 7.93 |
| Sex, n (%) | ||||||||||||||
| Male, n (%) | 34 (69.4) | 7 (38.9) | 74 (64.3) | 15 (38.5) | 617 (60.5) | 189 (57.4) | 15 (75.0) | 3 (75.0) | NR | NR | 17 (39.5) | 11 (47.8) | 66 (73.3) | 20 (83.3) |
| Female, n (%) | 15 (30.6) | 11 (61.1) | 41 (35.7) | 24 (61.5) | 403 (39.5) | 140 (42.6) | 5 (25.0) | 1 (25.0) | NR | NR | 26 (60.5) | 12 (52.2) | 24 (26.7) | 4 (16.7) |
| Weight (kg), mean ± SD | NR | NR | NR | NR | NR | NR | 64.3 ± 8.29 | 67.0 ± 7.14 | NR | NR | 64.9 ± 14.7 | 67.8 ± 16.1 | NR | NR |
| BMI (kg/m²), mean ± SD | 30.5 ± 2.6 | 29.4 ± 2.5 | 32.4 ± 17.0 | 33.0 ± 11.1 | 31.5 ± 47.2 | 31.8 ± 32.9 | 23.9 ± 1.97 | 24.2 ± 1.23 | NR | NR | 23.8 ± 5.1 | 24.2 ± 4.1 | 32.1 ± 4.00 | 32.1 ± 4.18 |
| Lipid profile | ||||||||||||||
| Triglyceride (mg/dL), mean ± SD | 203.7 ± 132.8 | 167.3 ± 70.8 | 253.7 ± 121.2 | 251.1 ± 48.1 | 244.6 ± 86.4 | 247.3 ± 85.2 | 166.7 ± 92.3 | 170.9 ± 116.4 | 260.3 ± 79.2 | 253.7 ± 60.4 | 2647.7 ± 1360.5 | 2596.0 ± 1256.0 | 281.9 ± 85.1 | 293.8 ± 86.7 |
| Apolipoprotein C-III (mg/dL), mean ± SD | 11.4 ± 4.5 | 11.5 ± 2.6 | 14.9 ± 5.2 | 15.9 ± 4.1 | 15.5 ± 4.2 | 15.6 ± 4.5 | 13.5 ± 4.5 | 14.2 ± 6.2 | NR | NR | 27.6 ± 10.9 | 27.7 ± 11.7 | 16.1 ± 4.0 | 16.6 ± 4.5 |
| Total cholesterol (mg/dL), mean ± SD | 226.7 ± 45.3 | 227.8 ± 36.6 | NR | NR | NR | NR | 218.0 ± 36.1 | 202.9 ± 41.2 | 161.7 ± 32.3 | 153.4 ± 25.0 | 299.7 ± 102.6 | 286.0 ± 113.9 | 159.8 ± 33.6 | 144.8 ± 26.0 |
| VLDL cholesterol (mg/dL), mean ± SD | 42.0 ± 24.5 | 36.1 ± 19.3 | 44.7 ± 20.1 | 46.2 ± 18.5 | 42.3 ± 15.4 | 42.5 ± 17.4 | 30.7 ± 18.0 | 37.1 ± 24.3 | NR | NR | 268.8 ± 109.1 | 255.3 ± 114.4 | 55.3 ± 19.9 | 53.6 ± 11.7 |
| Non-HDL cholesterol (mg/dL), mean ± SD | 178.6 ± 47.7 | 182.2 ± 39.5 | 129.8 ± 34.9 | 135.3 ± 38.1 | 126.8 ± 42.4 | 134.5 ± 45.2 | 159.8 ± 36.8 | 146.8 ± 39.4 | NR | NR | 284.1 ± 105.7 | 271.3 ± 113.3 | 125.0 ± 31.4 | 110.3 ± 24.0 |
| LDL cholesterol (mg/dL), mean ± SD | 136.6 ± 38.3 | 146.2 ± 33.1 | 82.3 ± 32.1 | 82.7 ± 31.5 | 82.9 ± 36.3 | 90.2 ± 38.1 | 128.5 ± 36.6 | 115.3 ± 40.8 | 78.1 ± 24.5 | 70.2 ± 19.1 | 20.3 ± 11.9 | 16.7 ± 8.4 | 71.3 ± 24.2 | 60.2 ± 27.2 |
| Apolipoprotein B (mg/dL), mean ± SD | 115.4 ± 29.8 | 120.4 ± 22.3 | 91.5 ± 21.7 | 95.5 ± 27.0 | 91.2 ± 26.3 | 96.4 ± 28.4 | 91.5 ± 22.9 | 85.3 ± 31.9 | NR | NR | 61.7 ± 15.6 | 59.7 ± 18.9 | 85.7 ± 18.0 | 77.1 ± 19.7 |
| HDL cholesterol (mg/dL), mean ± SD | 48.1 ± 14.5 | 45.6 ± 14.0 | NR | NR | NR | NR | 58.2 ± 12.5 | 56.1 ± 14.2 | 38.1 ± 8.4 | 39.9 ± 7.9 | 15.1 ± 4.3 | 14.7 ± 3.8 | 34.9 ± 9.4 | 34.6 ± 8.6 |
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