Appraisal of Olezarsen for Treatment of Hypertriglyceridemia
Open accessAbstract
Olezarsen is antisense antinucleotide under investigation that inhibits synthesis of apolipoprotein C3 (ApoC3) resulting in reduction of plasma triglycerides levels. In a phase 3 clinical trial of patients having familial chylomicronemia syndrome (FCS) with extreme hypertriglyceridemia at baseline (mean plasma triglycerides 2,630 mg/dl), olezarsen 80 mg administered subcutaneously every 4 weeks decreased triglycerides by 43.5 percentage points (95% CI, 69.1 to 17.9; P<0.001) after 6 months compared with placebo. By 53 weeks, 1 episode of acute pancreatitis occurred in olezarsen group versus 11 episodes in the placebo group, rate ratio (RR) 0.12 (95% CI, 0.02 TO 0.66). Two phase 2 trials evaluated olezarsen in patients with moderately elevated triglycerides (<500 mg/dl) and high cardiovascular (CV) risk recorded similar magnitude of reduction of triglycerides. Olezarsen reduced levels of atherogenic lipoproteins such as ApoC3 by 73%, non-high-density lipoprotein cholesterol (non-HDL-C) by 17-23% and increased high-density lipoprotein cholesterol (HDL-C) levels by 30-40%. Meanwhile, olezarsen increased mean values of low-density lipoprotein (LDL-C) from 22.8 to 37.6 mg/dl in patients with FCS but had no significant effects in patients with high CV risk having higher baseline LDL-C levels. Discontinuation rates due to adverse effects of olezarsen were 9-12% versus 0% with placebo. The most common adverse effects of olezarsen were elevation of liver enzymes, mostly below 3 times the upper limit of normal, and injection-site reactions. Platelet count < 140,000/µl occurred in 18% in patients receiving olezarsen versus 3% with placebo (risk ratio 6.8; 95% CI, 0.91 to 51.3; P=0.03). No patient had severe thrombocytopenia with platelet number < 75,000/µl. Overall, olezarsen is a promising new therapy for hypertriglyceridemia and for prevention of hypertriglyceridemia-induced pancreatitis. Long-term randomized trials are urgently needed to examine the effects of olezarsen on CV events and mortality and establish its long-term safety.
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Olezarsen binds to the mRNA of ApoC-III, resulting in increased destruction and decreased expression of mRNA, leading to reduction of ApoC-III level and ultimately decreases triglycerides levels.
“It binds to the mRNA of ApoC-III resulting in the increased destruction and decreased expression of mRNA.This leads to reduction of ApoC-III level and ultimately decreases the triglycerides levels [1,7].”
From Efficacy and safety of Olezarsen in treating hypertriglyceridemia: a systematic review and meta-analysis of randomized controlled trials (2025) · cites this paper as [1]
The Introduction identifies olezarsen as an antisense oligonucleotide targeting APOC3 mRNA, and the Effects section says it inhibits APOC3 mRNA expression and lowers ApoC3 levels. The Abstract links reduced ApoC3 synthesis to lower triglycerides. Our copy does not state that olezarsen increases destruction of the mRNA; page numbers are unavailable. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApoC-III is a key regulator of triglyceride metabolism, and its inhibition has been proven effective in lowering triglyceride levels in preclinical studies and early clinical trials.
“ApoC-III is a key regulator of triglyceride metabolism, and its inhibition has been proven effective in lowering triglyceride levels in preclinical studies and early clinical trials.”
From Efficacy and safety of Olezarsen in treating hypertriglyceridemia: a systematic review and meta-analysis of randomized controlled trials (2025) · cites this paper as [1]
The Introduction describes ApoC-III’s role in raising triglycerides, and the section on olezarsen in patients at high cardiovascular risk reports substantial triglyceride reductions in phase 2 trials (page numbers unavailable). The passages do not report triglyceride-lowering efficacy in preclinical studies, so that part of the claim is unsupported by our copy. (LLM, conf=0.87)
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Cited by 2
Research works printed but not linked: 17
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- Authors
- Mikhail, N.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Mikhail, Nasser
- ORCID
- Mikhail, Nasser
- Venue
- International Journal of Endovascular Treatment and Innovative Techniques
- Publisher
- Research Lake International Inc.
- Published
- 2024-06-29
- Volume
- 5
- Issue
- 1
- Pages
- 41-48
- ISSN
- 2564-3207 (ISSN-L)
- OpenAlex
- W4400303111
- Cited by
- 2
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- International Journal of Endovascular Treatment and Innovative Techniques (publishedVersion, cc-by-nc)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- olezarsen, antisense oligonucleotides, apolipoprotein C-III, hypertriglyceridemia, familial chylomicronemia syndrome, acute pancreatitis, non-HDL cholesterol, HDL cholesterol, LDL cholesterol, platelet count, liver enzymes, injection site reactions, cardiovascular risk, triglyceride-lowering therapy, drug safety and efficacy
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