Safety and Efficacy of the Novel RNA Interference Therapies for Hypertriglyceridemia and Mixed Hyperlipidemia Management: A Systematic Review and Meta-analysis
Abstract
BACKGROUND No meta-analysis has holistically analyzed and summarized the safety and therapeutic efficacy of the newer RNA interference (RNAi) therapies, olezarsen, plozasiran, and zodasiran, in managing conditions associated with hypertriglyceridemia (HTG). METHODS Randomized controlled trials (RCTs) involving patients with HTG or mixed hyperlipidemia (MHL) receiving either olezarsen, plozasiran, or zodasiran in the intervention arm and a placebo in the control arm were searched through electronic databases. The primary outcome was the safety profile of the drugs studied; secondary outcomes included the percent change from baseline (CFB) in the lipid levels, including triglyceride (TG). RESULTS Six RCTs with 334 participants were evaluated. Olezarsen, plozasiran, and zodasiran were well-tolerated with no higher risk of serious adverse events or injection-site reactions. After 24 weeks, plozasiran increased alanine aminotransferase and HbA1c more than placebo, although the difference was insignificant at 48 weeks. Plozasiran and zodasiran had little effect on hyperglycemia worsening. Olezarsen increased the likelihood of mild platelet count decreases without clinical harm. At their longest clinical trial follow-up, the highest doses of olezarsen, plozasiran, and zodasiran lowered TG by 55.2%, 50.57%, and 51.2% of baseline levels. All three drugs decreased non-HDL-C and remnant cholesterol. Olezarsen and plozasiran lowered ApoC-III and increased HDL-C, whereas zodasiran reduced HDL-C. Zodasiran decreased LDL-C, whereas olezarsen and plozasiran had no effects on LDL-C. Plozasiran and zodasiran lowered apolipoprotein B, but not olezarsen. CONCLUSION The newer RNA interference (RNAi) therapies appear safe and have excellent TG-lowering efficacy in patients with HTG and MHL.
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The previous meta-analysis by Kamrul-Hasan et al. (2024) insufficiently explored whether lipid-lowering effects differ between siRNA therapies targeting APOC3 and ANGPTL3.
“Moreover, a previous meta-analysis (Kamrul-Hasan et al., 2024) did not incorporate recently published trials, including emerging data on ANGPTL3-targeting agents such as solbinsiran, and insufficiently explored whether lipid-lowering effects differ between siRNA therapies targeting APOC3 and ANGPTL3.”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Kamrul-Hasan et al., 2024
A previous meta-analysis (Kamrul-Hasan et al., 2024) did not incorporate recently published trials, including emerging data on ANGPTL3-targeting agents such as solbinsiran.
“Moreover, a previous meta-analysis (Kamrul-Hasan et al., 2024) did not incorporate recently published trials, including emerging data on ANGPTL3-targeting agents such as solbinsiran, and insufficiently explored whether lipid-lowering effects differ between siRNA therapies targeting APOC3 and ANGPTL3.”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Kamrul-Hasan et al., 2024
Previous meta-analyses confirmed robust triglyceride and remnant lipoprotein reductions across RNAi therapies but often pooled interventions as a class without target-specific evaluation.
“Previous meta-analyses confirmed robust triglyceride and remnant lipoprotein reductions across RNAi therapies but often pooled interventions as a class without target-specific evaluation (Kamrul-Hasan et al., 2024).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Kamrul-Hasan et al., 2024
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- Authors
- Kamrul-Hasan, A. B. M., Dutta, D., Nagendra, L., Mondal, S., Bhattacharya, S., & Kalra, S.
- Affiliations
- Mymensingh Medical College Hospital (BD)
- JSS Academy of Higher Education and Research (IN)
- Indraprastha Apollo Hospitals (IN)
- Bharti Hospital (IN)
- ORCID
- Venue
- Endocrine Practice
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 30
- Issue
- 11
- Pages
- 1103-1112
- ISSN
- 1530-891X (ISSN-L)
- OpenAlex
- W4402305007
- Semantic Scholar
- f5accce3fcba82d3ce84b38059a28b62230c3425
- Cited by
- 17
- References
- 38
- Citations by year
- 2026: 8 · 2025: 9
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Practice (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- RNA interference therapy, olezarsen, plozasiran, hypertriglyceridemia, mixed dyslipidemia, triglyceride lowering, apolipoprotein C-III, remnant cholesterol, non-HDL cholesterol, HDL cholesterol, LDL cholesterol, apolipoprotein B, drug safety, adverse events, alanine aminotransferase, hyperglycemia
- MeSH terms
- Dicarboxylic Acids, Fatty Acids, Humans, Hyperlipidemias, Oligonucleotides, Hypertriglyceridemia, Randomized Controlled Trials as Topic, Treatment Outcome, RNA Interference, RNA, Small Interfering
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