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Cited by 0Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

Effectiveness and Safety of Target-Specific RNA-Based Lipid-Lowering Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Open access
Widjaja, Jordan Steven, Adji, Arga Setyo, Baraja, Aufa, Dharmasaputra, Alan, Rosyadi, Ragil Nur, Komalasari, Intan, Mustofa, Ali, Multazam, Chaq El Chaq Zamzam +2 more·2026·European Journal of Pharmacology
DOI 10.1016/j.ejphar.2026.179420
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Abstract

RNA-based therapies target distinct pathways involved in lipid metabolism and may therefore exhibit differential pharmacological effects according to their molecular targets. However, comparative evidence regarding the effectiveness and safety of these target-specific therapies remains limited. This study aimed to evaluate the effectiveness and safety of PCSK9-, APOC3-, and ANGPTL3-targeting RNA-based therapies in patients with hyperlipidemia or hypertriglyceridemia. We conducted a systematic review and meta-analysis of randomized controlled trials comparing inclisiran, olezarsen, plozasiran, or zodasiran with placebo. Treatment effects were expressed as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs), and pooled analyses were stratified according to molecular target. Sixteen randomized controlled trials involving 6,982 participants were included. PCSK9-targeting therapy produced the greatest reductions in LDL-C (MD -53.01 mg/dL, 95% CI -57.56 to -48.45), ApoB (MD -39.59 mg/dL, 95% CI -43.33 to -35.85), and non-HDL-C (MD -44.62 mg/dL, 95% CI -47.73 to -41.51), whereas APOC3-targeting therapies produced the greatest reduction in triglycerides (MD -52.26 mg/dL, 95% CI -56.50 to -48.02). Total adverse events, serious adverse events, and adverse events leading to treatment discontinuation were comparable between RNA-based therapies and placebo. Overall, these findings indicate that RNA-based lipid-lowering therapies exhibit target-specific pharmacological effects, with PCSK9 inhibition predominantly reducing atherogenic lipoproteins and APOC3 inhibition producing greater triglyceride lowering. Although the overall safety profile was comparable with placebo, differences in individual adverse outcomes and the limited availability of long-term clinical outcome data highlights the need for further investigation.

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Crossref · 10.1016/j.ejphar.2026.179420

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Research works printed but not linked: 4

  1. Hill, 2025, Hyperlipidemia, StatPearls
  2. Pappan, 2026, Dyslipidemia, StatPearls
  3. Pramono, 2015, Managing hypertriglyceridemia in daily practice, Acta Med. Indones, 47, 265
  4. The Cochrane Collaboration, 2020. Review Manager (RevMan) Version 5.4.1.

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Authors
Widjaja, J. S., Adji, A. S., Baraja, A., Dharmasaputra, A., Rosyadi, R. N., Komalasari, I., Mustofa, A., Multazam, C. E. C. Z., Alkaff, F. F., & Saputra, P. B. T.
Affiliations
  • Universitas Hang Tuah (ID)
  • Universitas Airlangga (ID)
  • University of Manchester (GB)
  • University Medical Center Groningen (NL)
Corresponding author
Alkaff, Firas Farisi
ORCID
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2026-10
Pages
179420
ISSN
0014-2999 (ISSN-L)
DOI
10.1016/j.ejphar.2026.179420
OpenAlex
W7221510244
Semantic Scholar
0f547ed365b4579f20527fed0f22a298b0d09750
Cited by
0
References
48
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Pharmacology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
antisense oligonucleotides, PCSK9 inhibition, LDL cholesterol lowering, hypercholesterolemia, lipid-lowering drugs, drug safety, drug effectiveness

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