RNA therapeutics
Molecular Mechanisms and Therapeutic Targets of RNA-Based and Traditional Lipid-Lowering Agents in Residual Cardiovascular Risk: A Scoping Review of Key Directions Towards Future Perspectives
This scoping review maps the molecular mechanisms and pharmacodynamic profiles of RNA-based lipid-lowering therapies targeting residual cardiovascular risk in patients inadequately controlled on standard care. GalNAc-conjugated siRNAs and ASOs demonstrate substantial efficacy, achieving 80–98% reductions in Lp(a), 50–80% in triglycerides, and 36–44% in LDL-C, with sustained effects every 3–6 months and a favorable safety profile. The analysis highlights how these novel agents address pathways beyond traditional statins and ezetimibe, offering clinicians a structured overview of emerging options for high-risk cardiometabolic patients.
Original abstract
Residual cardiovascular risk arises from dysregulated expression of genes encoding apolipoprotein(a) (LPA), apolipoprotein C-III (APOC3), angiopoietin-like gene 3 (ANGPTL3), and proprotein convertase subtilisin/kexin type 9 (PCSK9). RNA-based therapies, small interfering RNAs (siRNAs), and antisense oligonucleotides (ASOs) modulate these targets at the post-transcriptional level through RNA interference and RNase H-mediated degradation, respectively. This scoping review maps the molecular mechanisms, target involvement, and pharmacodynamic outcomes of RNA therapies for managing residual cardiovascular risk, with contextual comparison to traditional lipid-lowering agents. A systematic search of PubMed, Embase, Web of Science, and Scopus was performed from 2020 to February 2026. Of the 1088 records identified, 30 studies met the inclusion criteria. RNA therapies have demonstrated potential for engagement, with 80-98% reductions in Lp(a) (pelacarsen, olpasiran, zerlasiran, lepodisiran), 50-80% reductions in triglycerides (olezarsen, plozasiran, volanesorsen), and 36-44% reductions in low-density lipoprotein cholesterol (LDL-C). Mechanistically, siRNAs achieve gene silencing through RISC-mediated mRNA cleavage, with sustained pharmacodynamic effects (3-6 months) because of Argonaute-2 stability, while gapmer ASOs recruit RNase H1 for mRNA degradation. Conjugation with GalNAc allows for hepatocyte-specific delivery with a subcutaneous bioavailability of 70-85%. Safety profiles were favorable, with injection site reactions (4-12%) being the most common adverse event. This analysis maps the emerging molecular landscape of RNA therapies, highlighting their substantial precision for targeting residual cardiovascular risk pathways that cannot be addressed by traditional agents.
geneticslepodisiranmechanismsolpasiranPCSK9 inhibitionpelacarsenRNA therapeuticstherapy
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.