RNA-Targeted Therapeutics in Cardiovascular Risk Reduction: From Gene Silencing to Precision Cardiology

Advances in cardiovascular prevention and treatment have substantially improved patient outcomes. However, residual cardiovascular risk remains a major clinical challenge. Traditional lipid-lowering and antihypertensive therapies, although effective, remain limited by suboptimal adherence, adverse effects, and persistent residual cardiovascular risk. RNA-targeted therapeutics have emerged as a transformative therapeutic paradigm, offering durable and highly specific gene silencing through small interfering RNA and antisense oligonucleotide platforms. This review evaluates the current evidence on RNA-targeted therapeutics for cardiovascular risk reduction, with an emphasis on their mechanisms of action, clinical efficacy, safety, and emerging therapeutic applications. A review was conducted using PubMed, Embase, Scopus, ScienceDirect, the Cochrane Library, and ClinicalTrials.gov from inception to June 2026. A total of 154 eligible studies were included and narratively synthesized by therapeutic class and molecular target. Inclisiran reduced low-density lipoprotein cholesterol by approximately 50% with twice-yearly dosing, while pooled ORION analyses suggested a reduction in major adverse cardiovascular events. Pelacarsen, olpasiran, and lepodisiran achieved 80-98% reductions in lipoprotein(a), whereas zilebesiran lowered systolic blood pressure by more than 15 mm Hg with sustained effects for up to 24 weeks. Across studies, RNA therapeutics demonstrated favorable safety profiles, with predominantly mild injection-site reactions. Although definitive cardiovascular outcome data remain unavailable for several emerging agents, RNA-targeted therapeutics represent a promising advance in precision cardiovascular medicine by providing durable, mechanism-based therapies capable of addressing important residual cardiovascular risk.