Small Interfering RNA for LDL-Cholesterol Reduction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background Elevated low-density lipoprotein cholesterol (LDL-C) is a major modifiable risk factor for atherosclerotic cardiovascular disease. Although statins remain first-line therapy, many patients fail to achieve guideline-recommended LDL-C targets. Inclisiran, a small interfering RNA that inhibits hepatic proprotein convertase subtilisin/kexin type 9 synthesis, has emerged as a long-acting lipid-lowering strategy. This meta-analysis evaluated the efficacy of inclisiran vs placebo in reducing LDL-C levels. Objectives The purpose of this study was to systematically evaluate the efficacy of inclisiran compared with placebo in reducing LDL-C levels across diverse patient populations by synthesizing data from randomized controlled trials and to assess the consistency of LDL-C reduction and safety outcomes in the context of background lipid-lowering therapies. Methods PubMed, Embase, and Cochrane Central were systematically searched for randomized controlled trials comparing inclisiran with placebo. The primary outcome was the mean percent change in LDL-C from baseline. A random-effects model using the generic inverse variance method was applied. Heterogeneity was quantified with the I 2 statistic. Results Nine randomized control trials comprising 6,355 participants were included. Inclisiran produced a pooled mean LDL-C reduction of -48.77% (95% CI: -54.26 to -43.27, I 2 = 95.2%; P < 0.001). Follow-up ranged from 0.5 to 1.5 years. Significant heterogeneity was observed (I 2 = 95%), largely attributable to differences in background lipid-lowering therapy and treatment intensification. Conclusions Inclisiran achieves substantial reductions in LDL-C across diverse patient populations. Its twice-yearly dosing schedule and small interfering RNA mechanism of action position inclisiran as a promising long-term lipid-lowering therapy, with potential for broader implementation as clinical experience and outcomes data continue to evolve. (Small Interfering RNA Therapy for LDL-Cholesterol Reduction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials; CRD420251178991.).

Abstract of "Small Interfering RNA for LDL-Cholesterol Reduction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials" by Batista F, Mamede I, Dacoregio M, https://doi.org/10.1016/j.jacadv.2026.102932, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.