Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management.

BACKGROUND: Inclisiran is a novel small interfering RNA therapeutic developed to lower lipid levels by targeting hepatic production of proprotein convertase subtilisin/kexin type 9. Unlike monoclonal antibodies, Inclisiran silences messenger RNA expression, resulting in sustained reductions in low-density lipoprotein cholesterol with infrequent dosing. This study aimed to systematically evaluate the efficacy and clinical applicability of Inclisiran across randomized controlled trials. METHODS: A systematic literature search was conducted in PubMed, Scopus, Embase, and Cochrane CENTRAL databases up to December 2024. This meta-analysis updates the global evidence base by incorporating 14 randomized trials (> 13,000 participants) identified through December 2024. Beyond earlier syntheses, it provides pooled analyses of multiple lipid parameters, phenotype-stratified subgroup and sensitivity analyses, and meta-regression for baseline LDL-C and statin use, thereby offering the most comprehensive and clinically differentiated evaluation of inclisiran to date. The primary outcome was the mean change in low-density lipoprotein cholesterol levels in patients treated with Inclisiran compared to placebo. Data was pooled using a random-effects model. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated with funnel plot analysis. RESULTS: Inclisiran treatment resulted in a significant mean reduction of 44.9% in low-density lipoprotein cholesterol levels compared to placebo (95% confidence interval: 39.54% to 50.25%; p < 0.001). While statistical heterogeneity was high (I² = 90.3%), visual assessment of the funnel plot suggested minimal risk of publication bias. Subgroup analyses supported consistent efficacy across patient populations, including those with statin intolerance or poor adherence to conventional therapies. CONCLUSIONS: Inclisiran provides a durable, twice-yearly injectable option for lipid management, offering substantial reductions in low-density lipoprotein cholesterol. Its unique RNA-based mechanism and long-acting profile make it particularly suitable for patients who struggle with adherence or have limited response to traditional lipid-lowering medications. These findings support Inclisiran’s role as a promising addition to current strategies for cardiovascular risk reduction.