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Small Interfering RNA for LDL-Cholesterol Reduction: A Systematic Review and Meta-Analysis of Randomized Controlled
Fellipe Batista1, Isadora Mamede2, Maria Dacoregio3
1Department of Innovation, Research and Education, Centro Edson Bueno - CETEB, Rede Total Care, Rio de Janeiro, Rio de Janeiro, Brazil.
Insights
Inclisiran significantly reduces low-density lipoprotein cholesterol (LDL-C) by nearly 50% in diverse patients. This small interfering RNA therapy offers a promising long-term option for managing high cholesterol levels.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
Background:
- Elevated low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for atherosclerotic cardiovascular disease.
- Many patients do not reach target LDL-C levels with statin therapy alone.
- Inclisiran, a small interfering RNA (siRNA), offers a novel, long-acting approach to lipid reduction by inhibiting PCSK9 synthesis.
Purpose of the Study:
- To systematically evaluate the efficacy of inclisiran versus placebo in reducing LDL-C levels.
- To assess LDL-C reduction and safety across diverse patient populations in randomized controlled trials.
- To examine the consistency of inclisiran's effects within various background lipid-lowering therapies.
Main Methods:
- A systematic literature search of PubMed, Embase, and Cochrane Central was conducted for randomized controlled trials.
- The primary efficacy outcome was the mean percent change in LDL-C from baseline.
- A random-effects model was employed to pool data, with heterogeneity assessed using the I² statistic.
Main Results:
- Nine randomized controlled trials involving 6,355 participants were included in the meta-analysis.
- Inclisiran demonstrated a pooled mean LDL-C reduction of -48.77% (95% CI: -54.26 to -43.27).
- Significant heterogeneity (I² = 95%) was noted, influenced by background therapies and treatment intensification.
Conclusions:
- Inclisiran achieves substantial LDL-C reductions in a wide range of patient populations.
- The twice-yearly dosing and siRNA mechanism position inclisiran as a promising long-term lipid-lowering therapy.
- Broader implementation may increase as clinical experience and outcomes data expand.
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 I2 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, I2 = 95.2%; P < 0.001). Follow-up ranged from 0.5 to 1.5 years. Significant heterogeneity was observed (I2 = 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.).
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