RNA targeted therapies for lipoprotein(a) lowering: systematic review and meta analysis of siRNA and antisense oligonucleotides
B C J Buot, S R K Azuelo, B J David, F ChengAbstract
Background
Lipoprotein(a) [Lp(a)] is a genetically determined, causal driver of atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Conventional lipid-lowering therapies have minimal impact on Lp(a), leaving substantial residual cardiovascular risk. RNA-targeted therapies—antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)—directly suppress hepatic LPA transcription and have emerged as the first agents capable of achieving profound Lp(a) reduction. With Phase 2 and Phase 3 data now available, a quantitative synthesis is needed to compare efficacy across platforms.
Purpose
To evaluate the pooled efficacy of RNA-targeted therapies for Lp(a) reduction and to compare the magnitude and consistency of effect between ASO and siRNA modalities.
Methods
A systematic review and meta-analysis of randomized controlled trials through January 2026 was performed. Eligible studies enrolled adults with elevated Lp(a) (≥125 nmol/L or ≥50 mg/dL) and compared ASO or siRNA therapies with placebo. Random-effects inverse-variance models were used to pool absolute Lp(a) reduction. Prespecified sensitivity analyses evaluated siRNA-only trials.
Results
Five trials (n=8,799) met inclusion criteria. Across all RNA-targeted therapies, pooled analysis demonstrated a mean absolute Lp(a) reduction of −86.6 nmol/L (95% CI −98.5 to −74.7; I²=99%), corresponding to 82–95% relative suppression. siRNA-only sensitivity analysis (ALPACA 2025, ALPACAR 2024, OCEAN(a)-DOSE 2022) showed a larger pooled reduction of −92.3 nmol/L (95% CI −99.8 to −84.7; I²=95%), reflecting ≥90% suppression across all siRNA trials. ASO trials demonstrated more modest reductions (−74 to −80 nmol/L) with greater variability.
Conclusion
RNA-targeted therapies achieve unprecedented Lp(a) lowering, with siRNA agents demonstrating the greatest potency and consistency. These findings support broader Lp(a) screening and highlight siRNA as the leading platform for durable Lp(a) suppression in future dyslipidemia guidelines.RNA-Targeted therapies vs placeboSensitivity analysis - siRNA versus placebo