Antisense oligonucleotides and siRNAs cut Lp(a) by 98-101% in recent trials, though whether this reduces cardiovascular events remains unknown, a review (Expert Rev Cardiovasc Ther 2023)

Original title: Lipoprotein(a): cardiovascular risk and emerging therapies

Expert Rev Cardiovasc Ther · 1 April 2023 · 6

Fujino M, Nicholls SJ

This review by Fujino and Nicholls summarises current understanding of Lp(a) as an established residual cardiovascular risk factor, confirmed by observational and Mendelian randomisation studies, that is not lowered by conventional therapies such as statins and ezetimibe. In recent clinical trials, antisense oligonucleotides and small interfering RNAs achieved Lp(a) reductions of -98% to -101%. However, the authors note key unknowns remain: whether specifically lowering Lp(a) reduces cardiovascular events, how much lowering is needed for clinical benefit, and whether diabetes or inflammation modify this relationship. The review concludes that emerging Lp(a)-lowering therapies could support a personalised approach to atherosclerotic cardiovascular disease prevention, pending outcome trial results.

Original abstract

Introduction: There is abundant evidence that elevated lipoprotein(a) [LP(a)] associates with cardiovascular risk. Most lipid modifying therapies don't reduce Lp(a), but new technologies are emerging that act upstream, such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) that inhibit the translation of mRNA for proteins specifically involved in lipid metabolism.

Areas Covered: Despite the benefit of therapies for the prevention of atherosclerotic cardiovascular disease (ASCVD), Lp(a) is one of the 'residual risks,' established by observational and Mendelian randomization studies. Although current established lipid modifying therapies targeting low-density-lipoprotein cholesterol, such as statins and ezetimibe, do not lower Lp(a), ASOs and siRNAs demonstrated significant reduction of Lp(a) by -98 to -101% in recent clinical trials. However, we still don't know if specifically lowering Lp(a) reduced cardiovascular events, how much Lp(a) lowering is required to produce clinical benefit, and whether diabetes and inflammation have any impact. This review summarizes Lp(a), the knowns and unknowns about Lp(a), and focus emerging treatments.

Expert Opinion: New Lp(a) lowering therapies have the potential to contribute to the personalized prevention of ASCVD.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.