Potential of Lipoprotein(a)-Lowering Strategies in Treating Coronary Artery Disease

Abstract

High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person’s lifetime to identify those with inherited Lp(a) levels > 180 mg/dL (> 430 nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20–50%. AKCEA-APO(a)-LRX is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50–80%. A Phase III study with AKCEA-APO(a)-LRX will start in order to evaluate the effect on cardiovascular outcomes.