Lipoprotein(a) Lowering-From Lipoprotein Apheresis to Antisense Oligonucleotide Approach.

Maria Francesca Greco,Massimiliano Ruscica,Marat Ezhov,Alberto Corsini,Tiziana Sampietro,Cesare R Sirtori

doi:10.3390/jcm9072103

Abstract

It is well-known that elevated lipoprotein(a)—Lp(a)—levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)Lrx, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.

Highlights

An OverviewIn the last decade, an awareness of the association between cardiovascular (CV) risk and elevated levels of lipoprotein(a) [Lp(a)] has emerged from both epidemiological and genetic studies [1,2,3] and led to the need to improve treatments for patients with atherosclerotic cardiovascular disease (ASCVD), as therapeutic approaches able to lower Lp(a) levels to the extent required to achieve a CV benefit are missing
Familial hypercholesterolemia (FH) and elevated Lp(a) are a double heritable risk [8], i.e., carriers of a receptor-negative mutation in the low-density lipoprotein receptor (LDLR) gene with high Lp(a) (> 50 mg/dL) show a higher cardiovascular disease (CVD) risk compared to patients with the same mutation and Lp(a) levels < 50 mg/dL [9]
In a scenario missing a pharmacological approach to lowering Lp(a) to the extent required to achieve a CV benefit, in patients with progressive ASCVD and high plasma Lp(a), a potentially valuable therapeutic option is Lipoprotein apheresis (LA), alone or in combination with PCSK9 inhibitors

Summary

Introduction—An Overview

An awareness of the association between cardiovascular (CV) risk and elevated levels of lipoprotein(a) [Lp(a)] has emerged from both epidemiological and genetic studies [1,2,3] and led to the need to improve treatments for patients with atherosclerotic cardiovascular disease (ASCVD), as therapeutic approaches able to lower Lp(a) levels to the extent required to achieve a CV benefit are missing. Data from a Mendelian randomization analysis indicated that the Lp(a)-lowering therapeutic effect size [to reduce CAD risk in a similar way to a reduction of 38.7 mg/dL (1 mmol/L)] of LDL-C should be roughly 100 mg/dL (2.6 nmol/L) [21] This conclusion was not supported by other authors who replicated a similar approach, not considering, Lp(a)-elevating single-nucleotide polymorphisms (SNPs), but based on 13,781 individuals with median Lp(a) levels in a range typical of Caucasian populations. An Italian and Swedish series showed that elevated Lp(a) significantly contributed to the raised CV risk in patients with a genomic diagnosis of FH [39] It seems that FH does not cause hyperlipoproteinemia(a), but that a rise in Lp(a) increases the probability that an individual with genetic FH will be clinically recognized [13]. Evidence supports a causal association between Lp(a) and valve calcification

Statins

Nicotinic Acid

PCSK9 Inhibitors

Antisense Antinuocleotide

Findings

Future Perspectives and Conclusions