Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Abstract

<jats:p>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.</jats:p>

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

“…Despite the similarity of the structural organization of Lp(a) and LDL particles and the presence of an apoB100 molecule in both, the LDL receptor was shown not to be important for the catabolism of Lp(a), in transgenic animals [ 19 ], cell models [ 20 ], clinically [ 7 , 21 ] and in kinetic studies [ 22 ]. Statins promote the increase in the number of LDL receptors on hepatocytes and result in an increase of Lp(a) concentration versus a decline of LDL-C [ 2 ]. However, it has been shown that Lp(a) internalization by hepatocyte cell lines increased both after the enhanced expression of LDL receptor and blocking of PCSK9 synthesis [ 23 ].…”

“…An Lp(a) particle consists of an apoB100-containing low-density lipoprotein (LDL)-like particle covalently linked to a highly glycosylated and extremely polymorphic apolipoprotein(a) [apo(a)]. Plasma levels of Lp(a) are genetically controlled and cannot be reduced by statins, while the application of high doses of nicotinic acid has only minor effects on its concentration [ 2 ].…”

Lipid Lowering Drugs: Present Status and Future Developments

“…Despite the association between Lp(a) elevations and coronary artery disease risk has emerged from both epidemiological and genetic studies [64][65][66], a pharmacological approach able to lower Lp(a) levels to the extent required to potentially achieve a CV benefit in patients with progressive ASCVD and high plasma Lp(a) is still missing (reviewed in [67]). Available lipid-lowering therapies have little value for Lp(a) reduction.…”

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania

“…Lp(a) levels are associated with a high risk of cardiovascular mortality, requiring a new pharmacotherapeutic approach, and 5–20% of patients suspected of FH had elevated Lp(a) levels [ 51 ]. In our study, we did not measure the Lp(a) values, but these findings will be exploited in a future study in which the Lp(a) of the patients will be assessed.…”