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Lipoprotein(a) Lowering-From Lipoprotein Apheresis to Antisense Oligonucleotide Approach
Maria Francesca Greco1, Cesare R Sirtori2, Alberto Corsini1,3
1Dipartimento di Science Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Insights
Elevated lipoprotein(a) (Lp(a)) levels increase cardiovascular mortality risk. Current treatments are limited, but novel RNA-based therapies show promise in significantly reducing Lp(a).
Area of Science:
- Cardiovascular Medicine
- Lipidology
- Pharmacology
Background:
- Elevated lipoprotein(a) (Lp(a)) levels are a known risk factor for cardiovascular (CV) and all-cause mortality.
- Familial hypercholesterolemia (FH) combined with high Lp(a) significantly elevates CVD risk.
- A definitive pharmacotherapeutic strategy for hyperlipoproteinemia(a) remains undefined.
Purpose of the Study:
- To review the current understanding of Lp(a) atherogenicity and its impact on cardiovascular risk.
- To explore existing and emerging therapeutic strategies for managing elevated Lp(a) levels.
- To highlight the potential of novel RNA-based therapies in reducing Lp(a) and residual CV risk.
Main Methods:
- Literature review of studies on Lp(a) and cardiovascular risk.
- Analysis of current treatment options including lipoprotein apheresis (LA) and PCSK9 antagonists.
- Evaluation of emerging RNA-based therapies, specifically antisense oligonucleotides targeting APO(a).
Main Results:
- Lipoprotein apheresis (LA) is the most effective current strategy for lowering Lp(a).
- PCSK9 antagonists show a limited but clear effect on Lp(a) levels.
- Antisense oligonucleotides (e.g., APO(a)Lrx) demonstrate significant Lp(a) reduction (35-80%) with generally mild side effects.
Conclusions:
- Managing elevated Lp(a) is crucial for patients with high CV risk, especially those with FH.
- While LA is effective, new RNA-based therapies offer a promising avenue for Lp(a) lowering.
- Further research into Lp(a) atherogenicity and targeted therapies will benefit patients with residual CV risk.
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.
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