Highlights
- •Lp[a] is a significant risk factor for many cardiovascular disorders.
- •Most medical treatments for lowering high Lp[a] concentration have technical and clinical drawbacks.
- •Antisense therapy targeting either apo[a] or apoB is currently being developed.
- •Anti-apoB antisense therapy is effective to lower LDL between 18–33% and LDL between 26–39%.%
- •Anti-apo[a] antisense therapy is effective to lower Lp[a] between 35–80% and LDL between 6–16%.%
Abstract
Several lines of evidence now attest that lipoprotein[a] (Lp[a]) is a significant
risk factor for many cardiovascular disorders. This enigmatic lipoprotein, composed
of a single copy of apolipoprotein B (apoB) and apolipoprotein[a] (apo [a]), expresses
peculiar metabolism, virtually independent from lifestyle interventions. Several therapeutic
options have hence been proposed for lowering elevated Lp[a] values, with or without
concomitant effect on low density lipoprotein (LDL) particles, mostly encompassing
statins, ezetimibe, nicotinic acid, lipoprotein apheresis, and anti-PCSK9 monoclonal
antibodies. Since all these medical treatments have some technical and clinical drawbacks,
a novel strategy is currently being proposed, based on the use of antisense apo[a]
and/or apoB inhibitors. Although the role of these agents in hypercholesterolemic
patients is now nearby entering clinical practice, the collection of information on
Lp[a] is still underway. Preliminary evidence would suggest that apo[a] antisense
therapy seems more appropriate in patients with isolated Lp[a] elevations, while apoB
antisense therapy is perhaps more advisable in patients with isolated LDL elevations.
In patients with concomitant elevations of Lp[a] and LDL, either combining the two
apo[a] and apoB antisense therapies (a strategy which has never been tested), or the
combination of well-known and relatively inexpensive drugs such as statins with antisense
apo[a] inhibitors can be theoretically suggested. The results of an upcoming phase
3 study with antisense apo[a] inhibitors will hopefully provide definitive clues as
to whether this approach may become the standard of care in patients with increased
Lp[a] concentrations.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of Internal MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- (a): an emerging cardiovascular risk factor.Crit Rev Clin Lab Sci. 2003; 40: 1-42
- A new serum type system in man–The LP system.Acta Pathol Microbiol Scand. 1963; 59: 369-382
- cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137
- (a): from ancestral benefit to modern pathogen?.QJM. 2000; 93: 75-84
- Determination of lipoprotein(a) kringle repeat number from genomic DNA: copy number variation genotyping using qPCR.J Lipid Res. 2009; 50: 768-772
- (a): resurrected by genetics.J Intern Med. 2013; 273: 6-30
- A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies.J Am Coll Cardiol. 2017; 69: 692-711
- European atherosclerosis society consensus panel. Lipoprotein(a) as a cardiovascular risk factor: current status.Eur Heart J. 2010; 31: 2844-2853
- AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.J Am Coll Cardiol. 2018; 73 (2019): 3168-3209
- European atherosclerosis society (EAS) and the European federation of clinical chemistry and laboratory medicine (EFLM) joint consensus initiative. quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM.Clin Chem Lab Med. 2019 Dec 19; ([Epub ahead of print])https://doi.org/10.1515/cclm-2019-1253
- Evidence-based assessment of lipoprotein(a) as a risk biomarker for cardiovascular diseases - Some answers and still many questions.Crit Rev Clin Lab Sci. 2016; 53: 370-378
- Lipoprotein (a) and risk of cardiovascular disease–a systematic review and meta analysis of prospective studies.Clin Lab. 2011; 57: 143-156
- The relationship between LP(a) and CVD outcomes: a systematic review.Lipids Health Dis. 2016; 15: 95
- The role of lipoprotein (a) in primary and secondary cardiovascular disease prevention: a systematic review of epidemiological studies.Curr Opin Cardiol. 2019; 34: 424-434
- Prognostic value of lipoprotein (a) level in patients with coronary artery disease: a meta-analysis.Lipids Health Dis. 2019; 18: 150
- Risk factors for cardiovascular disease in heterozygous familial hypercholesterolemia: a systematic review and meta-analysis.J Clin Lipidol. 2019; 13: 15-30
- Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis.Lancet Diabetes Endocrinol. 2017; 5: 524-533
- Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.Nat Commun. 2017; 8: 910
- Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature.Semin Thromb Hemost. 2017; 43: 614-620
- Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature.Cardiovasc Diabetol. 2017; 16: 38
- The changing face of cardiovascular disease 2000-2012: an analysis of the world health organisation global health estimates data.Int J Cardiol. 2016; 224: 256-264
- Epidemiology of cardiovascular disease: the new ESC Atlas and beyond.Eur Heart J. 2018; 39: 489-492
- Worldwide disease epidemiology in older persons.Eur Geriatr Med. 2019 Nov 16; ([Epub ahead of print]): 1-7https://doi.org/10.1007/s41999-019-00265-2
- Therapeutic management of hyperlipoproteinemia (a).Drugs Context. 2019; 8212609
- Temporal variability in lipoprotein(a) levels in patients enrolled in the placebo arms of IONIS-APO(a)Rx and IONIS-APO(a)-LRx antisense oligonucleotide clinical trials.J Clin Lipidol. 2018; 12: 122-129
- Effects of physical activity and diet on lipoprotein(a).Med Sci Sports Exerc. 1997; 29: 1429-1436
- Effects of exercise on lipoprotein(a).Sports Med. 1999; 28: 11-24
- Evidence of lifestyle modification in the management of hypercholesterolemia.Curr Cardiol Rev. 2013; 9: 2-14
- Optimal therapy for reduction of lipoprotein(a).J Clin Pharm Ther. 2012; 37: 1-3
- Effect of extended-release niacin on plasma lipoprotein(a) levels: a systematic review and meta-analysis of randomized placebo-controlled trials.Metabolism. 2016; 65: 1664-1678
- Underberg JA. systematic review: evaluating the effect of lipid-lowering therapy on lipoprotein and lipid values.Cardiovasc Drugs Ther. 2013; 27: 465-479
- Lipoprotein apheresis for the treatment of elevated circulating levels of lipoprotein(a): a critical literature review.Blood Transfus. 2016; 14: 413-418
- Systematic review of low-density lipoprotein cholesterol apheresis for the treatment of familial hypercholesterolemia.J Am Heart Assoc. 2016; 5 (pii: e003294)https://doi.org/10.1161/JAHA.116.003294
- A meta-analysis of the effect of PCSK9-Monoclonal antibodies on circulating lipoprotein (a) levels.Am J Cardiovasc Drugs. 2019; 19: 87-97
- Long-term efficacy and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibodies: a meta-analysis of 11 randomized controlled trials.J Clin Lipidol. 2018; 12: 277-291
- Lipid and blood pressure meta-analysis collaboration (LBPMC) group. effect of ezetimibe monotherapy on plasma lipoprotein(a) concentrations in patients with primary hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials.Drugs. 2018; 78: 453-462
- Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy.Clin Res Cardiol. 2019; 108: 487-509
- Statin therapy increases lipoprotein(a) levels.Eur Heart J. 2019 May 20; (pii: ehz310[Epub ahead of print])https://doi.org/10.1093/eurheartj/ehz310
- Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.Lancet. 2018; 392: 1311-1320
- A half-century history of applications of antisense oligonucleotides in medicine, agriculture and forestry: we should continue the journey.Molecules. 2018; 23 (pii: E1302)https://doi.org/10.3390/molecules23061302
- Antisense therapy in the treatment of hypercholesterolemia.Eur J Intern Med. 2011; 22: 541-546
- FDA-Approved oligonucleotide therapies in.Mol Ther. 2017; 25 (2017): 1069-1075
- Oligonucleotides to the (Gene) rescue: FDA approvals 2017-2019.Trends Pharmacol Sci. 2020; 41: 27-41
- Novel therapeutic strategy for atherosclerosis: ribozyme oligonucleotides against apolipoprotein(a) selectively inhibit apolipoprotein(a) but not plasminogen gene expression.Circulation. 1998; 98: 1898-1904
- Adenovirus-mediated apo(a)-antisense-RNA expression efficiently inhibits apo(a) synthesis in vitro and in vivo.Gene Ther. 2001; 8: 425-430
- Antisense technology to lower LDL cholesterol.Lancet. 2010; 375: 959-961
- Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice.Circulation. 2008; 118: 743-753
- Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.Lancet. 2010; 375: 998-1006
- Effect of mipomersen, an apolipoprotein b synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia.Am J Cardiol. 2010; 105: 1413-1419
- Efficacy and safety of mipomersen: a systematic review and meta-analysis of randomized clinical trials.Drugs. 2019; 79: 751-766
- Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials.J Clin Lipidol. 2015; 9: 217-225
- Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study.Lancet. 2015; 386: 1472-1483
- Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans.J Lipid Res. 2016; 57: 340-351
- Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice.J Am Coll Cardiol. 2011; 57: 1611-1621
- Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.Lancet. 2016; 388: 2239-2253
- Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis.J Lipid Res. 2019; 60: 2082-2089
- AKCEA-APO(a)-LRx study investigators. Lipoprotein(a) reduction in persons with cardiovascular disease.N Engl J Med. 2020; 382: 244-255
- Lipid and blood pressure meta-analysis collaboration (LBPMC) group. Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials.BMC Med. 2017; 15: 22
- Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.JAMA. 2009; 301: 2331-2339
- Further advices on measuring lipoprotein(a) for reducing the residual cardiovascular risk on statin therapy.Clin Chem Lab Med. 2020 Feb 12; (Epub ahead of print)https://doi.org/10.1515/cclm-2020-0076
- Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype.Atherosclerosis. 2019; 289: 201-205
- Statins for preventing venous thrombosis: for or against?.Semin Thromb Hemost. 2019; 45: 834-836
Article info
Publication history
Published online: April 24, 2020
Accepted:
April 15,
2020
Received in revised form:
April 11,
2020
Received:
January 19,
2020
Identification
Copyright
© 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
