Lipoprotein(a) Reduction in Persons with Cardiovascular Disease
Open accessAbstract
BACKGROUNDLipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis.There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODSWe conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter).Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L Rx , referred to here as APO(a)-L Rx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months.The lipoprotein(a) level was measured with an isoform-independent assay.The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTSThe median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter.Administration of APO(a)-L Rx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001).There were no significant differences between any APO(a)-L Rx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms.The most common adverse events were injection-site reactions.CONCLUSIONS APO(a)-L Rx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease.
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Pelacarsen was well tolerated; only injection site reactions were more frequently observed in the treatment group.
“At the same time, pelacarsen was well tolerated. Only injection site reactions were more frequently observed in the treatment group.”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [182]
The Safety Analyses section reports that injection-site reactions were more frequent with APO(a)-L Rx than placebo (27% versus 6%) and were mostly mild, supporting the tolerability characterization. The word “only” overstates the findings: the same section reports higher observed rates of adverse events overall (90% versus 83%) and serious adverse events (10% versus 2%) in the treatment group, although neither showed a dose-dependent pattern. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn a randomized, double-blind, placebo-controlled phase 2 trial of 286 patients with elevated Lp(a) levels and established CVD, pelacarsen reduced Lp(a) in a dose-dependent manner by up to −80% from baseline.
“Consistently, in a randomized, double-blind, placebo-controlled phase 2 trial of 286 patients with elevated Lp(a) levels and established CVD, pelacarsen reduced Lp(a) in a dose-dependent manner by up to − 80% from baseline [182].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [182]
Lp(a) has been identified as an independent risk marker for CVD as it exerts pro-atherogenic, pro-inflammatory, and pro-thrombotic effects.
“Lp(a) has been identified as an independent risk marker for CVD as it exerts pro-atherogenic, pro-inflammatory, and pro-thrombotic effects which may play a critical role in the pathogenesis of atherosclerosis [182].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [182]
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“Consistently, in a randomized, double-blind, placebo-controlled phase 2 trial of 286 patients with elevated Lp(a) levels and established CVD, pelacarsen reduced Lp(a) in a dosedependent manner by up to − 80% from baseline [182].”
BackgroundClinical Trial Design for Lipoprotein(a)-Lowering Therapies
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Lipoprotein(a)—The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation
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Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification
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Self-citationTargeting RNA With Antisense Oligonucleotides and Small Interfering RNA in Dyslipidemias
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Small non-coding RNA therapeutics for cardiovascular disease
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Self-citationLipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood
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Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx
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Self-citationDiet and Lp(a): Does Dietary Change Modify Residual Cardiovascular Risk Conferred by Lp(a)?
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Lipoprotein(a) and Cardiovascular Disease in Chinese Population
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Lipoprotein(a) and Cardiovascular Diseases ― Revisited ―
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Existing and emerging strategies to lower Lipoprotein(a)
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New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins
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- Authors
- Tsimikas, S., Karwatowska-Prokopczuk, E., Gouni-Berthold, I., Tardif, J.-C., Baum, S. J., Steinhagen-Thiessen, E., Shapiro, M. D., Stroes, E. S., Moriarty, P. M., Nordestgaard, B. G., Xia, S., Guerriero, J., Viney, N. J., O’Dea, L., & Witztum, J. L.
- Affiliations
- University of Cologne (DE)
- From the Divisions of Cardiovascular Medicine (S.T.) and Endocrinology and Metabolism (J.L.W.), University of California, San Diego, La Jolla, and Ionis Pharmaceuticals, Carlsbad (S.T., S.X., N.J.V.) — both in California; Akcea Therapeutics, Boston (E.K.-P., J.G., L.O.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany (I.G.-B.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Excel Medical Clinical Trials, Boca Raton, FL ...
- Oregon Health & Science University (US)
- University of Copenhagen (DK)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-01-16
- Volume
- 382
- Issue
- 3
- Pages
- 244-255
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2997944188
- Semantic Scholar
- 725c405ccc1ec3726f9ba922da158107891d134f
- Cited by
- 1,094
- References
- 28
- Citations by year
- 2026: 204 · 2025: 176 · 2024: 156 · 2023: 149 · 2022: 159 · 2021: 153 · 2020: 96 · 2019: 1
- FWCI
- 127.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Akcea Therapeutics
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- lipoprotein(a), antisense oligonucleotides, cardiovascular disease, injection site reactions, genetic risk factors
- MeSH terms
- Adult, Aged, Hypolipidemic Agents, Cardiovascular Diseases, Cholesterol, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Oligonucleotides, Risk Factors, Least-Squares Analysis, Lipoprotein(a), Hydroxymethylglutaryl-CoA Reductase Inhibitors
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