Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol–like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk.
Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid–based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials.
Conclusions and Relevance
Epidemiologic and genetic studies suggest a potentially causal association between elevated Lp(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis. Emerging nucleic acid–based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: March 24, 2022.
Published Online: May 18, 2022. doi:10.1001/jamacardio.2022.0987
Correction: This article was corrected on July 13, 2022, to fix the SI conversion factor for lipoprotein(a), 2 typographical errors in the population column of Table 1 and 2 typographical errors in the main text, and the key findings cell in the CCHS row in Table 1.
Corresponding Author: Robert P. Giugliano, MD, SM, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 350 Longwood Ave, First Floor, Boston, MA 02115 (firstname.lastname@example.org).
Author Contributions: Drs Duarte Lau and Giugliano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Duarte Lau.
Critical revision of the manuscript for important intellectual content: Giugliano.
Study supervision: Giugliano.
Conflict of Interest Disclosures: Dr Giugliano has received research grant support to the Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, Ionis Pharmaceuticals, and Daiichi Sankyo; honoraria for lectures and CME programs from Amgen, Centrix, Daiichi Sankyo, Dr Reddy’s Laboratories, Medical Education Resources, Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, and Voxmedia; and consulting fees from Amarin, Amgen, CryoLife, CSL Behring, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Labcorp, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Luke’s Hospital Kansas City, Samsung, and Sanofi Aventis. No other disclosures were reported.
Additional Contributions: Special thanks to Michelle L. O’Donoghue, MD, MPH (Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts), for her invaluable comments ad honorem during the revision of this article. We thank Maria J. Monterroso, BA (Universidad del Valle de Guatemala, Guatemala City, Guatemala), for designing the figures of this article. Neither contributor was compensated for their work.
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