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Review
. 2025;19(1):8.
doi: 10.1007/s12170-025-00760-1. Epub 2025 Feb 18.

Lipoprotein(a) as a Causal Risk Factor for Cardiovascular Disease

Sean Doherty  1 , Sebastian Hernandez  1 , Rishi Rikhi  2 , Saeid Mirzai  2 , Chris De Los Reyes  3 , Scott McIntosh  4 , Robert C Block  5 , Michael D Shapiro  2
Affiliations
Review

Lipoprotein(a) as a Causal Risk Factor for Cardiovascular Disease

Sean Doherty et al. Curr Cardiovasc Risk Rep. 2025.

Abstract

Purpose of review: Lipoprotein(a) [Lp(a)], an atherogenic low-density lipoprotein cholesterol (LDL-C)-like molecule, has emerged as an important risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). This review summarizes the evidence supporting Lp(a) as a causal risk factor for ASCVD and calcific aortic valve stenosis (CAVS).

Recent findings: Lp(a) is largely (~ 90%) genetically determined and approximately 20% of the global population has elevated Lp(a). The unique structure of Lp(a) leads to proatherogenic, proinflammatory, and antifibrinolytic properties. Data from epidemiological, genome-wide association, Mendelian randomization, and meta-analyses have shown a clear association between Lp(a) and ASCVD, as well as CAVS. There are emerging data on the association between Lp(a) and ischemic stroke, peripheral arterial disease, and heart failure; however, the associations are not as strong.

Summary: Several lines of evidence support Lp(a) as a causal risk factor for ASCVD and CAVS. The 2024 National Lipid Association guidelines, 2022 European Atherosclerosis Society, and 2021 Canadian Cardiology Society guidelines recommend testing Lp(a) once in all adults to guide primary prevention efforts. Further studies on cardiovascular outcomes with Lp(a) targeted therapies will provide more insight on causal relationship between Lp(a) and cardiovascular disease.

Keywords: Atherosclerotic cardiovascular disease; Calcific aortic valve stenosis; Lipoprotein(a); Low-density lipoprotein cholesterol.

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Conflict of interest statement

Conflict of InterestSaeid Mirzai is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (T32-HL-076132). Robert C. Block is site PI for the Novartis-sponsored clinical trial study called “A randomized double-blind, placebo-controlled, multicenter trial assessing the impact of lipoprotein(a) lowering with pelacarsen (TQJ230) on the progression of calcific aortic valve stenosis [Lp(a)FRONTIERS CAVS]”, and the Lilly-sponsored study called “J3L-MC-EZEF: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults with Elevated Lipoprotein(a) who have Established Atherosclerotic Cardiovascular Disease or Are at Risk for a First Cardiovascular Event – ACCLAIM-Lp(a)”. He has given talks, at scientific sessions, in which lipoprotein(a) was a focus but did not receive compensation for these from pharmaceutical companies. Michael D. Shapiro is supported by institutional grants from Amgen, Arrowhead, Boehringer Ingelheim, 89Bio, Esperion, Novartis, Ionis, Merck, and New Amsterdam; and he has participated in Scientific Advisory Boards with Amgen, Agepha, Ionis, Novartis, New Amsterdam, and Merck. He has also served as a consultant for Ionis, Novartis, Regeneron, Aidoc, Shanghai Pharma Biotherapeutics, Kaneka, Novo Nordisk, Arrowhead, and Tourmaline. All other authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
Mechanisms Linking Elevated Lp(a) with ASCVD. Abbreviations: Apo(a), apolipoprotein(a); ApoB100, apolipoprotein B-100; ASCVD, atherosclerotic cardiovascular disease; KIV2, kringle IV subtype 2; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); OxPL, oxidized phospholipids; SNP, single-nucleotide polymorphism
See this image and copyright information in PMC

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