Commentary

New consensus statement on lipoprotein(a)

More than a decade after first highlighting lipoprotein(a) [Lp(a)] (1), the European Atherosclerosis Society (EAS) has published an updated consensus statement (2). This 2022 statement brings together extensive evidence for elevated Lp(a) concentration as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) (3), irrespective of gender and ethnicity, as well as for aortic valve stenosis (4-6), and provides practical guidance on testing and treating high Lp(a) levels.

Two key novelties stand out from this new statement. First, the statement challenges the concept of a risk threshold for Lp(a) levels, as advocated previously (1). According to latest research from the UK Biobank (7), cardiovascular risk increases continuously as Lp(a) concentration increases, both in men and women and across different ethnic groups.

A second important take home message is that Lp(a) interacts with other risk factors to increase global cardiovascular risk. The impact of high Lp(a) is therefore greater among individuals with higher than lower absolute risk. This concept is consistent with other reports indicating that cardiovascular risk is substantially higher among individuals with high Lp(a) and an unhealthy ‘Cardiovascular Health Score’ versus those with a healthy score (8, 9).

Why is this important? In the absence of licensed treatments that specifically lower Lp(a), clinicians need direction on how to manage the excess risk associated with elevated Lp(a) concentration. Previously, guidelines recommended intensive risk factor modification but did not provide specific information on how best to personalise this for the individual (10). This EAS consensus statement provides guidance on the optimal approach to manage the risk associated with elevated Lp(a) by targeting other major risk factors, taking into account both baseline global risk and the Lp(a) level. For example, the statement provides a table showing how lowering low-density lipoprotein cholesterol by 0.5 mmol/L can help to mitigate the increase in global risk associated with an Lp(a) level of 120 nmol/L. A similar approach can be used for intensive blood pressure modification. As recommended by guidelines(10), the earlier the intervention is started, the greater the impact on lifetime cardiovascular risk.

The consensus panel recognises that there are still challenges regarding Lp(a) measurement. It is evident that the ideal clinical assay, which uses an antibody for a unique non-repetitive epitope in apolipoprotein(a), is not yet available in routine practice. In response to uncertainty regarding units, the panel does not recommend using a standard factor to convert between mg/dL and nmol/L, but does suggest a ‘best guess’ of 2–2.5 for conversion (mg/dL to nmol/L). Working groups are in progress on assay standardisation, essential to moving the Lp(a) field forward.

The extensive evidence-base for the causality of Lp(a) in ASCVD outcomes, largely driven by the use of Mendelian randomization design, catalysed the clinical development of several novel RNA therapeutics that target apolipoprotein(a) within Lp(a). These include antisense oligonucleotides (pelacarsen) and small interfering RNA (siRNA) treatments (olpasiran, SLN360), which have been shown to be highly efficacious in lowering elevated Lp(a) levels (11-14). Testing the ‘Lp(a) hypothesis – whether specifically targeting high Lp(a) levels reduces cardiovascular events – is in progress, with the ongoing Lp(a)HORIZONS trial (NCT04023552).

Beyond ASCVD, the 2022 consensus statement confirmed that elevated Lp(a) is likely causal in aortic valve stenosis, an increasingly prevalent condition which so far lacks medical therapies to treat symptoms or slow disease progression. The design of clinical trials targeting Lp(a) to lower aortic valve stenosis progression is, however, problematic. The key challenges are defining the most appropriate patient population to study, and the best endpoint. Most recently, the population-based Rotterdam study reported that Lp(a) was associated with baseline and new-onset aortic valve calcium, but not progression of aortic valve calcium(15); however, these results are far from definitive and require corroboration in other studies. Imaging trials using novel techniques are critical to clarifying the molecular pathogenesis of aortic valve stenosis and could provide insights to aid trial design.

This consensus statement is important given that elevated Lp(a) is common, affecting about 20% of the general White population, with a higher frequency in the Black population (16). Prevalence is even higher in individuals with coronary artery disease (7). Practical guidance on testing Lp(a) and personalising risk factor intervention to mitigate the risk associated with elevated Lp(a) address key clinical concerns. The panel recognises, however, that gaps remain in understanding the genetic regulation of Lp(a) and its pathogenicity, and possible mechanisms that may underlie the link between (very) low Lp(a) concentration and the development of diabetes. The last decade has seen enormous progress; future research will undoubtedly unravel these persistent unanswered questions about Lp(a), spurred by this new consensus statement.

References

  1. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-53.
  2. Kronenberg F MS, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, Dweck MR, Koschinsky M, Lambert G, Mach F, McNeal CJ, Moriarty PM, Natarajan P, Nordestgaard BG, Parhofer KG, Virani SS, von Eckardstein A, Watts GF, Stock JK, Ray RR, Tokgözoğlu LS, Catapano AL. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022; https://doi.org/10.1093/eurheartj/ehac361.
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  11. Tsimikas S. Potential Causality and Emerging Medical Therapies for Lipoprotein(a) and Its Associated Oxidized Phospholipids in Calcific Aortic Valve Stenosis. Circ Res. 2019;124(3):405-15.
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  13. Koren MJ, Moriarty PM, Baum SJ, Neutel J, Hernandez-Illas M, Weintraub HS, et al. Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a). Nat Med. 2022;28(1):96-103.
  14. Nissen SE, Wolski K, Balog C, Swerdlow DI, Scrimgeour AC, Rambaran C, et al. Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels. JAMA. 2022;327(17):1679-87.
  15. Kaiser Y, van der Toorn JE, Singh SS, Zheng KH, Kavousi M, Sijbrands EJG, et al. Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification. Eur Heart J. 2022.
  16. Mehta A, Jain V, Saeed A, Saseen JJ, Gulati M, Ballantyne CM, et al. Lipoprotein(a) and ethnicities. Atherosclerosis. 2022;349:42-52.