Consensus and guidelines on lipoprotein(a) - seeing the forest through the trees

Abstract

Purpose of the review: Over the past decade, lipoprotein(a) [Lp(a)] made it to several consensus and guideline documents. This review aims to summarize the literature which underlies the various recommendations and compares recent European and North American consensus and guideline documents of the recent 3-4 years.

Recent findings: Multiple large epidemiological and genetic studies have provided strong evidence for a causal association between Lp(a) concentrations and atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. There is a dose-dependent linear relationship between Lp(a) and ASCVD risk advocating to consider Lp(a) on a continuous scale rather than using thresholds. The best way to implement this in the clinic is by individualizing the Lp(a)-related risk using tools such as the 'Lp(a) risk calculator' ( http://www.lpaclinicalguidance.com ) that takes into account the Lp(a) level in the context of an individual's traditional risk factors and global risk for ASCVD. There is growing agreement across the guidelines regarding the clinical utility of measuring Lp(a) and more recent expert groups advocate for a general screening approach applied to all adults. As long as the cardiovascular outcomes trials for specific Lp(a)-lowering drugs are in progress, the current management of patients with high Lp(a) should focus on the comprehensive management of all other modifiable ASCVD risk factors which can be therapeutically addressed as per guideline recommendations.

Summary: Since the contribution of high Lp(a) concentrations to global ASCVD risk has been underestimated in the past, a clear recommendation to measure Lp(a) at least once in a person's lifetime is imperative. Recent expert consensus recommendations provide clinicians with direction on how to manage the excess risk associated with elevated Lp(a) concentration by comprehensive and individualized management of modifiable ASCVD risk factors while awaiting the results of clinical trials of Lp(a) targeted therapies.

Figure 1.

Panel A: Frequency distribution of Lp(a) concentrations and risk for myocardial infarction. Data are derived and extrapolated from Kamstrup et al. [13]. Reproduced with permission of Florian Kronenberg. Panel B: Data from the UK Biobank show the linear relationship of Lp(a) concentration with risk for major cardiovascular events in White individuals. Given are the smoothed adjusted hazard ratio (HR) and 95% confidence interval (95%CI) for lifetime risk for major cardiovascular events for a given Lp(a) concentration relative to the median Lp(a) in the population (19.7 nmol/L). These data were estimated using a Cox proportional hazards regression model adjusted for age at enrolment, sex, and the first 10 principle components of ancestry and modelled using cubic natural splines. Figure is taken with permission from the recent EAS Lp(a) Consensus paper and is based on data from the UK Biobank provided by Prof. Brian Ference and Prof. Alberico L. Catapano [1*].

Figure 2:

Principle of Mendelian randomization studies demonstrating that a lifelong genetic exposure to high or low Lp(a) concentrations supports causality between Lp(a) concentrations and atherosclerotic cardiovascular disease (ASCVD). Panel A shows Lp(a)-increasing variants such as small apo(a) isoforms characterized by a low number of K-IV repeats [11, 12], or a low sum of K-IV repeats of both alleles [13] or single nucleotide polymorphisms such as rs10455872 and rs3798220 [14] which show a pronounced association with high Lp(a) concentrations are also significantly associated with ASCVD outcomes. In this case the association between Lp(a) concentrations and ASCVD is strongly supported to be causal. Panel B illustrates the Lp(a)-decreasing variants such as large apo(a) isoforms or the splice site variants 4733G>A [22**] and 4925G>A [21] within the kringle-IV type 2 or the missense variant rs41267813 are associated with low Lp(a) and concentrations and a lower ASCVD risk supporting a protective role of low Lp(a) concentrations against ASCVD.

Figure 3:

This Figure shows the estimated remaining lifetime risk of a major atherosclerotic cardiovascular events (ASCVD) among 415,274 participants of European ancestry in the UK Biobank. Participants are divided into categories of baseline estimated lifetime risk (5%, 10%, 15%, 20%, and 25%) calculated using the Joint British Societies (JBS3) Lifetime Risk Estimating algorithm (derived from a similar UK population). Within each baseline risk category, participants are then further divided into categories defined by baseline measured Lp(a) concentration. The incremental increase in risk caused by higher Lp(a) concentrations from 30 to 150 mg/dL (75 from 375 nmol/L) was estimated by adding Lp(a) as an independent exposure to the JBS3 risk estimating algorithm. The numbers at the upper end of each bar represent the increment of increased absolute risk above the estimated baseline risk caused by Lp(a). For example, for a person with a baseline risk of 25% and an Lp(a) concentration of 150 mg/dL the absolute risk of a major cardiovascular event increases by 43.1% to 68.1% (versus a person with an Lp(a) of 7 mg/dL). Figure is taken and adapted with permission from the recent EAS Lp(a) Consensus paper and is based on data from the UK Biobank provided by Prof. Brian Ference and Prof. Alberico L. Catapano [1*].