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Center for Lipid Metabolomics, Division of Preventive Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, and Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada
British Heart Foundation Centre for Cardiovascular Science, Edinburgh Heart Centre, University of Edinburgh, Chancellors Building, Little France Crescent, Edinburgh, EH16 4SB, UK
Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USAand Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK
In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options.
In 2022 the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) (Lp[a)] in atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis [
]. There is now extensive evidence, especially from epidemiology and genetics, strongly supporting a causal association of high Lp(a) with ASCVD outcomes [
Some argue that measuring Lp(a) is not relevant given the lack of approved specific treatment options. However, the 2022 EAS consensus statement recommends that Lp(a) measurement is an important pillar of comprehensive ASCVD risk evaluation, and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentrations. The statement provides a clinical framework for personalizing the management of high Lp(a) to reduce ASCVD risk with currently available therapies [
This document addresses 30 of the most frequently asked questions (FAQ) about Lp(a) (Fig. 1), providing both a short answer and more detail to each question.
Fig. 1Overview on the main topics of the 30 frequent questions addressed in this review.
]. This results in a remarkable size polymorphism of the encoded apolipoprotein(a) [apo(a)], with an inverse correlation between the size of the apo(a) isoform and plasma Lp(a) concentration [
]. Individuals carrying a low number of K-IV repeats (≤22 K-IV repeats) have 4–5 times higher median Lp(a) concentrations than those with a large number of K-IV repeats (>22 repeats) [
]. In contrast, a larger apo(a) protein due to a higher number of K-IV repeats results in protein trapping within hepatocytes and therefore decreased hepatic secretion of apo(a), leading to lower plasma Lp(a) concentration [
(A) Structure of the LPA gene containing a protease domain, a kringle (K)-V-domain and 10 different types of K-IV domains (K-IV type 1 to 10). Each K-IV type 2-encoding segment has a size of 5.6 kb and is repeated up to >40 times resulting in a protein size polymorphism with a molecular weight between 300 and 800 kDa as shown in (B). Panel B shows 11 samples and 2 lanes with a reference standard with 13, 19, 23, 27 and 35 K-IV repeats. (C) Main (causal) determinant of the Lp(a) concentrations is the number of K-IV repeats with an inverse relationship: carriers of a low number of K-IV repeats (small isoforms) have usually 4–5 times higher Lp(a) concentrations than carriers of a high number of K-IV repeats (large isoforms). However, as shown in this panel the variability of Lp(a) concentrations is high in each of the isoforms groups. Some of this variability is explained on the one hand by additional single nucleotide polymorphisms (SNPs) which functionally increase Lp(a) concentrations or on the other hand by splice site variants or other SNPs causing null alleles which decrease Lp(a) concentrations (A). Many of the SNPs in the wider LPA gene regions are not functionally active but are simply in strong linkage with small apo(a) isoforms. Notable examples are the two SNPs rs10455872 and rs3798220 which simply "tag" about half of the small apo(a) isoforms. Panel C has been published in [
]. While many of these may not be of direct functional relevance, they may have a strong correlation with certain K-IV repeat numbers and therefore Lp(a) isoforms sizes. Two very widely studied SNPs, rs10455872 and rs3798220 [
Genome-wide association study and identification of a protective missense variant on lipoprotein(a) concentration: protective missense variant on lipoprotein(a) concentration-brief report.
], are causally associated with low Lp(a) concentration. This can result in a complicated pattern. For example, the splice site variant 4925G>A occurs mostly in individuals with smaller apo(a) isoforms; due to the isoform size, such carriers would be expected to have high Lp(a) concentration but because of the splice site variant, Lp(a) concentration is approximately 30 mg/dL lower than expected [
]. Lp(a) concentration increases slightly with age, particularly in women after the menopause, with levels by up to 27% higher, decreasing by 12% with postmenopausal hormonal therapy [
]. Hormones known to influence lipoprotein metabolism also influence Lp(a) concentration: in particular, these include thyroid, growth and sex hormones [
FAQ-02: Does lifestyle affect Lp(a) concentration?
In contrast to genetic determinants, modifiable lifestyle factors (diet and physical activity) do not have a major influence on plasma Lp(a) concentration
Several studies evaluating the effect of diet on Lp(a) concentration had contrasting results. A randomized feeding trial showed that a low carbohydrate diet high in saturated fat lowered Lp(a) concentration moderately (by 15% compared with a high carbohydrate diet) and improved insulin resistance in a dose-dependent manner [
Aerobic, resistance and combined training and detraining on body composition, muscle strength, lipid profile and inflammation in coronary artery disease patients.
]. Despite this, lifestyle changes will influence global ASCVD risk by favorably modulating other cardiovascular risk factors (e.g. blood pressure or the metabolic syndrome, see below) and therefore reduce the long-term risk of ASCVD and diabetes [
Mendelian randomization studies minimize confounding or reverse causation often observed in conventional epidemiological studies and are therefore a highly effective tool to support causality between a biomarker and clinical outcomes [
], showed that those genetic variants associated with high Lp(a) were more often observed in ASCVD patients than in controls. Conversely, rare genetic variants resulting in loss-of-function [
] with Lp(a)-lowering effects were found to be protective against the development of cardiovascular disease. Although this is a strong indication for causality, it remains to be proven whether specific Lp(a)-lowering therapies will decrease ASCVD outcomes.
3. Risk assessment
FAQ-04: How do I incorporate Lp(a) into the assessment of a patient's global cardiovascular risk?
Risk calculators do not typically include Lp(a) as a predictor variable. To address this, a new risk calculator was introduced under the umbrella of the 2022 consensus statement which considers Lp(a) together with traditional cardiovascular risk factors (http://www.lpaclinicalguidance.com/). This calculator estimates the risk of having a heart attack or stroke up to age 80 years with and without including the effect of measured Lp(a) concentration. The risk estimates are not fixed for a certain time span (e.g. 10 years) as for SCORE-2 [
Score working group ESC Cardiovascular risk collaboration, SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe.
ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American heart association task force on practice guidelines.
], but rather calculated for a wider range of years. Fig. 3 provides a typical example, showing risk curves with and without Lp(a) concentration, for estimating how the risk for an MI or stroke can be reduced by lowering low-density lipoprotein cholesterol (LDL-C) concentration and blood pressure. There are two key conclusions from this figure; first, the risk for a cardiovascular event is underestimated substantially if Lp(a) is high but not considered in the risk estimation. Second, identifying and modifying risk factors such as elevated LDL-C and/or blood pressure can mitigate at least part of the global risk of an individual even if the Lp(a)-attributable risk is not changed. This also helps to motivate physicians and patients to adhere to the recommended treatment of other modifiable risk factors in the absence of an available therapy for Lp(a) lowering (see http://www.lpaclinicalguidance.com and Fig. 3C).
Fig. 3Example of the Lp(a) risk calculator provided by Prof. Brian Ference based on data from the UK Biobank.
(A) In the first step the health information based on traditional risk is filled in for the patient. Panel B shows the results for this patient, assuming a median Lp(a) concentration of 7 mg/dL (blue curve). The red curve shows the risk curve for this patient if Lp(a) concentration is 100 mg/dL; risk at the age of 80 years increases from 33.4% to 52.1%. Be aware that the risk for the endpoint can be read for any particular age. Panel C shows how the risk curve changes for this patient when LDL-C concentration is lowered by 40 mg/dL and systolic blood pressure by 5 mmHg over the rest of life (light blue curve). This shows that the global risk for this person can be lowered significantly to approach that of a person with an Lp(a) of 7 mg/dL. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
FAQ-05: Why should I measure Lp(a) when there is no drug treatment than can effectively lower elevated Lp(a) concentrations?
Knowledge of an elevated Lp(a) value influences the management of other risk factors
Currently, there are no licensed therapies which specifically and potently lower Lp(a) concentration. The 2022 consensus statement recommended that other risk factors should be treated intensively and - importantly - as early as possible. As discussed above, the Lp(a) risk calculator can be used to predict how much global risk can be influenced by lowering other risk factors such as elevated LDL-C and blood pressure in individuals with high Lp(a) (Fig. 3). Early intervention is key to optimizing risk reduction. Lifestyle changes have minor effects on Lp(a) concentration but will substantially modify global risk. The recommendation to target modifiable risk factors (e.g. smoking, obesity, diabetes, hypertension, high cholesterol, physical inactivity and unhealthy diet) is supported by observational data from the EPIC-Norfolk study, in which subjects with Lp(a) concentration >50 mg/dL and few of these risk factors had one-to-two-thirds lower risk of an ASCVD event during 11.5 years of follow-up compared to those with an unhealthy lifestyle [
Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: the EPIC-Norfolk prospective population study.
]). This simple recommendation for universal screening is more likely to be followed than more complex rules for when, why, and in whom Lp(a) should be measured. The simplest approach is to include Lp(a) as part of the patient's initial lipid testing, as recommended in the 2022 Lp(a) consensus statement [
]. Practical measures such as inclusion in lipid panels, easy access to request forms, and no justification required for testing can help to remove unnecessary barriers for Lp(a) testing. Moreover, as Lp(a) is requested more frequently, the cost per measurement will decrease. In addition, digital solutions can alert the requesting physician on the results of previously performed Lp(a) measurements to avoid non-necessary multiple measurements.
FAQ-07: Should I screen for Lp(a) in families if an ‘index’ patient is diagnosed with a (very) high Lp(a) concentration?
Yes. With co-dominant transmission of genetic variants causing high Lp(a) concentration [
], screening can help to detect other affected first-degree relatives (parents, siblings, children)
If a patient with high Lp(a) has a family history of ASCVD, screening other family members becomes even more important, especially in the case of premature ASCVD [
], except that no genetic testing is required. This makes it easier and less expensive compared with familial hypercholesterolemia since the hurdles and regulations surrounding DNA analysis are avoided and all that is required is the simple measurement of Lp(a) plasma concentrations in all relevant family members. However, pre- and post-test counselling for the interpretation of the results in context of the global risk of a particular individual is required. Family (cascade) screening in families with high Lp(a) concentration is important for two reasons; 1) the prevalence of very high Lp(a) is much higher than the prevalence of FH [
FAQ-08: Is there an Lp(a) concentration threshold for increased ASCVD risk?
The relationship between Lp(a) concentration and ASCVD risk is continuous without any threshold effect: i.e., the higher the concentration, the higher the risk [
Using data from the UK Biobank, the 2022 consensus statement showed that compared with individuals with a median Lp(a) concentration of 7 mg/dL, those with levels of 30, 50, 75, 100 and 150 mg/dL had a 1.22-, 1.40-, 1.65–1.95- and 2.72-fold increase in ASCVD risk, respectively (Fig. 4). This relative increase in risk is the same in all baseline risk categories defined according to traditional risk factors. Importantly, however, when the baseline risk of an individual is already very high due to other ASCVD risk factors (e.g. absolute lifetime risk of 25%) and that individual also has a very high Lp(a) concentration (e.g. 150 mg/dL), the absolute life-time risk increases to 68% (25% * 2.72 = 68%). Another individual with the same Lp(a) concentration but a very low baseline ASCVD risk (5%) has an absolute life-time risk of 13.6% (5% * 2.72 = 13.6%) (Fig. 4). This 13.6% value is still relatively low given that around a third of people in European or North American populations will die from cardiovascular causes.
Fig. 4This Figure shows the estimated remaining lifetime risk of a major atherosclerotic cardiovascular disease (ASCVD) events 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) that considers the traditional ASCVD risk factors of age, sex, blood cholesterol, blood pressure, smoking, diabetes, family history of heart attacks in early life, and body mass index. Within each baseline risk category, participants are then further stratified into categories defined by baseline measured Lp(a) concentration. The incremental increase in risk caused by increasing Lp(a) concentration 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). The right side of the Figure provides the relative increase in risk for each of the Lp(a) concentration strata, ranging from 30 to 150 mg/dL, compared to subjects with a median Lp(a) concentration of 7 mg/dL. The left side of the panel Figure is adapted with permission from the 2022 Lp(a) consensus statement and is based on data from the UK Biobank provided by Prof. Brian Ference and Prof. Alberico L. Catapano.
FAQ-09: Is the association between Lp(a) concentration and different ASCVD outcomes similar?
No, there are differences. The strongest associations are seen for MI and aortic valve stenosis, with weaker associations for heart failure, ischemic stroke, and peripheral arterial disease
To date, only a few studies have been sufficiently powered to make direct comparisons between Lp(a) concentration and different ASCVD outcomes. Meta-analysis is also challenging since this requires that measurement of Lp(a) concentration and collection of endpoints are performed in a standardized way [
], but even this requires care with direct comparison as over the years, different thresholds (ranging from the 66th to the 99th percentile) and reference groups (ranging from the <22nd percentile to less than the median of Lp(a)) were defined for each outcome [
The adjusted hazard ratios for selected outcomes comparing participants in the top percentiles of the Lp(a) distribution versus a reference group in the lower percentiles are presented. This figure is taken with permission from the authors and the publisher of reference [
], adapted by adding the Lp(a) percentiles of the risk categories and the percentiles of the reference categories in blue numbers for each of the outcomes. All measurements were performed using the same Denka Seiken assay. Data for this figure were taken from Refs. [
Based on available data, the strongest associations are for myocardial infarction (MI) and aortic valve stenosis; exposure to higher Lp(a) concentration is required for a similar increase in risk for ischemic stroke, peripheral arterial disease, heart failure, cardiovascular mortality and total mortality [
]. This is not surprising, especially for total mortality, as approximately two-thirds of the population die from non-cardiovascular causes which diminishes the association between Lp(a) and the heterogeneous endpoint of total mortality. Additionally, heart failure is secondary to MI and aortic valve stenosis [
]. The heterogeneous etiology of ischemic stroke weakens the association with Lp(a); similar to other lipid risk factors, Lp(a) increases the risk of large artery stroke but not of cardioembolic stroke [
Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.
FAQ-10: Why does a high Lp(a) concentration not necessarily result in an ASCVD event?
High Lp(a) is no guarantee that a person will develop ASCVD (the same holds true for other risk factors such as elevated LDL-C or high blood pressure)
This point is often raised, reminiscent of anecdotes about individuals who smoked 40 cigarettes a day for decades but did not die of lung cancer. Based on what has been presented previously (Fig. 3, Fig. 4), it is evident that the absolute global risk for ASCVD depends not only on Lp(a) concentration but also on the baseline risk category (the product of both). Thus, a person with a high Lp(a) concentration (>100 mg/dL) but without any of the traditional risk factors might not develop ASCVD (Fig. 4, Fig. 6). However, if the individual has several traditional risk factors, global risk will increase when Lp(a) concentration is between 30 and 50 mg/dL.
Fig. 6Schematic illustration how the risk attributable to Lp(a) contributes to the global risk.
Shown is the distribution of risk for atherosclerotic cardiovascular disease (ASCVD) in the general population caused by "unmeasured" (unknown since not measurable) residual risk and the genetic risk factors (rarely measured). It depends from where in the distribution a given individual starts with the additional risk caused by traditional risk factors and the risk caused by high Lp(a) concentrations (for the sake of simplicity, the risk increase caused by Lp(a) is only given for persons with high Lp(a) concentrations). An individual with a low residual risk (unmeasured and genetically determined), may be better able to tolerate the impact of high Lp(a) concentrations on global risk than a person with a high residual risk. This might explain why not everybody with high Lp(a) concentration will develop an ASCVD event.
All of these calculations include some degree of uncertainty given that they are based on estimated probabilities. The duration of exposure to risk factors is one uncertainty. The concept of pack-years (how many cigarettes are smoked and over how many years) is one approach to measure smoking exposure and can much easier be accomplished. Determining cumulative exposure to high cholesterol or high blood pressure [
], however, is less precise since both are often undetected for a long period of time. The "unmeasured genetic backbone" of an individual is another uncertainty. Capturing traditional risk factors might already take into account at least part of this genetic backbone. However, there are numerous genetic variants which are not related to traditional risk factors that are not considered in current risk calculations but do contribute to the susceptibility and global risk of the individual [
] (Fig. 6); this is often referred to as individual susceptibility. Third, social determinants of disease, including socioeconomic variables (e.g education, income, employment status), environmental factors (e.g. air pollution and traffic noise), and lifestyle (e.g. diet, physical activity, sleep behaviour) also influence ASCVD risk beyond their effects on traditional risk factors. These effects are reflected by the different SCORE2 versions for different European countries [
Score working group ESC Cardiovascular risk collaboration, SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe.
]). Median Lp(a) concentration does vary with ethnicity by up to four-fold (in increasing order: Chinese, white, South Asian and black individuals with 16, 19, 31 and 75 nmol/L, respectively). Nevertheless, data from the UK Biobank showed very similar relationships between Lp(a) concentration and ASCVD risk in white, black and South Asian individuals [
Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study.
Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis, Arterioscler.
Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study.
] (although changes in absolute risk decrease not only with baseline risk categories but also LDL-C strata). Patel and colleagues showed no major interactions with sex, diabetes, hypertension, obesity, smoking, median LDL-C concentration, and family history of heart disease and stroke. The associations were less strong but still significant for older individuals, those with prevalent ASCVD at enrolment, or on statin treatment for primary prevention [
], studies and intervention trials in primary and secondary prevention settings revealed that Lp(a) is a risk factor even among (statin-treated) individuals with very low LDL-C concentration [
Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
Lp(a) (Lipoprotein[a])-Lowering by 50 mg/dL (105 nmol/L) may Be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study.
Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (atherothrombosis intervention in metabolic syndrome with low HDL/high triglyceride and impact on global health outcomes).
Lp(a) (Lipoprotein[a])-Lowering by 50 mg/dL (105 nmol/L) may Be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study.
Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (atherothrombosis intervention in metabolic syndrome with low HDL/high triglyceride and impact on global health outcomes).
]. In a patient-level meta-analysis including primary and secondary prevention trials, elevated Lp(a) showed an independent and approximately linear relationship with cardiovascular disease risk [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
A recent study in two independent cohorts used measurement of Lp(a) and CAC to investigate ASCVD risk after a follow up of 13.2 and 11 years, respectively [
]. Elevated Lp(a) concentration and the presence of CAC were each independently associated with ASCVD events, with a more than five-fold increase in risk in individuals with both elevated Lp(a) and CAC ≥100 compared to those with low Lp(a) and no CAC. Furthermore, the association between Lp(a) and ASCVD was only observed among participants with elevated CAC scores [
FAQ-15: Why is Lp(a) no longer considered a risk factor for venous thromboembolic events?
Large observational and genetic studies in adults have not demonstrated an association between genetically increased Lp(a) concentrations and venous thromboembolism [
It has been suggested that Lp(a) potentially inhibits the fibrinolytic activity of plasmin in a competitive manner due to the similarity of apo(a) with plasminogen [
]. However, the protease domain of apo(a) does not possess an enzymatic function. Despite some in vitro evidence in support, it has proven challenging to demonstrate any anti-fibrinolytic effect of Lp(a) elevation in vivo in humans. This is in line with a recent phase I/II clinical trial, in which lowering elevated Lp(a) by >80% with an apo(a) antisense therapy did not result in any change in a series of ex vivo fibrinolytic assays [
Genetic variants which are associated with lifelong exposure to high Lp(a) concentration do not appear to increase risk for venous thromboembolic events [
]. It has been suggested that the situation might be different in the arterial system, and that high Lp(a) concentration might promote plaque-associated thrombosis after plaque erosion and rupture. However, in this case the pathogenic contribution of Lp(a) would have started long before the event by contributing to the development of atherosclerotic plaques. Indeed, Lp(a) binds to the extracellular matrix, stimulates monocytes and promotes their transendothelial migration into the vessel wall where it contributes to arterial wall inflammation and cytokine release by its oxidized phospholipids, promotion of smooth muscle cell proliferation, and development of fatty streaks [
Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).
]. When the plaque becomes unstable and ruptures, the resulting thrombosis might be a consequence of the naturally occurring coagulation process rather than a direct effect of Lp(a). On the other hand, the observation that (very) high Lp(a) associates with both first and recurrent arterial stroke in children [
Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood.
] supports an arterial thrombogenic potential. It has been suggested that the etiology and relationship of Lp(a) with stroke is age-dependent, with the more purely antifibrinolytic properties predominating in children. Also, children with strokes of unclear etiology frequently have other exacerbating diseases including congenital heart disease, coagulation disorders, or chronic inflammatory conditions. Thus, the more proinflammatory and proatherogenic effects of Lp(a) might predominate in young adults whereas in the elderly, multiple risk factors with an elevated Lp(a) may enhance the possibility of cerebral vascular events [
FAQ-16: How reliable are the available assays for Lp(a) measurement?
The assays available in clinical practice are not yet ideal, but they are most likely adequate for risk discrimination
Most assays can readily identify individuals with high or very high Lp(a) concentrations relative to those with low or intermediate concentrations. Despite this, care should be taken when comparing results measured by different assays and even different laboratories, because Lp(a) assays are not yet internationally standardized.
Apolipoprotein(a) with its repetitive structure of K-IV repeats poses a challenge to measurement of Lp(a) [
]. The assays utilized in clinical laboratories use polyclonal antibodies most likely directed against the repetitive K-IV repeat structures of apo(a). Depending on the calibrators used, this can result in underestimation of Lp(a) concentration in the presence of small apo(a) isoforms, and overestimation of Lp(a) concentration with large apo(a) isoforms [
]. For most samples, this underestimation and overestimation is not substantial and will not change risk classification. However, when the Lp(a) concentration is close to a "threshold" for clinical decision-making, it can lead to misclassification. Therefore, the 2022 Lp(a) consensus statement suggested a pragmatic approach, with Lp(a) cut-offs to ‘rule out’ (<30 mg/dL or <75 nmol/L) or ‘rule-in’ (>50 mg/dL or >125 nmol/L) risk. The interim grey zone (i.e. 30–50 mg/dL; 75–125 nmol/l) is relevant for two reasons; first, for uncertainties caused by the mentioned analytical issues of Lp(a) measurement close to clinical decision thresholds (including thresholds for the inclusion or exclusion of patients for clinical trials) and second, when considering Lp(a)-attributable risk in the presence of other risk factors and in risk stratification (Fig. 6, Fig. 7) [
]. For the latter, in the absence of other risk factors, an Lp(a) value in the grey zone might be more acceptable than if other risk factors are present.
As discussed in the text, there is a continuous association between Lp(a) concentration and cardiovascular outcomes. However, in the clinical setting, physicians and patients demand thresholds for risk classification and shared decision-making. Therefore, the consensus panel suggested a pragmatic approach, with Lp(a) cut-offs to ‘rule out’ (<30 mg/dL or <75 nmol/L) or ‘rule-in’ (>50 mg/dL or >125 nmol/L) Lp(a)-attributable risk. The interim grey zone (i.e., 30–50 mg/dL; 75–125 nmol/l) is relevant for two reasons: 1) the absolute Lp(a)-attributable risk in the presence of other risk factors has a wide variability (see also Fig. 4) and 2) the grey zone does also consider some uncertainties introduced by the assay used. Colour-coding reflects the risk attributable to Lp(a): green for low risk, yellow for medium risk and red for high risk. This Figure has been published in Ref. [
Towards an SI-traceable reference measurement system for seven serum apolipoproteins using bottom-up quantitative proteomics: conceptual approach enabled by cross-disciplinary/cross-sector collaboration.
Commutability assessment of candidate reference materials for lipoprotein(a) by comparison of a MS-based candidate reference measurement procedure with immunoassays.
]. Their work will provide new reference methods for Lp(a) measurement and improve reference materials that are accessible to clinical assay manufacturers. In the next couple of years, these efforts will improve standardization and harmonization of Lp(a) assays.
FAQ-17: Why do we have two units for Lp(a) concentration and why is there not a simple conversion factor?
One unit measures Lp(a) particle numbers (nmol/L) and the other unit measures Lp(a) mass (mg/dL). Since the mass of Lp(a) particles is variable, a direct conversion can only be an approximation
Ideally, Lp(a) should be measured in molar units, as this ensures that each Lp(a) particle is only recognized once. However, this is difficult to achieve when polyclonal antibodies are used in assays since these antibodies most likely recognize the repetitive K-IV repeat domain of apo(a) (see above) [
]. Thus, many clinical Lp(a) assays likely report Lp(a) in mass units even if they claim to report results in molar units which is - strictly speaking - almost impossible with polyclonal antibodies. Given what is possible with current techniques, the 2022 Lp(a) consensus statement recommends that the units in which the assay is calibrated should be used for reporting results [
The 2022 consensus statement does not recommend using a standard factor to convert between mg/dL and nmol/L since this would require a linear correlation between measurements in each unit. Instead, this relationship is influenced by the apo(a) isoform size of the measured Lp(a) particle and therefore specific to a particular clinical sample [
]. In practice clinicians are often confronted with working with patients with Lp(a) measurements from different laboratories and in different units. As a pragmatic approach (even though not scientifically accurate), multiplication of a mg/dL measurement by a factor of 2–2.5 can give an approximate nmol/L value of Lp(a) [
Towards an SI-traceable reference measurement system for seven serum apolipoproteins using bottom-up quantitative proteomics: conceptual approach enabled by cross-disciplinary/cross-sector collaboration.
FAQ-18: Why should I never report an Lp(a) concentration without naming the unit?
This sounds trivial but could result in substantial confusion especially in discussions between clinicians and with patients
Since Lp(a) concentrations are reported in mg/dL, mg/L, or nmol/L, a number reported without any unit cannot be interpreted. For example, Lp(a) concentrations of 100 mg/dL, 100 mg/L and 100 nmol/L represent very different levels of Lp(a) and therefore have very different implications for risk assessment. In contrast, the situation is different for LDL-C, where the measurement unit can be inferred (e.g. 2 mmol/L = 77 mg/dL, based on the molar mass of cholesterol).
FAQ-19: Is a single measurement of Lp(a) sufficient for risk discrimination?
Yes, in most people a single life-time measurement is sufficient
Given that Lp(a) concentration is mainly determined by genetics, levels are believed to be stable over time. Indeed, analysis of data from 6597 participants in seven studies with a mean interval of 8.3 years reported a very high within-person correlation (0.87) for serial measures of Lp(a) [
]. Here, the median absolute change in Lp(a) was a modest 3.1 mg/dL, although was more pronounced at very high Lp(a) concentrations. For the overall cohort, the relative change was 33%, highest in individuals with Lp(a) concentration <10 mg/dL, which is irrelevant in absolute terms. Individuals with Lp(a) levels <30 mg/dL and >50 mg/dL at first visit tended to remain in these risk category groups, although almost 60% of those in the grey zone (30–49 mg/dL) were subsequently reassigned to the category >50 mg/dL. Black race, female sex, diabetes, hypertension, total cholesterol, and albuminuria were associated with a significantly greater likelihood for a change in Lp(a) ≥20 mg/dL over time [
]. In another study which analysed repeated Lp(a) measurement taken over a median interval of 4.4 years in >16,000 individuals, only 10% and 5% of individuals had an increase or decrease in Lp(a) by at least 25 nmol/L, respectively. There was no association between the change in Lp(a) and incident coronary artery disease [
Added to this, there is information from waterfall plots of changes in Lp(a) in patients allocated to placebo in intervention studies. For example, Tsimikas and colleagues reported absolute changes in the placebo group ranging from −68.0 mg/dL to +101.4 mg/dL, which were very similar to those in the statin group (−68.3 mg/dL to +101.3mg/dL) [
]. Trials with specific Lp(a)-lowering therapies (pelacarsen and olpasiran) in patients with high and very high Lp(a) reported relative changes in Lp(a) concentrations in the placebo group ranging from +10% to +30% to −10% to −30%. In summary, although occasionally significant changes in Lp(a) may occur in individuals, for the vast majority the risk category remains unchanged.
Repeated measurement of Lp(a) might be considered in patients who develop chronic kidney disease, in particular nephrotic syndrome, since these disease states can result in considerable increases in Lp(a) [
]. As a pragmatic approach, serial testing is not required in most cases, especially when Lp(a) concentration is low (e.g. <30 mg/dL, present in ≈70% of the white population and ≈50% of the black population) or >80–100 mg/dL, since no major change in risk classification is anticipated over time. This may change when specific Lp(a)-lowering therapies become available.
FAQ-20: Should I measure Lp(a) in children?
Yes, in the context of family cascade testing and in selected cases of stroke in youth
Lp(a) concentration in children increases with age, especially during the first year, and varies considerably, which makes a single measurement less reliable. In a prospective Danish cohort study of 450 newborns which measured Lp(a) plasma concentration in cord blood and neonatal venous blood at 2 and 15 months, mean Lp(a) concentrations were 2.2, 2.4, 4.1, and 14.6 mg/dL, respectively, with a pronounced increase over the first year of life. Birth concentrations ≥90th percentile in cord blood or venous blood (≈5 mg/dL, which is below the lower limit of detection for some clinical assays) can help identify newborns at risk of developing high concentrations (>42 mg/dL) until the age of 15 months [
]. Additionally, in a study with repeated Lp(a) measurement in 2740 children referred to a Dutch pediatric lipid clinic, mean levels increased from age 8 years, although this was less frequent in those who reached adulthood without lipid-lowering medications than in those subsequently on a statin (22% versus 43%, respectively; 9% for those on ezetimibe). The intra-individual variation in Lp(a) was 70%, which argues against a single measurement in this age group [
]. For older children, the Young Finns Study showed that most individuals with Lp(a) ≥30mg/dL at any time continued to have a high Lp(a) concentration [
Given the trajectories of Lp(a) concentration in the first two decades of life, the key question is what at age to start Lp(a) testing. While FH guidelines routinely recommend testing children of affected parents from age 10 years, there are no specific recommendations for Lp(a) measurement. Selective measurement is recommended for:
i)
Youth with the rare history of hemorrhagic or ischemic stroke. Limited data suggest an association between Lp(a) and incident arterial ischemic stroke in children, somewhat stronger if there are recurrent events [
Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood.
]. Some small studies suggested that thrombophilic risk factors combined with an Lp(a) >30 mg/dL amplify the risk of ischemic stroke and venous thromboembolism/sinus venous thrombosis [
Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies.
FAQ-21: When and how should I adjust LDL-C for the cholesterol content of Lp(a)?
Not required routinely; currently only in patients with clinical suspected FH and statin resistance
Routine LDL-C concentrations reported by clinical chemistry laboratories comprise the cholesterol contained in both LDL and Lp(a), as the cholesterol content of the individual lipoprotein particles cannot be separated. Initial analyses of isolated Lp(a) particles suggested that this corresponded to 30%–45% of Lp(a) mass concentration [
Use of a reference material proposed by the international federation of clinical chemistry and laboratory medicine to evaluate analytical methods for the determination of plasma lipoprotein(a).
]. Using a novel assay that directly determines the cholesterol content in Lp(a), revealed a high interindividual and - following intervention - intraindividual variation (nearly 6%–60% of Lp(a) mass concentration) [
]. Until there are data from large population-based studies for the distribution of Lp(a) cholesterol content, the 2022 Lp(a) consensus statement recommends avoiding routine correction of LDL-C (by subtracting 30% of the Lp(a) mass measurement). Exceptions to this are 1) patients with clinically suspected FH [
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
] and elevated Lp(a) concentrations, where correction may result in reclassification and avoid unnecessary genetic sequencing in 15–25% of individuals with probable/definite FH [
]; and 2) possibly, among patients with statin resistance. The LPA locus has been identified as a cause of statin resistance and Lp(a)-cholesterol as a statin-resistant fraction of LDL-C [
]. Therefore, correcting LDL-C for Lp(a)-cholesterol may explain why some patients have an inadequate response to statin therapy as most of the cholesterol in their LDL-C is derived from Lp(a). However, further study of the influence of Lp(a)-derived cholesterol on the response to statin therapy is needed.
FAQ-22: When should I measure Lp(a) following a clinical event?
No clear advice can be given for this question until additional systematic studies are carried out
Some - but not all – studies report that Lp(a) may be an acute phase reactant. In one small study, Lp(a) levels more than doubled in the first 8–10 days after an acute MI and during subsequent surgical intervention with subsequent normalization of levels within 30 days [
]. Another study with sequential measurement of Lp(a) before and after percutaneous coronary intervention showed a 64% increase in Lp(a) immediately after intervention, returning to baseline levels within 6 hours [
Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.
]. In contrast, another small study reported that Lp(a) concentration decreased by 80–95% in patients with sepsis and extensive burns associated with pronounced inflammation [
]. In patients hospitalized for COVID-19 infections, one study reported increasing Lp(a) concentration (mean 16.9 mg/dL) in the following 3 weeks, with the increase correlated with the change in interleukin-6 concentration, although the latter increased at least one week before the rise in Lp(a) [
]. Another study reported that elevated levels of interleukin-6, C-reactive protein, and procalcitonin were associated with lower Lp(a) concentration [
Based on these data, it might be suggested that Lp(a) should be measured 2–3 months after an acute event, but this has the disadvantage of closing a convenient opportunity to assess initial Lp(a)-mediated risk during hospitalization. As a compromise, measuring Lp(a) before hospital discharge offers a pragmatic solution, noting that patients with low Lp(a) (e.g. <30 mg/dL) at that occasion are unlikely to require further testing.
FAQ-23: Is an Lp(a) genetic investigation required for risk assessment?
In almost all contexts and with very few exceptions, the response is NO
The Lp(a) concentration is sufficient, reflecting the complex interplay of Lp(a)-increasing and Lp(a)-decreasing genetic variants. For clinical purposes, measurement of Lp(a) concentration is easy to perform and readily incorporated in risk classification [
Investigation of apo(a) isoforms by Western blot analysis or investigation of SNPs might provide additional information in the case of rare conditions in which large changes in Lp(a) are expected. Patients with kidney impairment are a prime example, since the increase in Lp(a) is mainly observed in large apo(a) isoform carriers [
Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).
]. Knowing the apo(a) isoform provides information about the duration of exposure to high Lp(a) concentration, i.e. lifetime or only since development of the renal disorder [
]. For scientific purposes, investigating genetic variants might help to ascertain whether elevation in Lp(a) in patients with other diseases is due to primary (genetic) or secondary causes [
FAQ-24: What do I do with an asymptomatic patient who has a very high Lp(a) concentration?
Management of other modifiable risk factors by lifestyle intervention and medical treatment according to guidelines is essential
Patients should be supported to stop smoking and avoid second-hand smoke. CAC evaluation can be considered at the age of 50; if patients are very concerned about their Lp(a) concentration, a CAC score of zero or low for age/sex/race may reduce anxiety. Check whether there is a family history of (premature) ASCVD and propose family screening for high Lp(a). Finally, referral to a lipid clinic or cardiovascular specialist may be considered for certain patients.
FAQ-25: A patient with ASCVD has LDL-C at goal but high Lp(a): what should I do?
Management of risk factors other than LDL-C is of utmost importance; lipoprotein apheresis is an option
Shorter intervals for follow-up may be required. Careful recording of family history of premature ASCVD and family (cascade) screening are important. Lipoprotein apheresis may be an option in some countries (e.g. Germany) in patients with cardiovascular disease progression (e.g. multiple events) [
] in ASCVD patients with an elevated Lp(a) demonstrated a significant reduction in the ASCVD event rate (>80%) over 7 years, irrespective of baseline LDL-C levels, attributable to reduction of apoB-containing lipoproteins including Lp(a), as well as improved rheology and reduced vascular inflammation. Apheresis is also approved in the United States for treatment of ASCVD patients, and recently received preliminary approval from the FDA for patients with elevated Lp(a) concentration (>60mg/dL or >150nmol/L) irrespective of baseline LDL-C levels [
]. This relative effect varies widely; the percentage decrease in Lp(a) is lowest (10–20%) but absolute reduction is highest in individuals with high Lp(a) concentration. Nonetheless, using a PCSK9 inhibitor to reduce isolated high Lp(a) concentration might not be sufficiently effective and therefore cannot be recommended. As mentioned in FAQ 4 and 5, optimal treatment of other risk factors including LDL-C is recommended in patients with high Lp(a) concentration; if LDL-C goal is not achieved with oral combination LDL-lowering therapy (statins, ezetimibe, and bempedoic acid), adding a PCSK9 inhibitor is an option. Post-hoc analysis of the FOURIER Trial [
] suggest that the additional lowering of Lp(a) by PCSK9 inhibitors contributes to cardiovascular risk reduction in patients with higher Lp(a) concentration. Similar observations were reported in a pooled data analysis from 10 controlled phase 3 ODYSSEY trials for patients with Lp(a) concentrations ≥50 mg/dL [
FAQ-27: What is the effect of statins on Lp(a) concentration? Should I stop statin treatment in case of an Lp(a) increase associated with statin treatment?
Statins shouldnotbe stopped in patients with high Lp(a), rather the opposite as use of statins is clearly beneficial as demonstrated in extensive randomized trials [
] in most cases, these changes appear to be minimal.
Three meta-analyses evaluating the effect of statins on Lp(a) concentration provide a confusing picture. In one individual-patient data meta-analysis of seven trials in 14,536 patients (on statin or placebo), three trials showed a mean increase in Lp(a) (between 2% and 15%) and four trials reported a mean decrease (between −1% and −13%), with a non-significant pooled percentage change of −0.4% (95%CI -7 to 7%) [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
]. Recently, a meta-analysis of 39 studies in 12,411 patients on statin and 11,221 patients on placebo reported absolute and percentage changes in the statin vs. placebo arms of 1.1 mg/dL (95%CI 0.5–1.6, p<0.0001) and 0.1% (95%CI -3.6%–4.0%, p=0.95), respectively [
], leading the authors to conclude that statin therapy does not lead to clinically-important differences in Lp(a) concentration (when compared to placebo) in patients at risk for ASCVD [
]. From these three meta-analyses it is reasonable to conclude that any increase in Lp(a) that is associated with statin treatment is - in most patients - relatively small. Importantly, it will not justify a decision to discontinue the statin given robust evidence for statins reducing ASCVD events [
]. The net benefit of statin treatment outweighs any potential risk associated with any relatively small increase in Lp(a). For example, in the first meta-analysis discussed above, patients on placebo had a cumulative risk for an ASCVD event of 21.3% (3148 patients of 14,536) versus 17.9% (2603 of 14536) for those on a statin, equating to 17% relative risk reduction on statin treatment [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
FAQ-28: Why do we need drugs that specifically target Lp(a) and how do they work?
In patients with very high Lp(a) concentration and a high global ASCVD risk, we require specific and highly effective Lp(a)-lowering drugs
Using the Lp(a) risk calculator clinicians can act now to reduce increased ASCVD risk by managing modifiable traditional risk factors with lifestyle and behavioural changes (e.g. smoking cessation, increase physical activity) and effective drug therapy (e.g. LDL-C, blood pressure and glucose-lowering agents). As Fig. 3 demonstrates, global risk can be reduced when these therapies are started early in life and are given life-long. However, where most of the increased global risk is derived from very high Lp(a) concentration, these therapies although important are unlikely to be enough to lower global risk sufficiently. For these patients, future therapies that specifically and potently lower Lp(a) are eagerly awaited.
These specific Lp(a)-lowering drugs act at apo(a) production in the liver cells using RNA-targeting strategies. One therapeutic approach is a single-strand antisense oligonucleotide (ASO) called pelacarsen; this binds to the RNA for apo(a) resulting in approximately 80% reduction in Lp(a) plasma concentrations with a 60–80 mg subcutaneous injection every 4 weeks [
]. Results from the first cardiovascular outcomes studies are expected in 2025 (HORIZON; gal-nac apo(a)-antisense pelacarsen) and 2026 (OCEAN(a); gal-nac silencing RNA olpasiran).
FAQ-29: Will I increase the risk of diabetes by using potent Lp(a)-lowering drugs?
There is no evidence to suggest that Lp(a)-lowering will increase the risk of diabetes
Several observational studies have shown that very low Lp(a) concentrations are associated with an increased risk of diabetes mellitus [
]. To investigate this further, the 2022 Lp(a) consensus statement undertook a new meta-analysis of available studies. This showed that individuals with Lp(a) concentrations in the lowest quintile (<3–5 mg/dL) have a 38% higher risk for new-onset diabetes than those in the top quintile [
], although the mechanism underlying this association is poorly understood. Together, this has raised questions whether lowering Lp(a) may increase the risk of diabetes, of relevance given that there are now specific therapies that can decrease Lp(a) by >95% to very low levels that have been associated with increased diabetes risk in observational studies (see meta-analysis [
]). Ongoing trials have to monitor this and whether there is any impact on the risk of macro- and microvascular complications such as nephropathy, retinopathy, and diabetic foot. If so, risk-benefit assessments would be required to determine whether the dose of Lp(a) therapeutic would require adjustment.
FAQ-30: Should I treat my patient with low dose aspirin in case of high Lp(a) concentrations?
Before clear advice can be given, we need a randomized trial directly testing whether aspirin given to people with high Lp(a) concentration or high Lp(a)-related genetic risk for primary prevention results in a benefit
]. Whether aspirin might be beneficial among individuals with markedly elevated Lp(a) is uncertain". In support, a post hoc analysis of the Women's Health Study, a randomized primary prevention trial, showed that use of aspirin (100 mg every other day) in women with Lp(a) >65 mg/dL did not significantly reduce cardiovascular events over a 10-year period compared with placebo. However, in a subgroup analysis, 19 patients who were carriers of the rs3798220 variant with baseline median Lp(a) ≈80 mg/dL appeared to derive some benefit from aspirin (hazard ratio 0.44, 95% CI 0.20–0.94, p=0.03) [
]. Therefore, it was concluded that individuals with high Lp(a) concentration may be considered for aspirin therapy if they have other indications for aspirin therapy (e.g. very high ASCVD risk and low bleeding risk).
Since then, results from the primary prevention ASPREE (ASPirin in Reducing Events in the Elderly) trial have been published [
]. ASPREE is a randomized controlled trial of aspirin 100 mg daily versus placebo with a median follow-up of 4.7 years in individuals without prior cardiovascular disease events. The study did not measure Lp(a) concentration. A post hoc analysis of 12,815 individuals with European ancestry aged ≥70 years, used rs3798220-C carrier status and quintiles of an Lp(a) genomic risk score as a surrogate for Lp(a) concentration. In the total study population, aspirin reduced major adverse cardiovascular events (MACE) by 1.7 events per 1000 person-years but increased clinically significant bleeding by 1.7 events per 1000 person-years (no net benefit). However, in the rs3798220-C and high LPA-genomic risk score subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1000 person-years respectively, without significantly increased bleeding risk. From this analysis it might be concluded that aspirin may be considered for selected individuals in primary prevention with elevated Lp(a) concentration (>70–80 mg/dL) and no bleeding tendencies. However, before providing general advice for aspirin use, a randomized trial is needed to directly test whether aspirin given to people with high Lp(a) for primary prevention reduces ASCVD events sufficiently to justify the increased risk of bleeding in such patients, a side-effect that is well documented in many randomized trials in primary prevention patients.
6. Conclusions
Lp(a) has seen a resurgence of interest, largely driven by evidence from genetic studies for the causality of high Lp(a) concentration with ASCVD risk, which has prompted the development of drugs that specifically lower Lp(a). The 2022 Lp(a) consensus statement provides a clinical framework for personalizing the management of high Lp(a) levels to reduce ASCVD risk with available therapeutic strategies. Increasing knowledge about Lp(a) among healthcare professionals will be a high priority, so as to ensure optimal patient care within the framework of personalised medicine.
Author contributions
The panel was co-chaired by Florian Kronenberg (FK), Samia Mora (SM) and Erik S.G. Stroes (ESGS). All authors contributed to drafting the manuscript, which was reviewed and edited by the writing group, comprising FK, SM, ESGS, Alberico L. Catapano (ALC), Lale S. Tokgözoğlu (LST), Kausik K. Ray (KKR) and Jane K. Stock (JKS). A revised draft was reviewed by all members of the panel, and the final manuscript was approved by all authors before submission to the journal.
Declaration of competing interest
Potential conflicts of interest outside the submitted work are summarized below. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (KKR, LST, BG Nordestgaard [BGN]), Abcentra (M Koschinsky [MK]), Abdi-Ibrahim (LST), Actelion (LST), Aegerion (ALC, PM Moriarty [PMM]), Affiris AG (G Lambert [GL]), Akcea (ALC, BGN, KG Parhofer [KGP], ESGS), Amarin (ALC, PMM, BGN, KGP), Amgen (ALC, BA Ference [BAF], F Kronenberg [FK], F Mach [FM], PMM, P Natarajan [PN], BGN, KGP, KKR, ESGS, LST, GF Watts [GFW]), Amgen Germany (A von Eckardstein [AvE]), Amgen Switzerland (AvE), Amryt (ALC), Amundsen/Amgen (FM), Apple (PN), Arrowhead (GFW), Ayma Therapeutics (MK), AstraZeneca (ALC, PN, BGN, KKR, GFW), Bayer (LST), Berlin-Chemie (KGP), Boehringer-Ingelheim (KKR), Boston Scientific (PN), CiVi Pharma (BAF), Daiichi-Sankyo (ALC, BAF, FM, KGP, KKR, LST), Daiichi Switzerland (AvE), dalCOR (BAF), Denka (BGN), Eli Lilly (ALC, BAF, MK, KKR), Esperion (ALC, BAF, PMM, BGN, KKR, ESGS, GFW), FH Foundation (PMM), Foresite Labs (PN), Fresenius (FK), GB Life Sciences (PMM), Genentech (PN), Genzyme (ALC), Horizon/Novartis (FM, BGN), Ionis Pharmaceuticals (BA, ALC, BAF, BGN, MK, PMM), Jupiter Bioventures (MR Dweck [MRD]), Kaneka (FK, PMM), Kowa (ALC, BGN, KKR), KrKa Phama (BAF), Lupin (KKR), Menarini (ALC), Merck (ALC, BAF), MSD (KGP), Mylan (ALC, BAF, LST), New Amsterdam (KKR), Noetic Insights (MK), Novartis (B Arsenault [BA], ALC, MRD, BAF, FK, FM, CJ McNeal [CJMN], PMM, PN, BGN, KGP, KKR, ESGS, LST, GFW), Novartis Canada (MK), NovoNordisk (BAF, CJMN, BGN, KKR, ES, LST), Nyrada Inc (GL), Pfizer (BA, MRD, BAF, MK,SM, KKR, LST, GFW), Quest Diagnostics (SM), Recordati (ALC, LST), Regeneron (ALC, BAF, PMM, BGN, KKR, ESGS), Renew (PMM), Resverlogix (KKR), Sandoz (ALC), Sanofi (ALC, BAF, FM, BGN, KGP, KKR, ESGS, LST, GFW), Sanofi-Aventis Switzerland (AvE), Sanofi-Regeneron (GL, ESGS), Servier (LST), Sigma Tau (ALC), Silence Therapeutics (BA, MRD, BAF, BGN, KKR, GFW), The Medicines Co (BAF) and UltraGenyx (BGN). PN declares spousal employment at Vertex and KGP is a member of the Data Monitoring and Safety Board at Boehringer-Ingelheim. SSV declares an honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org), and grant funding from the U.S. Department of Veterans Affairs, National Institutes of Health, World Heart Federation, and Tahir and Jooma Family. Manuscripts have been published in collaboration with non-academic co-authors by PN and LST (Fitbit), GFW (Amgen), and BA (Pfizer). Equity interests including income from stocks, stock options, royalties, or from patents or copyrights were reported from AstraZeneca (JKS), Boston Scientific (L Berglund [LB]), Cargene Therapeutics (KKR), Gilead Sciences (LB), J & J (LB), GSK (JKS), Medtronic (LB), New Amsterdam Pharma (KKR), NovoNordisk (LB), Pemi31 Therapeutics (KKR), and Pfizer (LB).KKR is President of the European Atherosclerosis Society. LST is Past-President of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal.
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