Lipoprotein (a): An Update on a Marker of Residual Risk and Associated Clinical Manifestations

Abstract

Lipoprotein (a) [Lp(a)] is a low-density, cholesterol-containing lipoprotein that differs from other low-density lipoproteins due to the presence of apolipoprotein(a) bound to its surface apolipoprotein B100. Multiple epidemiologic studies, including Mendelian Randomization studies, have demonstrated that increasing Lp(a) levels are associated with increased risk of heart disease, including atherosclerotic cardiovascular disease and calcific aortic stenosis. The risk associated with elevations in Lp(a) appears to be independent of other lipid markers. While the current treatment options for elevated Lp(a) are limited, promising new therapies are under development, leading to renewed interest in Lp(a). This review provides an overview of the biology and epidemiology of Lp(a), available outcome studies, and insights into future therapies.

Introduction:

Despite advances in treatment of traditional risk factors for cardiovascular disease (CVD), many still remain with residual CVD risk despite optimal medical therapy¹.One such lipid biomarker that confers residual risk is lipoprotein (a) [Lp(a)], which has been associated with premature accelerated atherosclerosis, ischemic heart disease, and calcific aortic stenosis.^2-6. Lp(a) is further recognized in the 2018 ACC/AHA cholesterol guidelines as a risk enhancer ^7,8. While there is no available treatment for Lp(a) alone, multiple therapies directly targeting Lp(a) are currently being evaluated, raising the possibility for Lp(a) to become a modifiable risk factor.

The Molecular Structure of Lp(a):

Lp(a) is a cholesterol-containing low-density lipoprotein. Similar to a low density lipoprotein cholesterol (LDL-C) particle, Lp(a) particles each contain a single apolipoprotein B100 (apoB). Where Lp(a) particles differ from LDL-C particles is the presence of an apolipoprotein (a) (apo(a)) covalently bound by a single disulfide bond to the apoB molecule (Figure 1). Apo(a) evolved from the plasminogen gene⁹. Normally plasminogen is composed of five kringles (KI, KII, KIII, KIV, and KV) and a protease domain. However, apo(a) does not contain KI, KII, or KIII, but instead varying numbers of KIV, one copy of KV, and an inactive protease domain. Given the differing numbers of KIV repeats, there are several different isoforms of apo(a), and thus several different sizes of Lp(a) (> 40 different isoforms)^9,10. Importantly, each Lp(a) particle also contains a core of cholesterol ester and triglycerides, similar to a low density lipoprotein particle. Therefore, elevated levels of Lp(a) can falsely elevate measured plasma LDL-C levels since traditional clinically used assays cannot distinguish between Lp(a) bound LDL-C and free LDL-C^10-12. Other molecules inside the Lp(a) core include oxidized phospholipids (OxPL).

Figure 1: Structure of Lp(a):

Molecular structure of two Lp(a) isoforms showing apoB bound by a disulfide bond to isomer of apo(a) with varying levels of KIV repeats. ApoB-100= apolipoprotein B100; OxPL= Oxidized Phospholipid; FC= Free Cholesterol; PL= Phospholipid; KIV= Kringle 4

Though there is not general consensus, Lp(a) is believed to cause atherosclerotic disease either through pro-atherogenic, pro-inflammatory, and/or pro-thrombotic mechanisms. Due to the concentration of OxPL, its contribution to atherogenesis may be promoted by oxidative mechanisms and the effects of these mechanisms on macrophages after entry into the vessel wall^13,14. Additionally, apo(a) may have anti-fibrinolytic effects by antagonizing plasminogen-binding sites (given similar homology) and allowing more accumulation within the vascular endothelium⁷. The purported pro-thrombotic effect of Lp(a) needs further study, but is also felt to be mediated by inflammatory mechanisms¹⁵.

Measurement of Lp(a)

Currently there is no standardized assay used to measure serum or plasma Lp(a) levels. Immunochemical methods are the most common and can be divided into “mass dependent” or “mass independent” assays¹⁶. Mass independent assays employ antibodies that target non-repeating kringles of Lp(a) to measure the actual particle number¹⁶. These assays are reported in nanomoles per liter (nmol/L). Mass dependent assays compute the entire molecular content (proteins, lipids, carbohydrates, etc) of Lp(a) and expressed in the SI unit of milligrams per liter¹⁶. Routine clinical testing of these assays are reported in mg/dL. Mass dependent assays can be limited due to heterogeneity of the Lp(a) particle size (i.e overestimation in cases of large isoforms and underestimation in cases of small isoforms). Many laboratories use calibrators to help overcome this limitation and link the results to reference reagents⁷. However, the lack of standardization could result in confounding when comparing between various assays.

Genetics of Lp(a):

Approximately 90% of circulating Lp(a) levels are inherited and strongly determined by a single gene, the LPA gene¹⁷. As a result, unlike other traditional lipid measures, lifestyle changes have little impact on Lp(a) levels.^18,19 Furthermore, Lp(a) levels are fairly stable over time. The size of the molecule is determined by polymorphisms of apo(a) due to a variable number of kringle IV repeats in the LPA gene allowing for numerous variants of the molecule. The LPA gene is highly expressed in the liver and the regulation of its expression is not well understood. Some variants in the gene have higher plasma concentrations of plasma Lp(a) levels. These variations include splice site mutations, non-sense mutations, single nucleotide polymorphisms (SNPs), or other non-genetic factors influencing Lp(a) levels, such as kidney, thyroid, or liver diseases¹⁷. Genetic conditions such as familial hypercholesterolemia, familial defective apoB, abetalipoproteinaemia, variants of apolipoprotein E (APOE)and others also influence Lp(a) concentrations¹⁷.

Certain Lp(a) variants have been shown to be more associated with coronary artery disease and cardiovascular events. For example, in a European genome wide association study two variants within the LPA locus (rs10455872 and rs3798220) showed an odds ratios (OR) for coronary disease of 1.70 (95% CI 1.49-1.95) and 1.92 (95% CI 1.48-2.49), respectively²⁰. These variants were also associated with increased levels of circulating Lp(a). Moreover, there was a graded risk of coronary disease with the number of LPA gene variations²⁰. Similarly, in a multinational study of 63,746 cases of coronary artery disease and 130,681 controls, there was a genome wide significance within the LPA locus for CVD events ²¹. Interestingly, this genetic association was numerically more potent than those for LDLR and PCSK9²¹.

Furthermore, several Mendelian randomization (MR) studies have shown causal links between LPA gene variations and CVD^20,22,23,24. MR methods are designed to see if a genetic exposure causes an outcome and addresses concerns about confounding that typical observational studies are often limited by. While a better methodology to help determine causality is a randomized clinical trial, clinical trials can be very expensive and time consuming if incorporating large populations. MR studies overcome some of these limitations, by determining causality based on genetic data without barriers of a clinical trial.

Epidemiology of Lp(a):

Because Lp(a) is not routinely measured as part of the traditional lipid panel, estimates of the population distribution of Lp(a) remain less clear than for traditional lipid biomarkers. The epidemiology of Lp(a) has been studied in several large cohort studies^25-28. Other studies have evaluated the distribution of Lp(a) in convenience samples of those who have it measured in clinical practice, but are likely impacted by surveillance bias as healthy adults are less likely to have Lp(a) levels tested than those with a positive family history of cardiovascular disease^29,30. In the United States, data from tertiary care referral centers found that approximately 35-40% of patients had Lp(a) levels > 30 mg/dL, and 24-30% have levels > 50 mg/dL²⁵. Lp(a) levels have a similar distribution between men and women with approximately 20% in both groups having Lp(a) levels > 50 mg/dL³¹. Lp(a) levels can also vary by race: African Americans have been shown to have higher mean Lp(a) values when compared to Whites, Chinese, and Hispanics ³². It is currently not clear if race or gender significantly alters the clinical prognosis of elevated Lp(a), but certainly an area of future study.

Lp(a) has also been shown to be a risk modifier in patients with monogenic lipid disorders including heterozygous Familial Hypercholesterolemia (FH). Studies have found that in addition to LDL-C, FH patients have higher Lp(a) levels than non-FH patients^30,33. Since the Lp(a) molecule can overestimate free LDL-C levels, it is thought that elevated Lp(a) may explain certain phenotypes of FH that are gene negative. This observation was first seen in Spanish subjects where elevated Lp(a) accounted for up to 6% of autosomal dominant hypercholesterolemia in patients without a LDLR or apoB mutation³⁴. Furthermore, in a Danish study by Langsted et. al. the investigators found that elevated Lp(a) and LPA risk genotypes could account for a quarter of patients diagnosed with clinical FH⁶. However, Lp(a) also predicts CAD manifestations in patients with genetically proven FH. In a study that included two registries of patients with a genetic diagnosis of FH, patients with elevated Lp(a) were more likely to have a previous myocardial infarction (MI), stroke, or peripheral arterial disease (PAD) compared to those without elevated Lp(a)³⁵. Thus, screening for Lp(a) in patients with FH can help with further risk stratification, and identify an already high risk population that may warrant targeted Lp(a) therapy. In the United states, serum values for Lp(a) that are considered clinically to represent negligible risk for CVD is < 30 mg/dL (<75 nmol/L)^7,36. The European Atherosclerosis Society Guideline uses a threshold of 50 mg/dL to identify those at high risk. ⁷

Role of Lp(a) in Predicting Risk in Primary Prevention:

In one of the largest clinical studies to evaluate the impact of Lp(a) from Denmark, majority of a 40,486 patient population was free of ischemic heart disease. The investigators found that after a 16 year follow up there was a graded risk of MI across levels of Lp(a)²². Higher number of kringle IV repeats were also associated with lower Lp(a) values and less MIs, possibly suggesting that larger isoforms may be less pathogenic²². Similar results were found in a more recent, but smaller, prospective study from Greece ³⁷.

These findings in primary prevention have also been reproduced outside of Europe, both in Pakistan and in a large United States cohort from the Atherosclerosis Risk in Community (ARIC) study^{38, 39}. Moreover, subgroup analyses from ARIC have shown a ~41% higher risk of ischemic stroke after adjustment of lipid profiles in patients with Lp(a) > 50 mg/dL²⁶. Lp(a) has also been seen as a marker of risk in women free of disease from the Women’s Health Study where post-menopausal participants with hypercholesterolemia had a ~88% higher risk for 10 year first CVD event if Lp(a) was > 50 mg/dL⁴⁰.

Knowing that patients in a primary prevention setting with elevated Lp(a) are at risk, a question arises if this risk is potentially modulated by LDL-C levels. In a study combining two large primary prevention prospective cohorts investigators concluded that at LDL-C levels below 2.5 mmol/L (~97 mg/dL) the risk of elevated Lp(a) appeared to be attenuated, a finding not seen in secondary prevention studies⁴¹. Thus, the results suggest an importance of reducing LDL-C levels as much as possible in the primary prevention setting for a patient with elevated Lp(a), as Lp(a) can serve to re-classify risk. A summary of the noted primary prevention studies is seen in table 1.

Table 1:

Summary of Noted Primary Prevention Observational Studies of Lp(a) in CVD Risk Prediction

Author, year	Country	Size	Age (Years)	Gender (Male)	Population	Follow up	Main Outcome	Main Results
Kamstrup 2009	Denmark	40,486	58	48%	Danish	16 years	MI	Graded risk for MI with Elevated Lp(a)
Kouvari 2019	Greece	3,042	44	48%	Greek	10 years	MACE	Lp(a) > 50 mg/dL with high risk of MACE
Saleheen, 2017	Pakistan	17,644	54	80%	Pakistani	MR study	MI	Lp(a) concentration associated with MI risk
Agarwala, 2017	United States	14,154	55	45%	United States	23.4 years	MI,HF	Lp(a) levels were associated with incident MI related heart failure
Aronis 2017	United States	9,908	63	43%	United States	15 years (median)	Stroke	High Lp(a) was associated with a 42% relative increase in stroke risk
Cook 2018	United States	8158	54	0%	US	10 years	MACE	Direct linear relationship of Lp(a) with MACE
Verbeek 2018	Denmark and UK	26,102	59	45%	British and Danish	Minimum 5 years	MACE	Lp(a) ≥80th percentile were at increased CVD risk

• Major Adverse Cardiovascular Event (MACE): Non-fatal MI, Non-Fatal Stroke, CV death, Coronary Revascularization

• MI: Myocardial Infarction

• HF: Heart Failure

Role of Lp(a) in Predicting Risk in Secondary Prevention:

Analyses from clinical trials have also highlighted Lp(a) as a marker for residual cardiovascular risk in those with established cardiovascular disease. In the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) patients with LDL-C of 62.5 mg/dL, but with Lp(a) levels > ~50 mg/dL had a 89% higher risk of major adverse cardiovascular events (MACE ) than those with similar LDL-C but lower Lp(a)⁴². Similarly, in the LIPID trial (Long term Intervention with Pravastatin in Ischemic Disease) patients with an LDL-C of 112 mg/dL and Lp(a) > 73.7 mg/dL had a 21% higher chance of MACE⁴³. In the ACCELERATE trial (The assessment of the clinical effects of cholesteryl ester transfer protein inhibition with Evacetrapib in patients at high risk for vascular outcomes), increasing Lp(a) levels were associated with increasing risk of MACE even if LDL-C was < 80 mg/dL on optimal medical management⁴⁴.

Investigators also evaluated the impact of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab on Lp(a) in an optimally medically managed secondary prevention population from the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 inhibition in Subjects with Elevated Risk) trial⁴⁵. In the placebo arm, the highest quartile of Lp(a) (>165 nm/L ~>69 mg/dL) had the highest risk of MACE, independent of LDL-C⁴⁵. At 48 weeks, patients in the evolocumab arm had significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%), and had reduced events by 23% in those with baseline Lp(a) > median (37 nmol/L ~ 15mg/dL). Furthermore, patients with baseline Lp(a) greater than the median on evolocumab had a higher absolute risk reduction (ARR) and lower number needed to treat (NNT) compared to the those with levels less than the median (ARR 2.49%; NNT 41 vs ARR 0.95%; NNT 105)⁴⁵. Similar reductions in Lp(a) levels were also seen with alirocumab over 1.5 years from a pooled analysis of 10 phase 3 studies in the ODYSSEY program, as well as a reduction in MACE in post ACS patients^46,47. Thus, these findings further support the benefit of PCSK9 inhibition in patients with elevated Lp(a) and provide a rational to screen for Lp(a) in certain instances. A summary of noted secondary prevention studies is seen in table 2.

Table 2:

Summary of Noted Secondary Prevention Studies of Lp(a) in CVD Risk Prediction within Clinical Trial Populations

Author, year	Country	Size	Age (Year)	Gender (Male)	Study Type	Follow up	Main Outcome	Main Results
Albers 2013	United States and Canada	3,144	64	85%	Post Hoc Analysis	2 years	MACE	Lp(a) was predictive of MACE
Nestel 2013	Australia and New Zealand	7,863	62	83%	Post Hoc Analysis	6 years (median)	CV death	Baseline Lp(a) was associated with CV death
Lincoff 2017	Multi-National	12,092	65	77%	Post Hoc Analysis	2.3 years	MACE	Lp(a) in the highest quartile had higher events
O’Donoghue 2019	Multi-national	27,564	63	75%	Post Hoc Analysis	1 year	MACE	Lp(a) lowering with PCSK9i had reduced MACE
Gaudet 2017	Multi-national	4,915	62	60%	Post Hoc Analysis	1.5 years	Change in Lp(a)	Alirocumab resulted in 23-29% reductions in Lp(a)
Willeit 2018	Multi-national	29,069	62	72%	Meta-analysis	3 years (median)	MACE	Increase in MACE with high Lp(a) level on statin therapy

• Major Adverse Cardiovascular Event (MACE): Non-fatal MI, Non-Fatal Stroke, CV death, Coronary Revascularization

The Role of Lp(a) Beyond Coronary Disease:

Lp (a) and Peripheral Arterial Disease

While there are many commonalities amongst risk factors between atherosclerotic CAD and peripheral arterial disease (PAD), the underlying epidemiologic models are different. Interestingly, Lp(a) has also been linked to the development of PAD in several observational studies. In a study from the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) cohort, patients within the highest Lp(a) quartiles had an increased risk of developing PAD³. This association was also not modified by LDL-C level. Similarly, in the Scottish Heart Health Extended Cohort Lp(a) levels increased the 20 year risk of PAD and mortality ²⁷. In both registries the predictive value of Lp(a) was higher for PAD than CAD. Furthermore, in patients with established PAD, elevated Lp(a) has also been shown to be linked to limb amputations⁴⁸. However, large randomized clinical trials are needed to further understand Lp(a)’s impact on PAD outcomes.

Lp(a) and Stroke:

Lp(a) is also associated with the development of strokes. For instance in a large study of 36 prospective trials the authors found an adjusted risk ratio per 3.5 fold of Lp(a) concentration above normal limits of 1.10 (95% CI, 1.02-1.18)²⁴. Similarly, in a meta-analysis of 20 articles comprising of 90,904 subjects the pooled estimated odds ratio was 1.41 (95% CI, 1.26-1.57) for case-control studies⁴⁹. Interestingly, this finding was more pronounced in younger populations which is consistent with prior literature suggesting the risk of premature atherosclerosis across various vascular beds.

Lp(a) and Diabetes:

Diabetes Mellitus is also another well-known risk factor for CVD. However, the interaction between Lp(a) and diabetes is interesting and a topic of further investigation. A small number of studies have shown an inverse relationship between Lp(a) levels and onset diabetes based on the underlying genetic composition of Lp(a)^50,51. Yet, there is limited literature on whether patients with both elevated Lp(a) and diabetes have more or less CVD risk than those without diabetes. In a recent multi-centered prospective analysis of Chinese patients with stable CAD, the investigators found a higher event rate in those with elevated Lp(a) and impaired glucose regulation compared to normal glucose regulation⁵². Similar studies are needed in western populations since patients with diabetes and CAD may also be good candidates to consider Lp(a) screening.

Risk of Calcific Aortic Valve Disease Associated with Elevated Lp(a) Levels

Calcific aortic stenosis (AS) also shares traditional risk factors with atherosclerotic CAD, but with different underlying models of risk. In a genome wide association study to identify genetic variants associated with calcific AS, a SNP in the LPA locus reached genome wide significance (OR per allele, 2.05 (95% CI 1.63-2.57); p-9.0 x 10⁻¹⁰) and was significant across multiple ethnicities⁵. The investigators also performed a prospective analyses and found the LPA genotype was associated with a higher incidence of AS and aortic valve replacement over time⁵. In another MR study, based on a multivariable adjusted HR model the authors found a graded association based on the level of Lp(a) and AS similar to prior CVD studies ⁴. These results have also been replicated and further support causality of AS by Lp(a)⁵³.

The link between Lp(a) and AS can been seen in clinical trial cohorts as well. In a post hoc analysis from the Effects of Rosuvastatin on Aortic Stenosis Progression (ASTRONOMER) trial, investigators found that AS progression was linear and faster in patients with Lp(a) levels greater than 58.5 mg/dL, particularly patients who were less than 57 years of age^54,55. Interestingly, patients with AS progression also had elevated oxidized phospholipids on apoB-containing particles (OxPL-apoB) which could suggest a synergistic role with Lp(a) in the pathophysiology of calcific valve disease. An enzyme known as autotaxin has also been found to promote inflammation and mineralization of the aortic valve and is transported to the aortic valve by Lp(a)⁵⁶. In a recent study combing two prospective cohorts the investigators used multimodality imaging to assess valvular calcification activity by ¹⁸F-sodium fluoride (¹⁸F-NaF) positron emission tomography (PET), progression of calcification by computed tomography calcium scoring (CAC), and hemodynamic progression of AS by echocardiography in patients with both elevated Lp(a) and OxPL-apoB. The authors found both molecules were associated with AS, as well as its progression ⁵⁷.

Therapeutic Modification of Lp(a) Levels:

There are currently no approved medications that specifically target Lp(a). Genetic studies suggest that Lp(a) reductions of up to 100mg/dL may be needed to detect a benefit on cardiovascular events⁵⁸. Lifestyle changes are thought to have minimal effects since Lp(a) is genetically based^18,19. There is some evidence that plant based diets may reduce Lp(a), but further study is needed in larger populations⁵⁹. Statins also do not reduce Lp(a), and there is evidence to suggest they may actually increase Lp(a) levels by 10-20%^60,61. Niacin at doses ranging from 1-3g per day has been shown to reduce Lp(a) levels by about 30%, however, Niacin has not been shown to improve CVD outcomes⁴². Estrogen and progestin replacement therapy in postmenopausal women has also been shown to reduce Lp(a) levels by 15-20%, but these have not been tested in women with elevated Lp(a) to determine if CV events can be reduced⁶². In general, HRT has been shown to actually increase CVD risk in postmenopausal women in part due to rises in certain lipid parameters, prothrombotic effects, and inflammation⁶³. Mipomersen (anti-sense oligonucleotide targeting apoB) modestly drops Lp(a) levels by approximately 25%, but also with unknown clinical effect in patients with primarily elevated Lp(a)^64,65. PCSK9 inhibitors have modest reductions in Lp(a), with the most benefit seen in patients with higher absolute values⁴⁵.

A therapy that has shown the most clinical benefit thus far is Lp(a) apheresis with mean percent reductions up to 73%. One study of 120 patients with established coronary artery disease and a mean Lp(a) level of 4.21 μmol/L (4, 210 nmol/L; ~1,684 mg/dL) received apheresis for a mean duration of 5 years and had an 81% reduction in annual MACE (P < 0.0001)⁶⁶. Similarly another apheresis study with lower Lp(a) levels of 170 high risk patients with mean LDL-C of 99.0 mg/dL and Lp(a) of 104.9 mg/dL showed significant reductions in cardiovascular events 2 years post apheresis⁶⁷. It is important to note that the data from apheresis studies is non-randomized and largely observational⁶⁸. Lipoprotein apheresis is generally reserved for patients with extremely elevated lipoproteinemia despite medical therapy or homozygous FH.

Efforts are currently being made to medically target Lp(a). A particular interest has risen in anti-sense oligonucleotides (ASO) targeting apo(a) on the Lp(a) molecule. Randomized controlled trials using an ASO to apo(a) have shown much promise with 62-92% reductions in Lp(a) in a dose dependent fashion, and with effect reversal off-treatment⁶⁹. A summary of Lp(a) lowering therapies can be seen in table 3.

Table 3:

Impact of lipid lowering therapy on Lp(a). CETPi= cholesterylester transfer protein inhibitor; PCSK9= proprotein convertase subsilisin/kexin type 9; apo(a)= apolipoprotein (a)

Therapy	Percent Change in Lp(a)
Apo(a) Antisense Oligonucleotide	Reduces by 70-90%
Lipoprotein Apheresis	Reduces by 30-40%
Niacin	Reduces by 30%
PCSK9 inhibitor	Reduces by 20-30%
CETPi	Reduces by 25%
Mipomersen	Reduces by 25%
Statin	May increase by 10-20%

Future Directions:

As the evidence on Lp(a)’s impact on cardiovascular disease and calcific valvular disease continues to rise, efforts are focused on new pharmacotherapies targeting Lp(a). Large outcome trials of therapies dedicated to Lp(a) are on the horizon with the completion of the ASO phase 2 clinical trial⁷⁰. Furthermore, efforts should also be made to help providers identify patients and families who would benefit from Lp(a) screening and targeted therapy. With the current implantation of real world evidence platforms where data can be collected from multiple sources (electronic health records, claims and billing platforms, product registries, health applications, etc) more clinically relevant information will be available to help identify these at risk populations earlier and possibly broaden these guideline recommendations. Current societal screening recommendations are seen in table 4⁷¹.

Table 4:

Major Societal Guidelines on Lp(a) Screening

	Class	Level of Evidence
2018 ACC/AHA Cholesterol Guidelines
Screening Lp(a) in intermediate risk patients who are considering statin therapy	IIa	B-NR*
2019 European Society of Cardiology Cholesterol Guidelines
One time screening of Lp(a) in general to identify those at higher overall risk	IIa	C
2019 National Lipid Association72
First degree relatives with premature ASCVD (men <55; women <65 years of age)	IIa	C-LD**
A personal history of premature ASCVD	IIa	C-LD**
Suspected FH or primary severe hypercholesterolemia (LDL-C ≥ 190 mg/dL)	IIa	B-NR*
To aid in risk discussion for intermediate risk patients ages 40-75	IIa	B-NR*
Identify cause of less than expected LDL-C lowering	IIb	C-LD**
Use as cascade screening in family members with severe hypercholesterolemia	IIb	C-LD**
Identify risk of progressive aortic stenosis	IIb	C-LD**

^*Nonrandomized data

^**Limited data

Therefore, taking in all the available information, Lp(a) should be considered in (but not limited to) patients with intermediate ASCVD risk (7.5-19.9%), those with strong family histories, children of patients with elevated levels, personal history of ASCVD without traditional risk factors, patients with FH, patients with uncontrolled LDL-C on lipid lowering therapy, patients with poor statin response, or patients with recurrent events despite optimal therapy.

Conclusions:

In conclusion, Lp(a) is a cholesterol molecule that serves as a potent mediator of cardiovascular disease. Several types of studies have highlighted Lp(a) as a major risk factor for CVD, even in patients on optimal medical management. Increased awareness of Lp(a) is needed by all providers to better understand risk and for early referrals to specialized centers. Currently, there are only a few therapies that lower Lp(a), many with uncertain clinical benefit. However, clinical trials evaluating the role of ASOs targeting Lp(a) have shown promise for the future.