Genetics and Pathophysiological Mechanisms of Lipoprotein(a)‐Associated Cardiovascular Risk

Abstract

Elevated lipoprotein(a) is a genetically transmitted codominant trait that is an independent risk driver for cardiovascular disease. Lipoprotein(a) concentration is heavily influenced by genetic factors, including LPA kringle IV‐2 domain size, single‐nucleotide polymorphisms, and interleukin‐1 genotypes. Apolipoprotein(a) is encoded by the LPA gene and contains 10 subtypes with a variable number of copies of kringle ‐2, resulting in >40 different apolipoprotein(a) isoform sizes. Genetic loci beyond LPA, such as APOE and APOH, have been shown to impact lipoprotein(a) levels. Lipoprotein(a) concentrations are generally 5% to 10% higher in women than men, and there is up to a 3‐fold difference in median lipoprotein(a) concentrations between racial and ethnic populations. Nongenetic factors, including menopause, diet, and renal function, may also impact lipoprotein(a) concentration. Lipoprotein(a) levels are also influenced by inflammation since the LPA promoter contains an interleukin‐6 response element; interleukin‐6 released during the inflammatory response results in transient increases in plasma lipoprotein(a) levels. Screening can identify elevated lipoprotein(a) levels and facilitate intensive risk factor management. Several investigational, RNA‐targeted agents have shown promising lipoprotein(a)‐lowering effects in clinical studies, and large‐scale lipoprotein(a) testing will be fundamental to identifying eligible patients should these agents become available. Lipoprotein(a) testing requires routine, nonfasting blood draws, making it convenient for patients. Herein, we discuss the genetic determinants of lipoprotein(a) levels, explore the pathophysiological mechanisms underlying the association between lipoprotein(a) and cardiovascular disease, and provide practical guidance for lipoprotein(a) testing.

Nonstandard Abbreviations and Acronyms

ARIC

Atherosclerosis Risk in Communities

HCHS/SOL

Hispanic Community Health Study/Study of Latinos

LPA

lipoprotein(a) gene

Lp(a)HERITAGE

Lipoprotein(a) Levels in a Global Population With Established Atherosclerotic Cardiovascular Disease

MASALA

Mediators of Atherosclerosis in South Asians Living in America

MESA

Multi‐Ethnic Study of Atherosclerosis

OxPL

oxidized phospholipid

Cardiovascular disease (CVD) is the predominant cause of death globally, accounting for ≈30% of deaths each year. ¹ The prevalence of CVD among adults (aged ≥20 years) in the United States was 48.6% between 2017 and 2020, with an age‐adjusted death rate of 207.1 per 100 000 in 2020. ² Elevated lipoprotein(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is estimated to be present in ≈20% of the global population, translating to >1 billion people. ³ Plasma levels of lipoprotein(a) are largely genetically determined, with levels ranging from <0.1 mg/dL to >300 mg/dL or from 2.5 to 750 nmol/L. ⁴ Considerable variability in lipoprotein(a) levels is observed across individuals from different racial and ethnic backgrounds and between sexes, which may be influenced to some degree by nongenetic factors, such as menopause, hypogonadism, and chronic kidney disease. ⁵ , ⁶ , ⁷ , ⁸

This narrative review discusses the genetic determinants of plasma lipoprotein(a) levels and explores the factors that influence interindividual heterogeneity, including single‐nucleotide polymorphisms (SNPs). In addition, we will clarify the pathophysiological mechanisms underlying the association between lipoprotein(a) and CVD and provide guidance for lipoprotein(a) testing in clinical practice.

What Is LipoprResotein(a)?

Lipoprotein(a) is an apolipoprotein B–containing lipoprotein that comprises a single apolipoprotein B particle covalently bound to an apolipoprotein(a) molecule via a disulfide bond. ⁹ Although a complete understanding of the role of lipoprotein(a) in humans remains elusive, it is distinct from low‐density lipoprotein (LDL) and comprises a relatively small amount of the total plasma cholesterol in the LDL cholesterol (LDL‐C) pool (Figure 1). ¹⁰

Figure 1. Structure of lipoprotein(a) vs LDL.

apoB indicates apolipoprotein B; CE, cholesterol ester; FC, free cholesterol; KIV, kringle IV; LDL, low‐density lipoprotein; Lp(a), lipoprotein(a); OxPL, oxidized phospholipid; PL, phospholipid; SS, disulfide bond; and TG, triglyceride.

While efforts have been made to estimate the cholesterol content of lipoprotein(a) by a fixed percentage of measured lipoprotein(a) in mg/dL, data have shown that there is considerable variability in the amount of cholesterol contained within different lipoprotein(a) particles, which restricts the use of this approach in clinical practice. ¹¹ The structural components of lipoprotein(a) are associated with multiple pathological effects that will be discussed later in this review. In particular, lipoprotein(a) is the major carrier of oxidized phospholipids (OxPLs) in human plasma that can be identified in the lipid phase and/or covalently bound to apolipoprotein(a). ⁹ , ¹²

Apolipoprotein(a) is encoded by the lipoprotein(a) LPA gene, which is located on the long arm of chromosome 6 (6q27). ¹³ LPA is expressed almost exclusively in the liver, and covalent lipoprotein(a) assembly is postulated to occur extracellularly, possibly on the cell membrane or in the space of Disse (reviewed in Boffa and Koschinsky ¹⁴ ). The apolipoprotein(a) component of lipoprotein(a) evolved from duplication of the plasminogen gene during primate evolution and contains sequences similar to kringle 4 and 5 of plasminogen, with an inactive protease domain (Figure 2). ¹⁵ The kringle IV‐2 sequence in apolipoprotein(a) is present in a variable number of identically repeated copies ranging from 2 to >40; this gives rise to the characteristic isoform size variability of lipoprotein(a) in the population. ¹³

Figure 2. Evolution and structure of apo(a), effect of kringle IV‐2 CNV on apolipoprotein(a) molecular weight, and relationship with plasma lipoprotein(a) levels.

apo(a) indicates apolipoprotein(a); CNV, copy number variation; K, kringle; kDa, kilodalton; KIV, kringle IV; KV, kringle 5; Lp(a), lipoprotein(a); and P, protease.

Plasma lipoprotein(a) can be measured using assays that report in either mass (mg/dL) or molar (nmol/L) units; however, assays that report in nmol/L are preferred. ¹⁶ This is because measuring the number of lipoprotein(a) particles versus the mass reduces apolipoprotein(a) isoform size bias and is a more accurate indicator of lipoprotein(a) concentration and associated CVD risk. ¹⁶ At present, there are 2 recommended thresholds for lipoprotein(a) levels to classify CVD risk: Low risk is defined as <75 nmol/L, and high risk is defined as ≥125 nmol/L, with an area of intermediate risk between the 2 thresholds, known as the “gray zone” (75–125 nmol/L). ⁶ Due to substantial variation between assays, and heterogeneity in the kringle‐2 repeats in different alleles circulating within populations, converting between nmol/L and mg/dL is not recommended; however, the European Atherosclerosis Society suggest an interim conversion factor of 2 to 2.5× to provide guidance in interpreting data from clinical studies. ⁶ The units presented in this review reflect those reported for each study.

Lipoprotein(a) concentrations are generally 5% to 10% higher in women than men, ⁶ and there is up to a 3‐fold difference in median lipoprotein(a) concentrations between racial and ethnic groups. ¹⁵ Population data show that lipoprotein(a) levels are higher in Black men and women compared with White individuals; median lipoprotein(a) levels increase consecutively across Chinese, White, Hispanic, South Asian, and Black/African ancestry populations. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ The results of the ARIC (Atherosclerosis Risk in Communities) study also showed that median lipoprotein(a) levels were significantly higher in women versus men in both Black and White populations (Black individuals: 13.7 versus 11.9 mg/dL, respectively; P<0.0001; White individuals: 4.8 versus 3.9 mg/dL, respectively; P<0.0001). ²¹ In the MASALA (Mediators of Atherosclerosis in South Asians Living in America) cohort, median lipoprotein(a) levels in South Asian individuals were higher than in White, Hispanic, and Chinese individuals (17.0 mg/dL versus 12.9 mg/dL, 13.1 mg/dL and 12.9 mg/dL, respectively) but lower than in Black individuals (35.1 mg/dL) from the MESA (Multi‐Ethnic Study of Atherosclerosis) cohort. ¹⁷ Similarly, the Lp(a)HERITAGE (Lipoprotein[a] Levels in a Global Population With Established Atherosclerotic Cardiovascular Disease) study showed that in patients with ASCVD, Black individuals had median lipoprotein(a) levels that were significantly higher (≈3‐fold) than White, Hispanic, or Asian individuals (125.8 nmol/L versus 37.0 nmol/L, 34.5 nmol/L, and 37.2 nmol/L, respectively). ¹⁸

There can also be variation between individuals within an ethnic group depending on genetic ancestry, as observed among Hispanic/Latino individuals in the United States in the HCHS/SOL (Hispanic Community Health Study/Study of Latinos); median lipoprotein(a) ranged from 12 nmol/L in those with Mexican ancestry to 41 nmol/L in those with a Dominican background. ²² Further, from quintile 1 to quintile 5 of lipoprotein(a) levels, median West African genetic ancestry increased from 5.5% to 12.1%, while Native American ancestry decreased from 32.8% to 10.7%. ²² Regional variation in lipoprotein(a) levels has also been observed in European populations; lipoprotein(a) distribution was shown to exhibit a north–south gradient with lower lipoprotein(a) levels in northern European populations compared with central and southern European populations (median lipoprotein[a] concentration: 4.9 versus 7.9 and 10.9 mg/dL, respectively). ²³

Lipoprotein(a) and CVD Risk

Several analyses have shown a strong association between elevated serum lipoprotein(a) levels and increased risk of ASCVD, stroke, and coronary heart disease (CHD), ²⁴ , ²⁵ , ²⁶ , ²⁷ as well as calcific aortic valve stenosis. ²⁸ , ²⁹ , ³⁰ In addition, multiple studies, including Mendelian randomization analyses, have demonstrated a causal role for lipoprotein(a) in the development of ASCVD and calcific aortic valve stenosis. A landmark report in 1989 demonstrated that lipoprotein(a) contributes to plaque formation and CHD, with a strong positive correlation reported between serum lipoprotein(a) concentration and the extent of lipoprotein(a) deposition in atherosclerotic plaques in patients undergoing aortocoronary bypass surgery. ³¹ More recently, meta‐analyses of prospective observational studies have shown an increasing risk of myocardial infarction, CHD, and ischemic stroke proportional to increasing lipoprotein(a) levels. ³² , ³³ , ³⁴ In a 2019 combined analysis of 2 observational studies, there was a 1.5‐fold increased risk of CVD death and a 1.2‐fold increased risk of all‐cause death in patients with high (>93 mg/dL [199 nmol/L]) compared with low (<10 mg/dL [18 nmol/L]) lipoprotein(a) levels. ³⁵ Furthermore, recent Mendelian randomization analyses, genome‐wide association studies, and large meta‐analyses support elevated lipoprotein(a) as a causal risk factor for ASCVD death. ³⁶ , ³⁷ , ³⁸ , ³⁹

Lipoprotein(a) is thought to contribute to ASCVD through proinflammatory, prothrombotic, and/or other proatherogenic mechanisms. ³ , ⁹ Current evidence suggests that lipoprotein(a) is causal in the development of calcific aortic valve stenosis, likely through its proinflammatory properties. ³⁰ A 2022 study showed that lipoprotein(a) concentration was independently associated with baseline aortic valve calcium (odds ratio, 1.43 for each 50 mg/dL increase in lipoprotein[a]; 95% CI, 1.15–1.79) and new‐onset aortic valve calcium (odds ratio, 1.30 for each 50 mg/dL increase in lipoprotein[a]; 95% CI, 1.02–1.65). ³⁰

The concentration of OxPLs on apolipoprotein B‐100 particles is primarily represented by lipoprotein(a), which is the preferential carrier of OxPL in human plasma and is associated with increased CVD risk. ¹² OxPL–apolipoprotein B levels are directly correlated with lipoprotein(a) levels, and as such, the highest lipoprotein(a) levels are observed in Black individuals compared with White or Hispanic individuals. ⁴⁰ Results of the Copenhagen General Population Study also showed that OxPL–apolipoprotein B levels correlate with an increased risk of calcific aortic valve disease. ⁴¹ These findings were echoed in a 2023 publication from the Catheter Sampled Blood Archive in Cardiovascular Diseases study, which showed that both lipoprotein(a) and OxPL–apolipoprotein B are associated with multivessel coronary artery disease in patients undergoing coronary angiography. ⁴²

Elevated lipoprotein(a) may also be associated with residual CVD risk despite treatment with statins. An individualpatient data meta‐analysis of statin‐treated individuals showed that elevated baseline‐ and elevated on‐statin lipoprotein(a) were associated with an independent, approximately linear relationship with CVD risk. ²⁷ For baseline lipoprotein(a) levels, age‐ and sex‐adjusted hazard ratios (HRs) for CVD risk were 1.04 (95% CI, 0.91–1.18) for 15 mg/dL to <30 mg/dL, 1.11 (95% CI, 1.00–1.22) for 30 mg/dL to <50 mg/dL, and 1.31 (95% CI, 1.08–1.58) for ≥50 mg/dL (all versus <15 mg/dL). The respective HRs for on‐statin lipoprotein(a) levels were 0.94 (95% CI, 0.81–1.10), 1.06 (95% CI, 0.94–1.21), and 1.43 (95% CI, 1.15–1.76). ²⁷

While the CVD risk associated with elevated lipoprotein(a) levels in secondary prevention has been widely investigated, data supporting the predictive role of elevated lipoprotein(a) in the primary prevention setting are more limited. Nonetheless, data from the UK Biobank study showed that among individuals without baseline ASCVD, 6.1% (n=3290) of those with lipoprotein(a) ≥150 nmol/L had an incident ASCVD event compared with 4.3% (n=16 643) of those in the population with lipoprotein(a) <150 nmol/L (adjusted HR, 1.50 [95% CI, 1.44–1.56]), suggesting the potential for lipoprotein(a)‐lowering as a primary prevention strategy. ²⁶

Other Associations of Lipoprotein(a) With Pathophysiological Responses

Lipoprotein(a) has been identified as an acute phase reactant that is often raised in patients with sepsis as well as after surgery, myocardial infarction, and viral infections, including COVID‐19. ⁴³ , ⁴⁴ , ⁴⁵ Data show that lipoprotein(a) synthesis may be induced by innate immune system mediators, as raised lipoprotein(a) levels have been observed in patients with chronic inflammatory conditions such as rheumatoid arthritis and Crohn disease. ⁴⁴ The OxPLs found on lipoprotein(a) are oxidation‐specific epitopes, which are associated with the recruitment of lymphocytes to the arterial wall. ⁴⁶ , ⁴⁷ Therefore, elevated lipoprotein(a) may also trigger an adaptive immune response in atherosclerosis.

An inverse relationship between low plasma lipoprotein(a) and risk of prevalent and incident type 2 diabetes has been suggested, ⁶ , ⁴⁸ , ⁴⁹ , ⁵⁰ with some studies demonstrating that large apo(a) isoforms as opposed to low lipoprotein(a) levels per se may be causal in the development of type 2 diabetes. Mechanistic studies are needed to confirm the basis for this association. ⁵¹ The latest evidence for other metabolic associations with plasma lipoprotein(a) include data showing that raised levels may increase the risk of carotid plaques (defined as focal carotid thickening of >1.2 mm) in patients with fatty liver disease, ⁵² including those with diabetes (4‐fold higher risk) or impaired glucose metabolism (prediabetes; 2‐ to 2.7‐fold higher risk); however, possible effects of lipoprotein(a) on CVD risk were not evaluated in these studies. ⁵³ Data also showed that low plasma lipoprotein(a) may be associated with increased risk of fibrosis and cirrhosis in patients with fatty liver disease, ⁵² and that in patients with more advanced fatty liver disease (ie, steatohepatitis and fibrosis), lipoprotein(a) levels were lower compared with those with steatosis alone. ⁵⁴ Potential explanations for the latter association include dysfunctional lipoprotein(a) particle assembly in the liver, or diminished apolipoprotein(a) production.

Genetic Determinants of Plasma Lipoprotein(a) Levels

Genetic determinants of lipoprotein(a) levels are summarized in Figure 3. As discussed above, there is marked variation in measured plasma lipoprotein(a) across individuals from different racial and ethnic backgrounds, ²⁶ which can be explained largely by genetic variants within the LPA gene locus. ⁶

Figure 3. Genetic determinants of Lp(a) levels.

apo(a) indicates apolipoprotein(a); Lp(a), lipoprotein(a); and SNP, single‐nucleotide polymorphism.

The Kringle IV‐2 Domain and Apolipoprotein(a) Isoform Size

Most individuals (>80%) express 2 different apolipoprotein(a) isoforms, ⁹ 1 inherited from each parent, which contribute to lipoprotein(a) levels in a codominant manner. ⁹ , ¹⁵ The kringle IV‐2–encoding domain of each apolipoprotein(a) allele can include from 2 to >40 repeats, with each kringle IV‐2–encoding repeat being 5.6 kb in size, ¹⁵ , ⁵⁵ , ⁵⁶ and a general inverse correlation has been observed between apolipoprotein(a) isoform size and plasma lipoprotein(a) levels, whereby smaller isoform sizes are associated with higher levels. ¹³ Median lipoprotein(a) concentrations are 4 to 5 times higher in individuals with small apolipoprotein(a) isoforms (<22 kringle IV repeats) than those with only large isoforms (≥22 kringle IV repeats) (Figure 2). ⁶ However, as previously discussed, the contribution of apo(a) isoform size to observed plasma lipoprotein(a) levels varies by up to 80% among individuals from different racial and ethnic backgrounds. ⁵⁷ The strength of the inverse correlation between isoform size and concentration appears stronger in European and Asian individuals compared with those of African descent. ¹⁵ Population studies suggest that 61% to 69% versus 19% to 44% of the variance in lipoprotein(a) levels can be explained by the inverse correlation with apolipoprotein(a) isoform size in individuals of European descent versus African descent, respectively. ¹⁵ Larger apolipoprotein(a) isoforms are less likely to be expressed in individuals of European descent compared with those of African descent, with SNPs thought to play a significant but varying role on lipoprotein(a) levels depending on race and ethnicity (Table 1). ⁵⁷ For instance, an LPA SNP associated with small apolipoprotein(a) isoforms, which may account for ≈8% of lipoprotein(a) variance, was found to be more prevalent in Hispanic individuals (42.4%) versus White and Black individuals (4.3% and 1.5%), respectively. ⁵⁸ Moreover, variability in lipoprotein(a) levels is associated with polymorphisms that span the length of the LPA gene, including the promoter region, the coding sequence, and several introns. ⁵⁹ In Europeans, polymorphisms that lead to the suppression of lipoprotein(a) assembly are more common, while in individuals of African descent, genetic alterations increasing apolipoprotein(a) promoter activity are more frequent, potentially explaining higher lipoprotein(a) concentrations in this population (Table 1). ⁵⁷

Table 1.

Impact on lipoprotein(a) Levels of SNPs With Known Variation Between Races and Ethnicities ⁶ , ⁵⁸ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴

	Effect on lipoprotein(a) levels	Association with race and ethnicity
lipoprotein(a) increasing
rs10455872 (intronic polymorphism)	≈30 mg/dL increase in lipoprotein(a) Explains ≈25% of lipoprotein(a) variance	Most common in White individuals (14.3%), less common in Hispanic (5.5%) and Black populations (1.8%)
rs3798220 (I4339M mutation in the protease‐like domain)	A rare variant associated with small apolipoprotein(a) isoforms Explains ≈8% of lipoprotein(a) variance ≈45 mg/dL increase in lipoprotein(a) levels	Most common in Hispanic individuals (42.4%), less common in White individuals (4.3%), and rare in Black individuals (1.5%) Moderately frequent in South Asian populations (≈12%)
Lipoprotein(a) lowering
rs143431368	Splice site mutation ≈9 mg/dL decrease in lipoprotein(a) levels	10× more frequent in people of Finnish descent (≈5%) compared with non‐Finnish Europeans
rs41272114 (G+1/in kringle IV‐8A)	LOF mutation 5–17 mg/dL decrease in lipoprotein(a) levels	Most frequent LOF mutation in White individuals, accounting for ≈25% of all null alleles Frequencies range from ≈0% to 18% between populations: 0.7% in African American individuals and 4.7% in European American individuals; 3% in European populations (PROCARDIS cohort); 18% in Peruvians
rs41272110 (T3888P)	Early studies suggest lipoprotein(a)‐lowering effect	Identified in European American (14.3%), African American (2.4%), White (26.7%), Black (4.5%), and Hispanic (17.4%) individuals
4925G>A	Splice variant The second strongest influence on lipoprotein(a) concentrations after apolipoprotein(a) isoform size ~≈31 mg/dL decrease in lipoprotein(a) levels	Common in White European individuals (22%)
4733G>A	The third strongest influence on lipoprotein(a) concentrations after isoform size ≈14 mg/dL decrease in lipoprotein(a) levels	Common in White European individuals (35.1%) and Latin‐American populations (26.3%) Rarer in South Asian (5.2%) and Black (1.5%) individuals and undetectable in East Asian populations

LOF indicates loss‐of‐function; PROCARDIS, precocious coronary artery disease; and SNP, single‐nucleotide polymorphism.

It is well documented that lipoprotein(a) levels are largely controlled at the stage of biosynthesis rather than the catabolism of the particle. ¹⁴ As such, a potential mechanism to explain the inverse association between apolipoprotein(a) isoform size and lipoprotein(a) concentration is based on decreased residency time of smaller apolipoprotein(a) isoforms in the endoplasmic reticulum, which results in decreased susceptibility to endoplasmic reticulum–associated degradation and more efficient maturation of smaller apolipoprotein(a) proteins. ⁶ This correlates with increased hepatic secretion of smaller apolipoprotein(a) isoforms and higher susceptibility of larger apolipoprotein(a) proteins to endoplasmic reticulum–associated degradation, resulting in reduced secretion of larger apolipoprotein(a) isoforms. ⁶

LPA Gene: Polymorphisms and Splicing

Recently, it has been shown that there are complex relationships between the genetic factors affecting lipoprotein(a) levels. This includes, for example, that modulation of the contribution of allele size to lipoprotein(a) levels is modified by many functional SNPs over the entire range of LPA allele frequencies, as well as interactions of SNPs with other SNPs and with short tandem repeats. ⁶⁰ SNPs known to impact phenotypic lipoprotein(a) levels are summarized in Table 1. ⁶ , ⁵⁸ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴

Several loss‐of‐function SNPs have been identified within the LPA gene locus, such as the null alleles rs41272114 and rs143431368, which are caused by splice site mutations and have been shown to decrease lipoprotein(a) levels by 5 to 17 mg/dL and 8.77 mg/dL, respectively. ⁶⁰ , ⁶¹ SNPs that have a substantial impact on lipoprotein(a) levels include rs10455872 (located within the intron near the kringle IV‐7 domain) and rs3798220 (located within the protease domain), which are associated with small apolipoprotein(a) isoforms and high lipoprotein(a) levels (136–138 nmol/L). ⁶ The rs10455872 SNP explains ≈25% of lipoprotein(a) variance and is associated with an ≈30 mg/dL increase in lipoprotein(a) levels. In comparison, ≈8% of lipoprotein(a) variance is attributed to rs3798220, which confers an ≈45 mg/dL increase in lipoprotein(a) levels. ⁶⁰

As mentioned above, there are significant differences in the frequency of LPA SNPs between racial and ethnic groups. ⁵⁸ Genotyping analysis of 3400 patients in the Dallas Heart Study showed that rs10455872 was found most frequently in White individuals (14.3%) and rs3798220 was most commonly identified among Hispanic individuals (42.4%); however, both SNPs were rare in Black individuals (1.8% and 1.5% for rs10455872 and rs3798220, respectively). ⁵⁸ Notable SNPs that contribute to the difference between lipoprotein(a) levels in White and Black individuals include the lipoprotein(a)‐lowering T3888P and G+1/in kringle IV‐8A SNPs, both of which decrease lipoprotein(a) assembly and are more common in White people. In addition, G‐21A increases apolipoprotein(a) promoter activity and lipoprotein(a) levels and is more common in Black individuals. ⁶²

Short tandem repeats, including the pentanucleotide sequence (TTTTA) repeat polymorphism, have also been demonstrated to influence lipoprotein(a) levels. ¹⁵ The TTTTA repeat is found in the promoter region of LPA and may explain 3% to 14% of the variability in lipoprotein(a) levels in Europeans. ¹⁵ Alleles with fewer pentanucleotide repeats have been associated with elevated lipoprotein(a) in Europeans but not in individuals of African descent. ⁶⁵

The latest evidence suggests that LPA gene splicing affects lipoprotein(a) concentration. The splice variant 4925 G>A is associated with low‐molecular‐weight apolipoprotein(a) isoforms and has been shown to decrease lipoprotein(a) levels by ≈31 mg/dL and have relatively high carrier frequency (22%) in European individuals. ⁵⁵ Similarly, the 4733 G>A variant reduces lipoprotein(a) levels by ≈14 mg/dL. It is frequently found in European (35.1%) and Latin American (26.3%) individuals but less often in South Asian (5.2%) and rarely in Black (1.5%) individuals. ⁶⁴ Both 4925 G>A and 4733 G>A have been associated with lower cardiovascular risk. ⁵⁵ , ⁶⁴ They are the second and third strongest relative contributors to lipoprotein(a) concentration, respectively, after isoform size. ⁶

Importantly, LPA variants may impact the effectiveness of certain treatments in patients with CVD. Interestingly, a genome‐wide association study identified 7 SNPs within the LPA locus that were associated with CHD events during statin therapy, including rs10455872, which persisted in individuals with LDL‐C levels ≤70 mg/dL. ⁶⁶ Recent evidence suggests that aspirin treatment in carriers of rs3798220, which is associated with high lipoprotein(a) levels (136–138 nmol/L), ⁶⁰ may decrease the risk of CVD events compared with nonusers of aspirin. ⁶⁷ However, additional studies are needed to investigate further the mechanisms underlying the potential beneficial effects of aspirin use in carriers of rs3798220. A study of potential genetic loci that might impact the lipoprotein(a)‐lowering effects of niacin, a lipid‐modulating drug with an unknown mechanism of action, was also conducted; however, no relevant loci were identified. ⁶⁸ Another study looked at the impact of apolipoprotein(a) isoform size on the efficacy of niacin–laropiprant in patients treated with statins. The results showed that in the overall population (N=3978; UK [n=2277], China [n=1701]), niacin–laropiprant therapy led to a mean lipoprotein(a) reduction of 31%, which decreased to 18% in patients with baseline lipoprotein(a) levels ≥128 nmol/L and small apolipoprotein(a) isoforms (n=797), indicating that proportional reductions in lipoprotein(a) levels may be dependent on apolipoprotein(a) isoform size in patients treated with niacin. ⁶⁹

Genetic Factors Beyond the LPA Locus

Beyond the LPA gene, genome‐wide association studies have identified significant associations between lipoprotein(a) and 3 other loci. The APOE2‐determining allele rs7412 was found to be associated with lipoprotein(a) levels, with each allele decreasing lipoprotein(a) by 3.34 mg/dL. ⁷⁰ A second, synonymous APOE SNP, rs769455, specific to populations of African descent, was reported to be nominally associated with lipoprotein(a) concentration, independent of rs7412. ⁷¹ A 2021 UK Biobank study of White individuals reported that the APOE SNP, rs1065853, was associated with decreased lipoprotein(a) levels (β [95% CI] (ln nmol/L), −0.11 [−0.12 to −0.10]). ⁷² The same study in White individuals identified an SNP upstream of the CETP gene on chromosome 16 (rs247617) and an SNP in the APOH gene on chromosome 17 (rs8178824) that were associated with decreased and increased levels of lipoprotein(a), respectively. ⁷²

CVD risk has been associated with interleukin‐1 genotypes in individuals with elevated lipoprotein(a). ⁷³ , ⁷⁴ The 2018 Ioannina Study evaluated the modulatory effect of the interleukin‐1 genotype on lipoprotein(a)‐mediated CVD risk in southern European patients undergoing angiography. ⁷³ In this study, the composite genotype termed interleukin‐1(+) was defined by the presence of 3 SNPs (rs16944, rs1143634, and rs17561) in the interleukin‐1 gene cluster that is associated with high levels of proinflammatory cytokines; all other interleukin‐1 genotypes were termed interleukin‐1(−). The results showed that patients with lipoprotein(a) >9.2 mg/dL and a proinflammatory interleukin‐1(+) genotype were at significantly greater risk of experiencing a major CVD event compared with patients with an interleukin‐1(−) genotype and lipoprotein(a) levels <9.2 mg/dL (event‐free cumulative survival: HR, 3.59 [95% CI, 1.07–12.03]; P=0.039). ⁷³ An earlier study on the association between the interleukin‐1(+) genotype and the risk of coronary artery disease in a predominantly (>97%) White population showed that among interleukin‐1(+) patients, the highest quartile of OxPL–apolipoprotein B was significantly associated with a higher risk of coronary artery disease compared with the lowest quartile (odds ratio, 2.84; P=0.001), while no association with coronary artery disease was identified in patients with interleukin‐1(−). ⁷⁴

Hepatic LPA expression is directly associated with plasma lipoprotein(a) levels. ⁵² In vivo correlation analysis of hepatic LPA gene expression showed significant associations with several interleukin‐6 acute phase response genes, indicating a relationship between interleukin‐6 activity and LPA expression in the human liver ⁴⁴ ; this is postulated to be mediated by an interleukin‐6 responsive element in the LPA promoter region.

Nongenetic Determinants of Plasma Lipoprotein(a) Levels

Several nongenetic factors may influence lipoprotein(a) levels, including hormone therapy and kidney disease. ⁷⁵ , ⁷⁶ , ⁷⁷ Treatment of overt hyperthyroidism with thyroidectomy, antithyroid drugs, or radioactive iodine was recently shown to increase lipoprotein(a) levels by a mean of 4.18 mg/dL (95% CI, 1.65–6.71), whereas treatment of overt hypothyroidism with levothyroxine decreased lipoprotein(a) levels by a mean of −5.6 mg/dL (95% CI, −9.06 to −2.14). ⁷⁸ In addition, data from a randomized controlled trial showed that treatment of patients with hypercholesterolemia with the liver‐selective thyroid hormone receptor agonist eprotirome significantly reduced lipoprotein(a) levels at week 12 versus baseline compared with placebo (absolute change in median lipoprotein(a)) concentration for 200 μg eprotirome versus placebo: −10 versus −86 (mg L⁻¹; P<0.001). ⁷⁹ These data suggest that treatment with liver‐selective thyromimetics could be further explored as a targeted lipoprotein(a)‐lowering strategy. Elevated lipoprotein(a) levels have been reported in hypogonadal men; a trend for significant lipoprotein(a) elevation (≥3 times the upper limit of normal) was observed in men with low serum testosterone, defined as <15 nmol/L. ⁸ Previously published data suggest that exogenous androgens may reduce lipoprotein(a) concentration. ⁷⁶ In contrast, a study from 2022 found that lipoprotein(a) levels increased following the administration of human growth hormone. ⁷⁷

Several studies have reported that reduced estrogen in postmenopausal women resulted in elevated lipoprotein(a) (up to 13% higher than in premenopausal women), ⁷⁵ which can be reversed by treatment with hormone replacement therapy. ⁸⁰ , ⁸¹ The increase in lipoprotein(a) observed in postmenopausal women may be explained by the effect of estrogen as a negative regulator of LPA, given that an estrogen response element was identified 26 kb upstream of the apolipoprotein(a) promoter. ⁷⁵ In postmenopausal women with elevated lipoprotein(a), hormone replacement therapy with estrogen significantly lowered lipoprotein(a) levels compared with placebo (−5.8 mg/dL versus 0.3 mg/dL; P<0.001), which was associated with decreased risk for myocardial infarction (relative HR, 0.46 [95% CI, 0.25–0.85]). ⁸¹ Despite these findings, the results of the Heart and Estrogen/Progestin Replacement Study showed that after 6 years, hormone replacement therapy did not continue to reduce the risk of CVD events in women with CHD. Accordingly, it was concluded that hormone replacement therapy should not be used to reduce the risk of CVD events in postmenopausal women with CHD. ⁸²

Findings from randomized crossover studies have suggested that reduction of saturated fatty acid intake may increase lipoprotein(a) levels. ⁸³ , ⁸⁴ A recent observational study also found that lipoprotein(a) concentration was negatively correlated with absolute intake of dietary saturated fatty acids (R=−0.43, P=0.02). ⁸⁵ With regard to the impact of physical activity on lipoprotein(a) in both healthy individuals and those with CVD risk factors, more robust evidence is needed to establish any association firmly; data so far suggest that physical activity has either no or marginal impact on lipoprotein(a) levels. ⁷⁷

Finally, there is evidence that decreased kidney function can influence plasma lipoprotein(a) levels and that chronic kidney disease is associated with elevated lipoprotein(a) partly due to reduced catabolism, which is postulated to occur in the kidney. ⁷ Patients with end‐stage kidney disease undergoing hemodialysis were shown to have increased lipoprotein(a) levels compared with healthy controls, and patients on regular hemodialysis had lipoprotein(a) levels 5 to 10 times higher than patients with stage 1 to 2 chronic kidney disease. ⁸⁶ High levels of lipoprotein(a) observed in patients undergoing hemodialysis are likely due to decreased clearance rather than increased lipoprotein(a) production. ⁷ However, in the 2023 Chronic Renal Insufficiency Cohort Study, lipoprotein(a) was not associated with increased CVD risk, suggesting that other factors may be more important in patients with end‐stage renal disease. ⁸⁷

How Does Lipoprotein(a) Contribute to Disease?

Lipoprotein(a) is associated with the formation of atherosclerotic plaques, prothrombotic effects, and proinflammatory mechanisms. ⁸⁸ Based on the latest data, it is thought that the proinflammatory and prothrombotic effects of lipoprotein(a) may work in tandem to promote plaque destabilization, plaque rupture, and subsequent CVD events. ⁸⁹

Covalent binding of OxPL to apolipoprotein(a), which is dependent on the strong lysine binding site in kringle IV‐10, mediates the critical proatherogenic and proinflammatory properties of lipoprotein(a). ⁸⁹ OxPLs have been associated with lipoprotein(a) deposition, particularly in vulnerable and ruptured plaques, and with inflammation in the arterial wall and the aortic valve leaflet, leading to atherosclerosis and calcific aortic valve disease, respectively. ⁸⁹ In addition, OxPLs may mediate monocyte activation, which contributes to the proinflammatory phenotype observed in ASCVD. ⁸⁹ , ⁹⁰ One study showed that monocytes isolated from individuals with elevated lipoprotein(a) levels (≥50 mg/dL) were more adhesive and had greater migratory capacity than monocytes from individuals with lower lipoprotein(a) levels (<50 mg/dL). ⁹⁰ Furthermore, lipoprotein(a) elicits a program of procalcific gene expression in valve interstitial cells while also transporting autotaxin into the aortic valve leaflet, leading to the generation of additional pro‐osteogenic species that promote calcification. ⁸⁹ , ⁹¹

Lipoprotein(a) and Thrombosis

Based on recent data, there are several hypotheses regarding the role of lipoprotein(a) in thrombosis, including the initiation of coagulation and the development of rupture‐prone plaques. ⁹² Lipoprotein(a) may accelerate coagulation through various mechanisms, including increased tissue factor expression on monocytes and binding to/inactivation of tissue factor pathway inhibitor via the apolipoprotein(a) moiety. ⁹² , ⁹³ A potential role for lipoprotein(a) in platelet aggregation has also been explored; however, studies have provided conflicting results overall. ⁹² Recent results from a subanalysis of the Aspirin in Reducing Events in the Elderly trial showed that patients with rs3798220‐C carrier status (n=406), which is associated with elevated lipoprotein(a) levels compared with noncarriers, derived greater benefit from aspirin in terms of major adverse cardiovascular event reduction compared with the whole population of genotyped participants (N=12 815) (event reduction: 11.4 versus 1.7 per 1000 person‐years, respectively). ⁶⁷ Since aspirin is a potent inhibitor of platelet activity, these results suggest a role for lipoprotein(a) in platelet function.

Studies on the role of lipoprotein(a) in the formation of venous thromboembolism have been largely negative, and further investigation on the potential association between lipoprotein(a) and arterial thrombosis is required. ⁴⁵

A study from 2019 questioned the extent to which lipoprotein(a) itself can inhibit fibrinolysis since neither ex vivo clot lysis time nor coagulation/fibrinolysis‐related biomarkers showed significant alterations following lipoprotein(a) lowering by antisense oligonucleotides targeting LPA mRNA. ⁹⁴ Based on these data, it has recently been suggested that lipoprotein(a) lowering does not impact fibrinolysis. ⁹²

Lipoprotein(a) and Inflammation

The association between lipoprotein(a), inflammation, and associated CVD risk is an area of ongoing investigation. Lipoprotein(a) activates monocytes in the arterial wall via the secretion of proinflammatory markers and the upregulation of chemoattractants, cytokines, and adhesion molecules. In turn, these factors may contribute to inflammation, resulting in greater endothelial permeability. In addition, lipoprotein(a) is associated with acute and chronic inflammatory diseases such as COVID‐19, chronic kidney disease, and rheumatoid arthritis. ⁹⁵ Since the LPA promoter contains interleukin‐6 response elements, interleukin‐6 release is thought to be directly associated with elevations in lipoprotein(a) levels. ⁹⁵ , ⁹⁶ lipoprotein(a) levels were shown to significantly increase by almost 3‐fold during the first 3 weeks after hospital admission for COVID‐19 following increases in interleukin‐6 (mean lipoprotein[a] before admission 10.1 mg/dL versus 27.0 mg/dL 3 weeks later; P<0.001; N=219). ⁹⁷ The same study also showed that elevated lipoprotein(a) was significantly correlated with increased interleukin‐6 levels (r=0.44 [95% CI, 0.30–0.56]; P<0.001). ⁹⁷

Recent studies have evaluated the association between systemic inflammation and lipoprotein(a)‐associated ASCVD risk. ⁹⁸ , ⁹⁹ Data from the MESA cohort showed that individuals with concomitant elevations of lipoprotein(a) and hs‐CRP (high‐sensitivity C‐reactive protein) are at greater risk of ASCVD compared with an elevation of either protein alone; hs‐CRP ≥2 mg/L was associated with significant CVD risk in patients with lipoprotein(a) levels of 50–99.9 mg/dL (HR, 1.36 [95% CI, 1.02–1.81]; P<0.03) and lipoprotein(a) ≥100 mg/dL (HR, 2.09 [95% CI, 1.40–3.13]; P<0.001). ⁹⁹ In 2023, a study of 6495 patients in MESA with no history of CVD showed that high lipoprotein(a) (≥75th percentile of the distribution) is a risk factor for incident CHD in adults with high factor VIII or high hs‐CRP. ¹⁰⁰

Similarly, a recent secondary analysis of the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes trial of patients at high risk for CVD showed that each unit increase in log lipoprotein(a) levels were associated with a 13% increased risk of cardiovascular death, nonfatal myocardial infarction, or stroke in patients with hs‐CRP levels ≥2 mg/L (P=0.008). ⁹⁸ On the other hand, a 2022 large prospective cohort study of individuals from the Copenhagen General Population Study found that the relationship between lipoprotein(a) and ASCVD/calcific aortic valve disease outcomes was independent of hs‐CRP levels. ¹⁰¹

Guidance for the Use of Lipoprotein(a) in Clinical Practice

Lipoprotein(a): Clinical Considerations for Diagnosis and Testing

Testing for elevated lipoprotein(a) is not routinely performed in clinical practice despite recommendations from numerous medical societies for cascade screening in people with a family history of premature ASCVD and/or elevated lipoprotein(a) (Table 2). ⁶ , ¹¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ In a 2022 Scientific Statement, the American Heart Association recommended testing lipoprotein(a) in individuals with a family/personal history of ASCVD. It proposed that once standardization of lipoprotein(a) assays is achieved, a reassessment of broader population‐based screening should be considered. ¹¹ Furthermore, the Canadian Cardiovascular Society and the European Atherosclerosis Society advise lipoprotein(a) testing at least once in all adults, irrespective of family history. ⁶ , ¹⁰⁴ The success of cascade screening for identifying affected family members has already been demonstrated in familial hypercholesterolemia and has been shown to be cost‐effective. ¹⁰⁹ , ¹¹⁰

Table 2.

Recommendations for lipoprotein(a) Testing ⁶ , ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁷ , ¹⁰⁸

Organization	Year	Recommendations
AHA	2022	Test lipoprotein(a) in individuals with a family or personal history of ASCVD and consider cascade testing in appropriate individuals International standards for measurement of lipoprotein(a) must be established to allow consistent measurement. When standardization is achieved, reassessment of general population–based screening should be considered
AACE/ACE	2020	Lipoprotein(a) should be tested in the following populations: All individuals with clinical ASCVD or a family history of premature ASCVD and/or elevated lipoprotein(a) People with South Asian or African ancestry Individuals with a 10‐year ASCVD risk ≥10% (primary prevention) People with a personal or family history of AVS or those with refractory elevations of LDL‐C levels despite treatment with aggressive LDL‐C‐lowering therapy
AHA/ACC/multisociety	2018	Lipoprotein(a) should be tested in patients with a family history of premature ASCVD
CCS	2021	Lipoprotein(a) should be tested once in a person's lifetime as a part of initial lipid screening
EAS	2022	Test lipoprotein(a) concentration at least once in adults Cascade screening may be valuable in patients with either FH, premature ASCVD, or a history of very high or high lipoprotein(a)
ESC/EAS	2019	A single lipoprotein(a) measurement may help to identify individuals with very high inherited lipoprotein(a) levels who may have a substantial lifetime risk of ASCVD
HEART UK	2019	Serum lipoprotein(a) levels should be measured in individuals with: A personal or family history of premature ASCVD (aged <60 y) First‐degree relatives with raised serum lipoprotein(a) (>200 nmol/L) Calcific aortic valve stenosis FH or other genetic dyslipidemias Borderline increased (<15%) 10‐y risk of a cardiovascular event
NLA	2019	Lipoprotein(a) testing may be useful to refine risk assessment for ASCVD events in adults with: First‐degree relatives with premature ASCVD (aged <55 y in men; aged <65 y in women) Primary severe hypercholesterolemia (LDL‐C ≥ 190 mg/dL) or suspected FH A personal history of premature ASCVD Lipoprotein(a) testing may be reasonable in adults: To aid in the clinician–patient discussion on whether to prescribe a statin in patients aged 40 to 75 y with borderline (5%–7.4%) 10‐year ASCVD risk To identify people at risk for progressive AVS To identify a possible cause for a less‐than‐anticipated LDL‐C lowering to evidence‐based LDL‐C–lowering therapy To use in cascade screening of family members with severe hypercholesterolemia Lipoprotein(a) testing may be reasonable in young people (aged <20 y) with: Clinically suspected or genetically confirmed FH A family history of first‐degree relatives with premature ASCVD (<55 years of age in men; <65 years of age in women) An unknown cause of ischemic stroke A parent or sibling found to have an elevated lipoprotein(a)

AACE indicates American Association of Clinical Endocrinologists; ACC, American College of Cardiology; ACE, American College of Endocrinology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; AVS, aortic valve stenosis; CCS, Canadian Cardiovascular Society; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; FH, familial hypercholesterolemia; LDL‐C, low‐density lipoprotein cholesterol; and NLA, National Lipid Association.

Practically, current lipoprotein(a) testing requires only routine, nonfasting blood draws, ¹¹¹ making it convenient for patients and health care professionals. While plasma lipoprotein(a) levels can be measured in nmol/L or mg/dL, ⁶ intensive CVD risk factor management should be recommended for all individuals with elevated lipoprotein(a) (high risk is defined as ≥50 mg/dL [>125 nmol/L]). ⁶ , ³⁰ The benefits of lipoprotein(a) testing include improved CVD risk stratification by proactively identifying individuals at ASCVD risk and reclassifying risk in patients with clinical ASCVD. ⁶ From a healthcare system perspective, early and intensive CVD risk factor management in individuals with elevated lipoprotein(a) may lead to significant long‐term cost savings. ¹

Lipoprotein(a)‐Associated CVD Risk Thresholds

While lipoprotein(a) levels vary among individuals from different racial and ethnic backgrounds, recent data suggest that the predictive value of lipoprotein(a) may not differ to the degree that warrants a need for race‐specific thresholds in clinical decision making ¹¹² ; however, further investigation is warranted. Regarding the impact of sex, there is a similar pattern of increase in ASCVD risk with increasing lipoprotein(a) levels among men and women. ⁶ In addition, data suggest that lipoprotein(a) does not confer additional CVD risk in women with low total cholesterol. ¹¹³ , ¹¹⁴ However, it should be noted that the risk of stroke is higher among women with elevated lipoprotein(a), particularly Black women, highlighting a possible need for greater awareness of the risk of cardiovascular events in these populations. ¹¹⁵

LPA genetic risk score and phenotypic measurement of lipoprotein(a) protein levels can be used to determine the risk of ASCVD. ¹¹⁶ In a cohort of 283 540 adults in the 2020 UK Biobank study, LPA genetic risk score and measured lipoprotein(a) were associated with comparable risk of ASCVD events. ¹¹⁶ Importantly, the genetic risk score does not account for the variability in SNPs among patients from different racial and ethnic backgrounds. Since elevated lipoprotein(a) levels predict CVD risk regardless of ethnicity, genetic testing offers little advantage over lipoprotein measurement and may be associated with higher costs. Accordingly, it has since been suggested that genetic testing may not be required in individuals with elevated lipoprotein(a) following lipoprotein testing. ¹¹⁷

Lipoprotein(a): Hope on the Horizon

Lipoprotein(a) Lowering

Mendelian randomization studies have estimated that a reduction in lipoprotein(a) levels of >50 to 100 mg/dL is required for a clinically meaningful reduction in the short‐term risk of ASCVD events (within 5 years). ⁶ The lipoprotein(a)‐lowering effects of currently available therapies are summarized in Table 3. ¹¹⁸ , ¹¹⁹ , ¹²⁰ , ¹²¹ At present, there are no drugs specifically approved for lipoprotein(a) lowering; however, lipoprotein apheresis can be effective in reducing lipoprotein(a) levels in patients with high lipoprotein(a) (>120 nmol/L) and progressive ASCVD. While apheresis is associated with meaningful lipoprotein(a)‐lowering effects, it can take up to 3 hours for each treatment to be administered, ¹²² which may be inconvenient for many patients.

Table 3.

Lipoprotein(a)‐Lowering Effects of Currently Available Therapies ¹¹⁸ , ¹¹⁹ , ¹²⁰ , ¹²¹

Intervention type	Agent	Study*	Effects on lipoprotein(a)	Clinical use
Lipoprotein apheresis	…	…	>60% reduction	Lipoprotein(a) >60 mg/dL with either documented CHD or documented PAD
Statins (HMG‐CoA reductase inhibitors)	Atorvastatin	CARDS	13% reduction	LDL‐C lowering
	Simvastatin	4S	15% increase
	Statins	Meta‐analysis of statins vs placebo	Up to a 19.6% increase
PCSK9 inhibitors	Evolocumab (mAb)	FOURIER	27% reduction	LDL‐C lowering
	Alirocumab (mAb)	ODYSSEY OUTCOMES	Median change −5.0 mg/dL (overall population), −20.1 mg/dL (baseline lipoprotein(a) ≥60 mg/dL population)
	Inclisiran (siRNA)	ORION‐11	18.6% reduction
Niacin	…	AIM‐HIGH HPS2‐THRIVE	~20% reduction	LDL‐C, apolipoprotein B, and triglyceride lowering
ACL inhibitors	Bempedoic acid	CLEAR harmony	No notable effect	LDL‐C lowering
ANGPTL3 inhibitors	Evinacumab	NCT03175367	Placebo‐corrected mean difference: −16.5%	LDL‐C lowering

4S indicates Scandinavian Simvastatin Survival Study; ACL, adenosine triphosphate‐citrate lyase; AIM‐HIGH, Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes; ANGPTL3, angiopoietin‐like protein 3; CARDS, Collaborative Atorvastatin Diabetes Study; CHD, coronary heart disease; CLEAR, Cholesterol Lowering via Bempedoic Acid, an ACL‐Inhibiting Regimen; HMG‐CoA, 3‐hydroxy‐3‐methylglutaryl coenzyme A; HPS2‐THRIVE, Treatment of HDL to Reduce the Incidence of Vascular Events; LDL‐C, low‐density lipoprotein cholesterol; mAb, monoclonal antibody; PAD, peripheral artery disease; PCSK9, proprotein convertase subtilisin/kexin type 9; and siRNA, small interfering RNA.

^*Note that some clinical studies were not designed to assess lipoprotein(a) lowering; that is, results were from post hoc/non‐prespecified or exploratory analyses.

The lipoprotein(a)‐lowering effects of established lipid‐lowering therapies have been studied in clinical trials. However, these studies were not conducted in populations enriched for patients with elevated lipoprotein(a) and were not powered to evaluate the lipoprotein(a)‐lowering effects of these agents. Anti‐proprotein convertase subtilisin/kexin type 9 monoclonal antibodies demonstrated modest reductions in lipoprotein(a) levels of up to 27%, ¹²³ while data for statins are conflicting, with some evidence suggesting that statins may slightly increase lipoprotein(a) levels. ¹²¹ , ¹²³ However, a 2022 meta‐analysis concluded that, compared with a placebo, statins do not lead to clinically important reductions in lipoprotein(a) levels in patients at risk for CVD. ¹²⁴

In recent years, investigational agents have shown promising lipoprotein(a)‐lowering effects in clinical studies and several studies are ongoing (Table 4). ¹²⁵ , ¹²⁶ , ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³² Pelacarsen, an antisense oligonucleotide currently in phase 3 development, showed lipoprotein(a) reductions of up to 80% in a phase 2 study of patients with established CVD and lipoprotein(a) levels ≥150 nmol/L. Adverse events in patients treated with pelacarsen were mostly mild or moderate, with injection‐site reactions the most commonly observed. ¹²⁹ Olpasiran, a small interfering RNA also in phase 3 development, demonstrated up to 101% placebo‐adjusted lipoprotein(a) reduction in patients with established ASCVD and lipoprotein(a) levels >150 nmol/L. ¹²⁵ Similarly, zerlasiran, a small interfering RNA, showed up to 98% lipoprotein(a) reduction in a phase 1 study of adults with lipoprotein(a) levels ≥150 nmol/L and without known CVD. ¹³⁰ Both olpasiran and zerlasiran were generally well tolerated in clinical studies with mostly mild adverse events. ¹²⁵ , ¹³⁰ Importantly, the potential for off‐target effects with small interfering RNAs and antisense oligonucleotides is generally considered to be low. ¹³³ The next steps for these agents will be to understand whether their lipoprotein(a)‐lowering effects will translate into a reduced incidence of cardiovascular events. Phase 3 trials are ongoing for pelacarsen and olpasiran, with outcome data expected in 2025 and 2026, respectively. ¹²⁸ , ¹³¹ An additional small interfering RNA, lepodisiran, is currently under investigation in a phase 2 study, ¹²⁷ as is muvalaplin, an oral small molecule inhibitor of lipoprotein(a) ¹²⁶ ; however, no results have been published to date for either of these agents.

Table 4.

Investigational Lipoprotein(a)‐Lowering Therapies ¹²⁵ , ¹²⁶ , ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³²

Therapy	Mechanism of action	Development phase	Completed studies/studies with results		Ongoing studies
			Study design	Lipoprotein(a)‐related outcomes	Study design/status	End points/outcomes
Muvalaplin	Oral small‐molecule inhibitor	2	–	–	KRAKEN (NCT05563246): Phase 2; high risk of CVD events and lipoprotein(a) ≥175 nmol/L; muvalaplin (oral) vs placebo; N = 233 (planned)	Primary: Lipoprotein(a) % change from baseline to week 12 Secondary: % of participants achieving lipoprotein(a) <125 nmol/L at week 12 Apolipoprotein B % change from baseline to week 12 hs‐CRP % change from baseline to week 12 Pharmacokinetics
Olpasiran	siRNA; induces LPA mRNA degradation	3	OCEAN(a)‐DOSE trial; phase 2; ASCVD and lipoprotein(a) >150 nmol/L; olpasiran (SC) vs. placebo; N = 281	71% (10 mg Q12W) to 101% (225 mg Q12W) placebo‐adjusted lipoprotein(a) reduction (9 mo)	OCEAN(a) (NCT05581303): Phase 3; ASCVD and lipoprotein(a) ≥200 nmol/L; olpasiran (SC) vs placebo; N = 6000 (planned)/recruiting	Primary: Time to CHD death, MI, urgent coronary revascularization Secondary: Lipoprotein(a) % change from baseline to Week 48 Time to (individual events/various combinations of): cardiovascular death, MI, ischemic stroke, coronary revascularization, urgent coronary revascularization, CHD death Time to any cause of death
Pelacarsen	ASO; inhibits apolipoprotein(a) expression	3	Phase 2b; CVD and lipoprotein(a) >60 mg/dL; pelacarsen (SC) vs placebo; N = 286	35% (20 mg Q4W) to 80% (20 mg QW) lipoprotein(a) reduction (6 mo)	Lipoprotein(a)HORIZON (NCT04023552): Phase 3; CVD and lipoprotein(a) ≥70 mg/dL; pelacarsen 80 mg Q4W (SC); N = 8323/ enrolled	Coprimary: Time to first expanded MACE in lipoprotein(a) ≥70 mg/dL and ≥ 90 mg/dL groups Secondary: Time to first composite MACE Time to first composite CHD All‐cause death
Zerlasiran	siRNA; induces LPA mRNA degradation	2	Phase 1; lipoprotein(a) ≥150 nmol/L and no CVD; SLN360; N = 32	10% (30 mg) to 98% (600 mg) lipoprotein(a) reduction (150 days)	Phase 2; high risk of ASCVD events and lipoprotein(a) ≥125 nmol/L; SLN360 vs placebo; N = 160 (planned)/ recruiting	Primary: Time‐averaged change from baseline in lipoprotein(a) Secondary: Change (time‐averaged and by visit) from baseline in lipoprotein(a) at weeks 48 and 60; other lipids/lipoproteins (LDL‐C, apolipoprotein B) at weeks 36, 48, and 60
Lepodisiran	siRNA	2	–	–	NCT05565742 Phase 2; lipoprotein(a) ≥175 nmol/L; lepodisiran (SC) vs placebo; N = 254 (planned)	Primary: lipoprotein(a) time averaged % change (baseline, days 60–180) Secondary: Lipoprotein(a) time averaged % change (baseline, days 240–360) % of participants achieving lipoprotein(a) <125 nmol/L and < 75 nmol/L, respectively (days 60, 180. 240, 360, and 540) Lipoprotein(a) % change from baseline to days 60, 180, 240, 360, and 540 Apolipoprotein B % change from baseline to days 60, 180, 240, 360, and 540 hsCRP % change from baseline to days 60, 180, 240, 360, and 540 Pharmacokinetics

ASCVD indicates atherosclerotic cardiovascular disease; ASO, antisense oligonucleotide; CHD, coronary heart disease; CVD, cardiovascular disease; HORIZON, Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD; KRAKEN, A Study of LY3473329 in Adult Participants With Elevated Lipoprotein(a) at High Risk for Cardiovascular Events; LDL‐C, low‐density lipoprotein cholesterol; LPA, lipoprotein(a) gene; mAb, monoclonal antibody; MACE, major adverse cardiovascular event; MI, myocardial infarction; OCEAN(a), Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction; Q12W, every 12 weeks; Q4W, every 4 weeks; QW, once a week; and siRNA, small interfering RNA.

Research Gaps

Outstanding questions on the prothrombotic potential of lipoprotein(a) remain to be answered, particularly the mechanisms by which lipoprotein(a) can impact thrombosis beyond a role in fibrinolysis are still to be elucidated. ⁹² In addition, our understanding of the metabolism of lipoprotein(a), including mechanisms of synthesis and clearance, remains incomplete. The mechanistic role of lipoprotein(a) in ASCVD versus aortic valve stenosis must be further explored.

While a potential association between low lipoprotein(a) levels and type 2 diabetes has been postulated, additional large‐scale studies are required to confirm whether the association is causal. ⁴⁸ In the meantime, the benefits of lipoprotein(a) lowering for the reduction of CVD risk must be weighed against the potential for the increased incidence of type 2 diabetes, ⁴⁸ particularly since the association may apply only to very low lipoprotein(a) levels, that is, <5 mg/dL, which are unlikely to be achieved with lipoprotein(a)‐lowering therapies in patients with substantially elevated baseline lipoprotein(a). ⁶

Conclusions

The key points and take‐home messages from this article are summarized in Video S1. In summary, lipoprotein(a) is a unique lipoprotein with multiple structural features that give rise to a vast array of potential pathogenic effects, likely contributing to the development of CVD. ¹⁵ , ⁸⁹ A clear understanding of the association between elevated lipoprotein(a) and CVD risk is compounded by the fact that lipoprotein(a) is subject to complex genetic regulation that differs between racial and ethnic populations. ⁶⁰ It should be noted that much of the data pertaining to the regulation of the LPA gene has been generated in White populations. Thus, more data are required for other populations, particularly for Black individuals who have higher median lipoprotein(a) levels compared with individuals from different racial and ethnic backgrounds. ⁶⁰

While we await the results of ongoing clinical trials of investigational lipoprotein(a)‐lowering therapies, healthcare professionals must recognize elevated lipoprotein(a) as a CVD risk factor and advocate for its routine testing in clinical practice. Lipoprotein(a) testing can facilitate intensive risk factor management and reclassification of ASCVD risk in patients found to have elevated lipoprotein(a). ⁶ , ¹⁰⁸ Routine testing may also help identify patients who are potentially eligible for treatment with investigational lipoprotein(a)‐lowering therapies, should these therapies become available in the future. ¹²⁵ , ¹²⁹ , ¹³⁰ Clinical trials are ongoing to clarify whether investigational therapies that lower lipoprotein(a) will lead to clinically meaningful reductions in the occurrence of cardiovascular events. ¹²⁸ , ¹³¹

Sources of Funding

Medical writing support was funded by Novartis Pharmaceuticals Corporation.

Disclosures

Dr. Volgman reports the following disclosures: Pfizer (consulting), Janssen, Novartis, National Institutes of Health (clinical research trials), and Apple Inc. stock competing Interests. Dr. Rosenson reports research grants to his institution from Amgen, Arrowhead, Avilar Therapeutics, Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, Avilar Therapeutics, CRISPR Therapeutics, Editas, Lilly, Lipigon, Novartis, Precision BioSciences, Regeneron, and Verve Therapeutics; royalties from Wolters Kluwer (UpToDate); stock holding in MediMergent, LLC; and patent applications on methods and systems for biocellular marker detection and diagnosis using a microfluidic profiling device; EFS ID: 32278349, application number 62654638 (provisional), and compositions and methods relating to the identification and treatment of immunothrombotic conditions; New International Application No. PCT/US2021/056247 (provisional). Dr. Koschinsky reports the following disclosures: University of Western Ontario (employment); Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Natural Sciences and Engineering Research Council of Canada (research grants); Abcentra (research contract); Novartis Canada, Moderna (consulting fees); Vindico CME (honorarium); and Obsorne Clark law firm (expert witness). Dr. Mehta reports research funding from Novartis paid to Virginia Commonwealth University.

Supporting information

Data S1

Video S1