Unveiling Lipoprotein(a): A New Frontier in Heart Health

Abstract

Extensive research on Lipoprotein(a) (Lp(a)) levels and their link to morbidity and mortality in regard to cardiovascular risk remains a cornerstone of cardiovascular studies. Recent findings suggest that in younger patients, Lp(a) serves as an independent risk factor for cardiovascular diseases (CVD). This is mediated by diverse processes, including signaling processes driving angiogenesis, cellular Inflammation and proliferation, cytokine formation, and antifibrinolytic activity. In addition, Lp(a) mediates the atherogenic properties of low-density lipoprotein (LDL).

Studies have shown worse long-term CVD morbidity and mortality outcomes, including acute myocardial infarction (MI), coronary atherosclerosis, and stroke in individuals with elevated plasma Lp(a) concentrations. In recent times, studies have also suggested a link between Lp(a) levels and calcified aortic valve disease (CAVDs), indicating that higher Lp(a) levels are associated with a faster progression of aortic stenotic valvular disease. In this review article, we discussed the effects of lifestyle modification, such as nutrition and exercise, on Lp(a) concentration, with a recommendation to promote novel therapeutic approaches to reducing Lp(a) levels. Given the significance of predicting atherosclerotic cardiovascular disease (ASCVD) risk through Lp(a) measurement, its importance cannot be overstated.

The Lp(a) lowering effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) mAbs and lipoprotein apheresis has been well established. In contrast, the effects of statins, fibrates, ezetimibe, niacin, and bempedoic acid on Lp(a) levels have been inconsistent. New emerging therapies with significant promise target RNA molecules to modify protein production and lower Lp(a). Further research is required to facilitate modalities to explore Lp(a) further and tackle cardiovascular morbidity and mortality.

Introduction

Cerebrovascular disease (CVD) remains a leading cause of morbidity and mortality, even with significant preventive and management advancements. ¹ Associated with atherosclerosis, it accounts for approximately 17.9 million deaths each year. Identifying modifiable risk factors for CVD, such as smoking, hypertension, obesity, diabetes mellitus, and dyslipidemias, has enabled the development of evidence-based guidelines and practice patterns for managing cardiovascular comorbidities and their risk factors. These developments have helped to lower the death rate from CVD. However, despite these advancements, cardiovascular disease (CVD) still accounts for over 40% of all deaths.^{2, 3}

Low-density lipoprotein (LDL) particles are the main carriers of cholesterol in the blood. Each LDL particle comprises a lipid core primarily made up of cholesteryl ester (CE) molecules, along with small amounts of triglycerides (TG) and unesterified cholesterol (UC). ⁴ Lipoprotein(a) (Lp(a)) consists of an LDL-like particle in which the pathognomonic component, apolipoprotein(a) (apo(a)), is covalently bonded to apoB through a single disulfide bond. Lp(a) was discovered in 1963 by Kare Berg and has garnered significant attention recently as large-scale observational studies, high-quality data from Mendelian Randomization research and meta-analyses have demonstrated a consistent, independent relationship between elevated Lp(a) levels and CVD risk.^{5, 6}

Structure of LPA

Morphologically, similarities exist between Lp(a) and LDL, but with the addition of glycoprotein apo(a). apo(a) comprises multiple plasminogen-like kringle IV structures (types 1-10), one plasminogen-like kringle V structure, and an inactive protease region. In contrast, plasminogen consists of five distinct kringle-shaped protein structures (I through V) and a protease region. The isoform size is determined by the amount of kringle IV type 2 (KIV2) structures and is inversely correlated with hepatic production rates. This is probably because larger isoforms undergo higher intracellular degradation, and intracellular processing takes longer. Significant apo(a) protein size variation exists among populations, with over 40 distinct isoforms and, consequently, over 40 distinct Lp(a) particle sizes. This is a unique phenomenon in contrast to other circulating proteins, which typically have a single specified mass. As a result, the size of an isoform and the quantity of Lp(a) in plasma correlate inversely. Most people express two isoforms that differ in size, with minor isoforms typically exhibiting high concentrations and large isoforms at low quantities.^{2, 7}

Mechanisms for the synthesis, production, and clearance of circulating Lp(a) levels.

Synthesis

Only the liver can manufacture apoprotein (a). ⁸ Circulating Lp(a) levels are primarily determined by the LPA gene locus; diet or environment has no discernible effect. However, the site of Lp(a) coupling remains unknown and could be in the plasma compartment, the hepatocyte, or the Disse space.^{2, 9} The number of KIV-2 repetitions, race/ethnicity significantly impact the generation of Lp(a). Research has demonstrated that Blacks and Hispanics have higher levels of Lp(a) than White people. ⁵

Production

Steps in the assembly process include apo(a) binding to LDL and the subsequent creation of a covalent disulfide link between apoB of LDL and KIV-9 of apo(a). Instead of originating from a precursor of very low-density lipoprotein (VLDL), the LDL part is derived from newly synthesized apoB-100. Compared to LDL, Lp(a) has a more extended plasma stay. This may occur because the apo(a) component is covalently linked close to the LDL receptor (LDLR) binding site of apoB and may be larger than apoB itself. This hinders apoB from attaching to the LDLR, which reduces LDLR clearance and requires alternative clearance pathways. Additionally, since hepatocytes consistently produce apo(a) and smaller isoforms can be synthesized in greater molar amounts over a given time than larger isoforms, the size of the apo(a) isoform shows a weak, inverse correlation with the plasma levels of Lp(a). ²

Clearance

The methods through which Lp(a) is cleared from plasma remain a topic of discussion. Although statins elevate LDLR levels without reducing Lp(a), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors boost LDLR counts while lowering Lp(a), this indicates a moderate role for LDLR. Studies in cell cultures and clinical manifestations of LDLR deficiency, like individuals with familial hypercholesterolemia caused by mutations of LDLR, show elevated Lp(a) levels compared to unaffected siblings. Furthermore, research involving labeled Lp(a) in both animals and humans suggests limited (if any) impact on its turnover. ² An Lp(a) plasma concentration increase could result from a decreased glomerular filtration rate (GFR). Additional factors include hypothyroidism or an acute phase reaction (such as a myocardial infarction [MI]). Pregnancy, aspirin use, or estrogen therapy results in a negligible or pertinent decrease in Lp(a) levels. ¹⁰

Mechanisms Through Which Lp(a) Mediates CVD

It is also being argued that Lp(a) is a stand-alone risk factor for CVDs (MI, stroke, and aortic valve stenosis). In particular, young individuals who suffer from an apoplectic insult may have Lp(a) as a contributing factor.^{11, 12} The Emerging Risk Factors Collaboration revealed, by analyzing individual data from 36 prospective studies involving 126,634 participants, that the risk ratio for CVD escalated following every rise in Lp(a) standard concentration. This risk remained constant even when traditional cardiovascular risk factors were considered. ¹³ Additionally, there was a higher incidence of stroke occurrences but not of non-cardiovascular death. ¹² Lp(a) raises the risk of CVD through several distinct, non-redundant processes. The artery-clogging risk linked to LDL stems from their propensity to oxidize once they infiltrate the wall of the artery, resulting in the formation of oxidized LDL with strong immunogenic and proinflammatory properties, predominantly transported by Lp(a). ¹⁴ The Copenhagen City Heart Study indicates that individuals in the 95th percentile have a risk of coronary artery disease (CAD) that is 2.6 times greater than those in the 22nd percentile. ¹⁵ Even after controlling for the number of KIV2 domains, this phenomenon is still present, indicating that the risk of CAD is independently correlated with the concentration of Lp(a) and the number of KIV2 domains. ¹⁶ Additionally, a prospective assessment of patients’ 15-year outcomes showed that patients in the top quintile had 2.34 times increased incidence of CVD, characterized by a combination of ischemic stroke and acute CAD, and vascular death, posed a greater risk than for patients in the other quintiles. ¹⁷ Elevated plasma Lp(a) levels are linked—both observationally and causally, through genetic evidence—to a higher risk of ischemic stroke in a large, contemporary general population study. Additionally, the likelihood of cardiac failure increases by 1.54 times in individuals with high Lp(a) compared to those with low levels.^{18, 19} Elevated Lp(a) levels have also been correlated with a heightened risk of developing progressive coronary atherosclerosis and suffering an acute MI, particularly among South Asian and Latin American populations.^20–22 Recent guidelines on lipids highlight the importance of assessing Lp(a) levels to evaluate CVD risk, given the elevated risk associated with high Lp(a) concentrations. ²³ However, because Lp(a), by definition, comprises both apo(a) and all of the proatherogenic components of LDL, it is more atherogenic than LDL on an equimolar basis. Apo(a) enhances atherothrombosis through various mechanisms, such as inflammation due to its oxidized phospholipid (OxPL) content, lysine binding sites that allow build-up in the walls of arteries, and potential antifibrinolytic effects resulting from inhibition of plasminogen activation. The atherogenicity of Lp(a) can be divided into three main categories: proatherogenic, proinflammatory, and possibly antifibrinolytic. Most individuals at risk for CVD (70%-80%) have low levels of Lp(a), indicating that LDL-C is present in much larger quantities than Lp(a). Consequently, the higher number of LDL particles contributes significantly to apoB-driven risk. Nonetheless, it is important to quantitatively analyze CVD risk caused by Lp(a). Conversely, the risk associated with Lp(a) rises linearly as Lp(a) levels increase, reaching over 25-30 mg/dl, affecting around 30% of the population. This conclusion is based on the absolute circulating mass of Lp(a). Lp(a)’s atherogenicity can be grouped into three primary categories: proatherogenic, proinflammatory, and possibly antifibrinolytic.

Association Between Lp(a) Concentrations and Calcified Aortic Valve Diseases

It has been reported that Lp(a) and calcified aortic valve disease (CAVD) are related. ²³ Aortic valve stenosis risk increased steadily with approximately three-fold increases in Lp(a) concentrations, as was the case for Lp(a) levels >90 mg/dl (95th percentile), according to data from a sizable prospective cohort. ¹³ One of the leading causes of vascular inflammation in atherosclerosis is oxidized lipids. ²³ The ASTRONOMER Trial studied rosuvastatin’s impact on aortic stenosis progression, showing that patients with mild-to-moderate aortic stenosis and high OxPL-apoB levels (>5.5 nM and >58.5 mg/dl) experienced quicker progression. The enzyme autotaxin converts OxPL in Lp(a) to pro-calcifying lysophosphatidic acid, leading to fibrosis and inflammation. ²⁴ Furthermore, these patients exhibited annual changes in peak aortic jet velocities of 0.26 ± 0.26 m/s, compared to 0.17 ± 0.21 m/s in those with the highest versus lowest tertiles. In addition, 20.4% of the entire group required aortic valve replacement. Similar findings: 48% of the study population with bicuspid valves showed a higher incidence of advancement than those with tricuspid valves. Notably, younger patients (median age less than 57) had the most requirement for replacement of the aortic valve and nearly double the progression rate, which is in keeping with the leading cause of genetically higher Lp(a). ²⁵ These results support the theory that Lp(a) mediates the evolution of aortic stenosis through its corresponding OxPL. Therefore, more randomized studies of apoB-lowering Lp(a) and OxPL treatments for aortic stenosis are required. ²³ Lp(a) and OxPL can induce CAVD by binding strongly to eroded valve surfaces through lysine-binding sites. In summary, the activities of OxPL and autotaxin present in Lp(a) may influence the progression of CAVD, characterized by stages of calcification, inflammation, fibrosis, lipid buildup, and even symptoms stenosis. ²³

Impact of Lifestyle Modifications on Lp(a) Levels

It has been demonstrated that therapeutic lifestyle modifications (TLCs) are successful treatment approaches for primary and secondary CVD risk prevention. However, dietary interventions have not been able to show a significant change in Lp(a) levels. Numerous randomized trials on diet suggest that nutritional interventions, such as a low-fat diet, might lower Lp(a) levels, as a healthy lifestyle has been shown to decrease the risk of CVD. However, the results of these studies surprisingly contradicted these expectations. Lp(a) levels were higher in a low-fat, high-vegetable diet than in a diet low in fat and vegetables, typically perceived as a diet to minimize CVD risk. ²³ Moreover, in comparison to the high-protein or high-carbohydrate groups in the Dietary Approaches to Stop Hypertension (DASH) trial, the experimental group receiving higher doses of unsaturated fat displayed elevated Lp(a) concentrations. ²⁶ Additionally, studies have explored the link between Lp(a) levels and physical activity, revealing an inverse correlation. Another investigation found that Lp(a) concentrations showed no significant association with body composition, age, gender, exercise capacity, or other lipoprotein levels in a sample of 150 Caucasians (50 women and 100 men). ²⁷ No associations were found in several cross-sectional studies between Lp(a) and physical activity.^{27, 28} Current data reveal that TLC—including dietary and lifestyle modifications—is not linked to improved serum Lp(a) concentrations. The significance of the genetic variables predisposing to high Lp(a) levels is indicated by the lack of effect that dietary or exercise treatments have on blood Lp(a) levels. Therefore, developing new therapeutic approaches to reduce Lp(a) levels is essential. ²³

Measuring Lp(a) in Patients: How, When, and Why?

Highly varied median Lp(a) concentrations have been reported by epidemiologic research; these variations, which are frequently large, may originate from the use of different tests in addition to known racial/ethnic population disparities. ¹⁵ It is now clear that high Lp(a) serves as an independent risk factor for CVD across all racial demographics. ² Clinicians have been urged to check Lp(a) levels at least once during a person’s life, supported by research demonstrating a causal relationship between Lp(a) and atherosclerotic cardiovascular disease (ASCVD), along with various announcements and recommendations. ⁵ Lp(a) levels are usually expressed in nanomoles per liter based on the particle count of apo(a) or in milligrams per deciliter reflecting the mass of the entire particle. Due to the heterogeneity of Lp(a) particle sizes, mass assays for Lp(a) are inherently limited, making it difficult to standardize experiments with appropriate calibrators. Furthermore, these tests might lead to an overestimation of Lp(a) levels in patients exhibiting large isoforms while potentially underestimating levels in those with smaller isoforms. This discrepancy arises because most antibodies utilized are polyclonal, which cross-react with multiple KIV2 variant repetitions. ²

A detailed meta-analysis with 126,634 participants and 1.3 million person-years of follow-up reaffirmed prior findings, revealing a significant rise in MI risk when Lp(a) levels exceed 30 mg/dl. The risk demonstrates a curvilinear trend, escalating sharply beyond 24 mg/dl. ² Typically, the average risk for CVD is higher than the Lp(a) concentration. Although the documentation of risk based on baseline Lp(a) levels in CAVS is limited, a notably higher risk was observed at levels exceeding 40-60 mg/dl. The European Atherosclerosis Society (EAS) recommends an optimal range of less than 50 mg/dl (approximately <100-125 nmol/l), which corresponds to 20% of the population with elevated levels. ²⁹ However, the Copenhagen data and recent Lp(a) analyses from randomized trials indicate that this recommendation fails to account for risks in patients with levels between 25 and 50 mg/dl.^30–31 The Canadian Cardiovascular Society’s 2016 Guidelines for the Management of Dyslipidemia identify Lp(a) levels greater than 30 mg/dl as a risk factor, suggesting that Lp(a) should be measured to inform treatment decisions, particularly for patients at moderate risk, a family history of early CAD, and younger patients who may not qualify under standard treatment criteria. ³² Lp(a) levels exhibit a leftward skew, unlike the typically distributed LDL-C and other lab results. Approximately 70% of individuals have Lp(a) levels below 30 mg/dl, which is within the normal range. Nonetheless, around 2 billion people, or 30% of the global population, possesses levels of Lp(a) which fall within the atherogenic range. Specifically, Lp(a) levels exceeding 60 mg/dl are utilized in the apheresis guidelines of Germany and the UK to justify reimbursement for patients experiencing solitary Lp(a) elevation alongside recurrent CVD events or combined with uncontrolled elevated LDL-C. ²

Genetic and epidemiological evidence strongly supports the prognostic role of Lp(a). However, for both patients and clinicians, the most critical aspect is the capacity to reclassify risk into lower or higher categories and adjust medication accordingly. ² The Bruneck study investigated this with 826 members of the public over a 15-year prospective follow-up. Incorporating Lp(a) levels into the Framingham and Reynolds risk score variables enabled the reclassification of 39.6% of subjects into different risk categories based on Lp(a) levels, particularly among those at intermediate risk, where the need for stratification is significant. Notably, Lp(a) levels, Reynolds risk scores, and allele-specific Lp(a) levels did not enhance the predictive capability of these risk scores, nor did apo(a) isoforms. These findings indicate that reclassification of almost four out of ten patients could be achieved by measuring Lp(a) levels within intermediate-risk groups. ¹⁷ Further research is essential to confirm these results, particularly with the new risk score algorithms from the American College of Cardiology/American Heart Association and SCORE (Systematic et al.) trials. This test is comparable to assessing a genetic SNP, given that more than 90% of circulating Lp(a) levels are inherited. These levels are closely linked to the LPA gene and remain largely stable throughout life, showing minimal variation due to diet or environmental factors. Since a laboratory Lp(a) level test are generally priced from $50 and $100, it is cost-effective, as it only requires a single test for screening or diagnosis. Adding Lp(a) testing to the initial lipid panel is warranted, since many patients are unaware of their Lp(a)-related cardiovascular risk. ² If Lp(a) falls within the normal range, additional testing is optional, regardless of any changes in the patient’s medication regimen. A one-time Lp(a) test is advised for individuals with early-onset CVD, moderate to high risk of CVD, familial hypercholesterolemia, a family history of premature CVD accompanied by elevated Lp(a), recurrent events despite statin treatment, or a 10-year coronary heart disease risk estimate of 3% to 10% for fatal or nonfatal outcomes. The National Lipid Association of the United States provided similar testing recommendations.^{30, 33} According to the 2016 European Society of Cardiology/EAS guidelines, Lp(a) should be measured in certain high-risk situations, patients with a family history of early CVD, and to reclassify individuals with borderline risk into Class IIa—evidence Level: C. ³⁴

Guideline and Scientific Statement Positions on Lp(a) Management

1. HMG-CoA reductase inhibitors (Statins): Statin therapy serves as the most effective first-line pharmacologic treatment for lowering ASCVD and LDL-C risk. These medications work by competitively inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is crucial in the cholesterol synthesis pathway. The hepatic LDLR are expressed more when HMG-CoA reductase is inhibited, lowering serum LDL-C levels. ³⁵ Significant evidence from the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Experiment Evaluating Rosuvastatin) study indicates that statins marginally increase Lp(a) rather than reduce it. ¹³ A meta-analysis conducted regarding statins and Lp(a) level showed statins were beneficial for traditional CV risk variables, but there was a slight rise in Lp(a) levels. Remarkably, however, patients assigned to the statin group showed a considerably stronger correlation with poor CV outcomes than patients assigned to the placebo group, even though high (≥50 mg/dl) Lp(a) concentrations were observed both at baseline and during the follow-up period. The remaining CV risk after statin medication may be explained by these high-Lp(a) population groups. Therapeutics aimed at Lp(a) may reduce cardiovascular risk associated with elevated Lp(a) levels in this population. ³⁶ A meta-analysis of 5,256 individuals from six randomized controlled trials examined the impact of different types and intensities of statin medications on Lp(a) levels. Statins groups experienced a mean percentage change in Lp(a) levels ranging from 8.5% to 19.6%, while placebo groups showed a change between −0.4% and −2.3%. ³⁷ Although the specific mechanisms through which statins increase Lp(a) levels are unclear, it is possible that they do so by enhancing apo(a) production via PCSK9, which also diminishes the effectiveness of statins in lowering LDL cholesterol. ⁶

2. Ezetimibe: Ezetimibe lowers LDL-C by 15%-25% and inhibits cholesterol absorption by binding to the cholesterol transporter Niemann-Pick C1-Like 1 (NPC1L1) in the intestines. Nonetheless, the exact mechanism by which the NPC1L1 transporter affects Lp(a) remains uncertain. ⁶ Two thousand three hundred thirty-seven patients with primary hypercholesterolemia and seven RCTs were included in a meta-analysis to examine the impact of ezetimibe monotherapy on plasma Lp(a). A slight reduction was seen after 12 weeks of ezetimibe treatment (−7.06% from baseline). ³⁸ Several further clinical trials examined the effect of ezetimibe plus statin combination therapy on Lp(a) levels. The majority of studies indicated that adding ezetimibe to statin therapy had little to no impact on Lp(a) levels.^39–42 When ezetimibe was added to maximally tolerated dosages of statins for a treatment period of three months, a small but negligible increase in Lp(a) was observed in a trial including statin-intolerant individuals with refractory familial hyperlipidemia. ⁶ When ezetimibe was combined with alirocumab, a PCSK9 monoclonal antibody (mAb), Lp(a) levels were not significantly lower than when alirocumab plus placebo was used. It was determined that PCSK9-targeting treatments, rather than ezetimibe, were most likely responsible for the observed Lp(a)-lowering effects. ³⁹ Data pooled from the phase III ODYSSEY program indicated a slight rise in plasma Lp(a) of 1.5% from baseline after 12 weeks of treatment with ezetimibe and a statin. However, after 24 weeks of treatment, a decrease of −5.3% from baseline was observed. ⁴⁰

3. PCSK9 mAb: PCSK9, an enzyme made by the liver, promotes the degradation of LDLR by attaching to it. Thus, medications that decrease the function or production of PCSK9 lead to more LDLR being available and a reduction of LDL-C in the bloodstream. When PCSK9 is inhibited by mAb (evolocumab, alirocumab), LDL-C levels fall by approximately 60%, which lowers the risk of ASCVD in patients with clinical symptoms ASCVD. The FOURIER trial provided evidence of the well-established Lp(a)-lowering effect of PCSK9 mAbs. Evolocumab, irrespective of baseline LDL-C concentrations, lowered Lp(a) by 26.9%. It is noteworthy that patients whose Lp(a) concentrations were higher than the median (>37 nmol/L) had a higher absolute risk reduction rate and number needed to treat (1.41% and 71%, respectively) when compared to the placebo control group. According to a pooled analysis from three phase II randomized controlled trials, ⁴⁰ alirocumab (150 mg every two weeks) significantly reduced Lp(a) levels by 30% compared to placebo after eight to twelve weeks. Furthermore, inclisiran, another PCSK9-targeting medication that inhibits PCSK9 synthesis through tiny interfering RNA, has shown long-lasting effects in lowering LDL-C. However, unlike evolucumab, inclisiran’s effects on Lp(a) reduction were not statistically significant (−14% or −26% with one or two doses). ²³

Other Lipid-lowering Therapies

Niacin

Niacin, a drug that binds to adipocytes’ hydroxycarboxylic acid receptor-2 and inhibits the mobilization of free fatty acids, somewhat lowers LDL-C levels by 7%-12%. Furthermore, HDL-C levels are markedly increased by blocking the cholesteryl ester transfer protein (CETP) enzyme. A meta-analysis of 14 RCTs and the AIM-HIGH trial indicates that niacin can reduce Lp(a) levels by 23%-25%. However, this treatment was halted because of side effects like hot flashes, liver toxicity, abdominal discomfort, and its inability to achieve the primary cardiovascular event reduction targets in two large, randomized trials: one conducting the niacin/laropiprant combination (HPS2-THRIVE) and the other using prolonged-release niacin (AIM HIGH).^{6, 42}

Bempedoic Acid

Bempedoic acid causes the overexpression of LDLR on hepatocytes. It facilitates LDL-C clearance from the bloodstream through the inhibition of ATP citrate lyase (ACL), an enzyme essential for cholesterol production. ⁶ Bempedoic acid decreased ASCVD occurrences by 13% compared to placebo, according to a new study from the CLEAR Outcomes trial, which included over 14,000 patients intolerant to statins. ⁴³ Bempedoic acid decreases LDL-C by about 20% when given as add-on therapy to a statin, ezetimibe, and PCSK9 mAb. ⁶ The impact of bempedoic acid on Lp(a) levels has been variable. In a secondary analysis of the CLEAR Harmony trial, it resulted in a modest yet statistically significant rise in Lp(a) concentrations. However, in contrast, it did not demonstrate any Lp(a) lowering effects when compared to the placebo group in a phase II randomized, double-masked, placebo-controlled study. ⁶

Fibrates

Fibrates, derivatives of fibric acid, mainly reduce TG by reducing the concentration of apo C3 and activating peroxisome proliferator-activated receptor alpha (PPARα). In a brief post hoc study of the ODYSSEY DM-DYSLIPIDEMIA trial involving 15 patients treated with fenofibrate and the highest tolerated statin dose, a 16% rise in Lp(a) levels was noted. On the other hand, research with eighty individuals receiving fenofibrate monotherapy revealed a marginally non-significant rise in Lp(a) levels of about 1.6%. ⁶ There is not much data to support the impact of fibrates on Lp(a) levels, such as gemfibrozil and fenofibrate. Pemafibrate’s possible function in managing Lp(a)-associated hazards is further complicated by the PROMINENT trial’s failure to show a reduction in cardiovascular risk. ⁴⁴

Omega-3 Fatty Acids

The primary purpose of omega-3 fatty acids is to lower TG levels; the only formulation that has been demonstrated to reduce ASCVD risk is icosapen ethyl, although it has little to no effect on Lp(a). Although homozygous familial hypercholesterolemia (HoFH) is a rare disease, patients with this condition can benefit from lomitapide and evinacumab; however, these treatments are not often used in clinical practice. The impact of both on Lp(a) is moderate; in research involving 29 patients with HoFH, lomitapide decreased Lp(a) levels by −13%, while in a study involving 43 patients with HoFH, evinacumab reduced Lp(a) levels by −5.5%. ⁶

Mipomersen

The FDA has given approval to mipomersen, a second-generation antisense oligonucleotide (ASO), for treating homozygous FH alongside statin treatment. It works by preventing the synthesis of apoB while leaving apo unaffected (a). Its therapeutic use is limited due to potential significant side effects such as hepatic steatosis, hypertransaminasemia, and injection site reactions, despite its ability to lower Lp(a) concentrations by 25%-40%. ⁶ The Lp(a) levels decreased by 26.4% in patients assigned randomly to receive 200 mg of mipomersen daily; however, cardiovascular benefits have not yet been shown. ⁴⁵

Lipoprotein Apheresis

Lipoprotein apheresis is a procedure that removes lipoproteins from the bloodstream. It is reserved for individuals whose lipoprotein levels cannot be reached satisfactorily by lifestyle changes or medication. Several rules govern the application of lipoprotein apheresis. ⁴⁶ Apheresis has been identified as the most effective and well-tolerated treatment for individuals with Lp(a) hyperlipoproteinemia. Available data on lipoprotein apheresis show impressive results, with a 60%-70% reduction in LDL-C and Lp(a) levels, leading to significant improvements in cardiovascular outcomes, including a 54%-90% decrease in cardiovascular events. ⁴² Since 2013, Lp(a) hyperlipoproteinemia has been listed as one of the indications for lipoprotein apheresis in the guidelines published by the American Society for Apheresis (ASFA). According to the HEART UK Lipoprotein Apheresis guidelines, patients with increasing coronary disease, Lp(a) more than 60 mg/dl, and LDL-C that maintains 125 mg/dl despite maximal lipid-lowering medication should consider apheresis. Currently, lipoprotein apheresis is only approved by the FDA for use in patients with confirmed CVD progression and elevated Lp(a) levels greater than 60 mg/dl.^{47, 48}

Emerging Therapies Targeting Lp(a)

Currently, the most researched strategies in this field include ASOs, small interfering RNAs (siRNAs), and microRNAs—therapies that target RNA molecules to regulate gene expression and alter protein synthesis, aiming to reduce Lp(a) levels. Trials recently conducted with ASOs, which can suppress apo(a) expression, were the first to be planned as randomized studies to evaluate an Lp(a)-lowering treatment. Once administered subcutaneously, anti-apo(a) ASOs bind to plasma proteins and are absorbed by the liver, where they target and attach to their specific mRNA. This technique decreases Lp(a) plasma levels by more than 80%, preventing Lp(a) assembly. ⁴² Two recent clinical trials have produced encouraging results regarding the direct inhibition of apo(a) synthesis by ASOs. In the first trial, patients with high Lp(a) levels received IONIS-APO(a)Rx subcutaneously once weekly for four weeks at doses of 100 mg, 200 mg, and 300 mg to evaluate the safety and effectiveness of the ASO. Subjects treated with 125-437 nmol/L and ≥438 nmol/L had 62.8% and 67.7% lower Lp(a) concentrations compared to the placebo group.^{42, 49}

Pelacarsen, also known as TQJ230, is a second-generation GalNAc conjugate ASO that targets the mRNA transcribed from the LPA gene, hence reducing the amount of apo(a) produced by the liver. ⁶ Lp(a) circulating concentrations were found to decrease by 35%, 58%, 80%, 56%, and 72%, respectively, when pelacarsen was administered to patients via subcutaneous injections at varying doses: 20 mg every four weeks, 20 mg every two weeks, 20 mg weekly, 40 mg every four weeks, and 60 mg every four weeks. The majority of side effects were limited to local reactions at the injection site, and they were also minor and infrequent. ⁵⁰ Phase III research is now underway, with completion scheduled for 2024. This research aims to assess the impact of pelacarsen on cardiovascular endpoints in individuals who have had a cardiovascular event during the last ten years and have Lp(a) levels ≥70 mg/dl. Patients are given a placebo or 80 mg of pelacarsen once a month as part of their treatment. ⁴²

Olpasiran (AMG 890) is a hepatocyte-directed synthetic small interfering RNA coupled with galNac that inhibits LPA expression and degrades apo(a) mRNA to stop Lp(a) particle assembly. In patients with established ASCVD (88% on statin therapy, 52% on ezetimibe, and 23% on PCSK9 mAbs at baseline), the phase II OCEAN(a)-DOSE trial assessed the safety and effectiveness of repeated administration of one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo. Lp(a) and LDL-C had baseline median amounts of 260.3 nmol/L and 67.5 mg/dl, respectively. The main outcome was the percentage change in Lp(a) concentration from baseline to week 36. The olpasiran group showed a significant dose-dependent decrease in Lp(a) concentration, with placebo-adjusted mean per cent reductions ranging from roughly −70% to −100% when the dose was given every 12-24 weeks. A 100% of patients obtained an Lp(a) concentration below 125 nmol/L with the 10mg dose given every 12 weeks; with the 75 mg and 225 mg doses given every 12 weeks, and 98.1% with the 225 mg dose given every 24 weeks. Subcutaneous olapasiran administration was usually well tolerated; injection site and hypersensitivity reactions were the most frequently reported side effects. ⁶ The phase III clinical trial OCEAN(a)-Outcome (NCT05581303) is currently enrolling 6,000 individuals with ASCVD and Lp(a) ≥200 nmol/L to examine the impact of olpasiran given every 12 weeks on schedule on MACE. This investigation is anticipated to be finished in 2026. ⁵¹

SLN360 is an additional N-acetyl GalNAc-conjugated siRNA that targets LPA and apo(a) production. ⁶ Although the ASO technology employed in these studies is still in its early stages, this has been made possible by the conjugation of GalNAc to the ASO, and this drug has the ability, at a tolerable dose, to successfully reduce Lp(a) by up to 99%. ²³ In a phase I single ascending dosage safety and tolerability evaluation, persons without known ASCVD who had Lp(a) of at least 60 mg/dl or 150 nmol/L at screening were enrolled in the study. Single subcutaneous doses of SLN360 (30, 100, 300, or 600 mg) or a placebo were randomly given to participants and monitored for 150 days. With only two documented major side events unrelated to the study treatment, SLN360 was generally well tolerated. The maximum median Lp(a) percentage changes ranged from −10% to −98% for 30 mg and 600 mg of SLN360, respectively. After injection, Lp(a) decreased for at least 150 days, with a dose-dependent duration. ⁵² To evaluate the efficacy of SLN360 in individuals at high risk of cardiovascular illnesses with elevated Lp(a) concentrations (≥125 nmol/L), a randomized, placebo-controlled phase II study (NCT05537571) is planned. This study is anticipated to be finished in 2024. ⁵³

Conclusion

LPA has been linked to the development of CVD, CVS, and cardiac failure, supported by genetic and observational evidence. Evidence supports that it is inherited genetically. Lifestyle changes have proven ineffective in lowering Lp(a) levels. Recommendations differ, but it is generally suggested that all adults undergo screening at least once in their lifetime, as Lp(a) levels tend to remain stable throughout life. PCSK9 inhibitors and Lipoprotein apheresis have been demonstrated to lower Lp(a) levels. New emerging medications, including Pelacarsen, SLN360, and Olpasiran, are also beneficial in reducing Lp(a) levels; however, research is still ongoing. Further studies are required to investigate other effective therapies, as studies occasionally contradict the use of these agents.