Clinical Feature: The ABCs of Lipoprotein(a)

What is Lp(a) and Why Is It Important?

In recent years, lipoprotein(a) [Lp(a)] has been recognized as a prevalent risk factor for cardiovascular disease. It is estimated that ~20% of the global population have elevated Lp(a) levels (greater than 50 mg/dL or 100 nmol/L). Lp(a) risk for major adverse cardiovascular events (MACE) is continuous, with risk evident as low as 30 mg/dL or 75 nmol/L in all ethnic groups studied to date.^1,2 Additionally, epidemiological studies and genetic evidence obtained from Mendelian randomization approaches have established that Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular diseases (ASCVD).³ Additionally, a major breakthrough in the field came in 2013 with the publication of Genome-Wide Association Study (GWAS) data showing that LPA (the gene encoding apo(a)) is the only single gene that is significantly associated with the presence of calcific aortic valve disease.⁴ Thus, the importance of an elevated Lp(a) level as a causal risk for disease is two-fold, increasing risk for both atherogenesis and the onset of calcific aortic valve disease.

Lp(a) contains a low-density lipoprotein (LDL)-like particle that is composed of apolipoproteinB-100 (apoB-100), phospholipid, cholesterol, cholesterol esters and triglycerides. Lp(a) is distinguished from LDL by the presence of the unique apolipoprotein(a) [apo(a)] that is linked by a single disulfide bond to the apoB-100 moiety. Apo(a) contains kringle (tri-looped protein structural domains) that are very similar to those found in plasminogen; differences in numbers of identically repeated copies of apo(a) kringle IV (corresponding to differently sized alleles in the LPA gene) give rise to isoform size heterogeneity.⁵

How Does Lp(a) Cause Cardiovascular Disease?

It is the potential dual mechanism of promoting both atherosclerosis and thrombosis that has been speculated to underlie the unique pathophysiological effects of Lp(a) in the vasculature. The similarity of apo(a) to the proenzyme plasminogen has fueled speculation regarding the potential of Lp(a) to compete with plasminogen for fibrin binding, and thereby to decrease fibrinolysis. Additionally, Lp(a) can increase plasminogen activator inhibitor-1 secretion from vascular endothelial cells, block tissue factor pathway inhibitor and promote platelet aggregation, all of which may contribute to increased clot formation.⁶ Lp(a) is also the preferential carrier of oxidized phospholipids in the plasma which mediate a variety of proinflammatory responses in vascular cells.⁷

How Are Plasma Lp(a) Levels Controlled?

Lp(a) levels are primarily under genetic control, with the vast majority of the variation in Lp(a) levels attributable to the LPA gene.⁸ A major contributor to this is LPA allele size: there is a general inverse correlation between apo(a) isoform size and Lp(a) levels.⁹ Median Lp(a) levels are higher among African and South Asian ancestry groups compared to those of European or East Asian ancestry² reflecting in part different distributions of LPA allele sizes in these populations. However, based on analyses to date, the risk conferred by a particular Lp(a) concentration does not vary in different ethnic groups.² Single nucleotide polymorphisms in LPA also play a role: carriers of rs10455872 or rs3798220 tend to have fewer kringle repeats, higher Lp(a) concentrations and higher risk for cardiovascular disease.¹⁰

How Can Lp(a) Levels Be Lowered?

While Lp(a) shares similarities with LDL, conventional lipid lowering treatments do not effectively lower Lp(a) to the extent observed for LDL. Although statins generally have no significant effect on Lp(a) lowering, some studies have reported an increase in Lp(a) levels in patients on statin therapy. However, a recent systematic review and meta-analyses suggest that changes observed in Lp(a) levels in response to statins are not significant.¹¹ Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and niacin reduce Lp(a) by ~25-30% and ~20-40%, respectively.¹² A recent analysis reported that alirocumab-mediated Lp(a) reduction showed benefit in MACE reduction independently of the LDL-lowering effect.¹³ While the mechanism for Lp(a) lowering with PCSK9 inhibition remains unknown, it appears that LDL receptors may play a role in removal of Lp(a) when LDL levels are low and LDL receptor numbers are significantly elevated.¹⁴

Disrupting synthesis of Lp(a) was initially approached using an antisense oligonucleotide (ASO) against ApoB-100 (Mipomersen)¹²; this approach was successful in reducing Lp(a) by 20-30%. Mipomersen, however, is associated with significant risk for hepatotoxicity; the potential for adverse side effects and resulting restricted use of the drug have limited its utility in clinical practice. The microsomal triglyceride transfer protein (MTTP) inhibitor, lomitapide, functions by inhibiting VLDL synthesis thus lowering the secretion of apoB-100-containing lipoproteins. The estimated reduction in Lp(a) is relatively modest (~15-20%) and use of this compound is also limited by extreme hepatotoxic effects.¹²

Lipoprotein apheresis (LA) is the most effective treatment available at the present time¹⁵ and can lower Lp(a) by 60-80%. Lp(a) reduction by LA was associated with significant MACE reduction in individuals with progressive ASCVD in the Pro(a)LiFe Study Group.¹⁵ However, lipoprotein apheresis remains a less accessible and more intrusive option for patients, making chronic treatment challenging. Currently, the FDA approves the use of lipid apheresis in individuals with ASCVD who have LDL >100 mg/dL and Lp (a) >60 mg/dL.¹⁵

Clinical trials testing an antisense oligonucleotide (ASO) against LPA as well as several short interfering RNA (siRNA) therapies (all of which feature enhanced liver specificity due to N-acetylgalactosamine (GalNAc) conjugation) that specifically target hepatic apo(a) production have demonstrated significant reductions in Lp(a) ranging from 60 to >90%. These treatments offer the most promise with respect to frequency of dosing, clinical efficacy, and minimal side effects (Table).

One should not forget the important role for antithrombotic treatment in managing the prothrombotic risk associated with elevated Lp(a). Low dose aspirin remains effective in lowering risk among patients with established atherosclerotic cardiovascular disease as well as in primary prevention. In the ASPREE (ASPirin in Reducing Events in the Elderly) trial sub-study, individuals treated with low dose aspirin who were carriers of the rs3798220 LPA polymorphism (see above) had a 46% relative risk reduction for the combined endpoint of MACE.¹⁷

In Whom Should Lp(a) Be Measured?

Since 20% of the population is estimated to have elevated Lp(a), why is screening of patients not more widely offered? It is well-established that Lp(a) is a prevalent genetically determined risk factor affecting diverse populations. The cumulative risk for ASCVD increases with time and serum concentration of Lp(a). At present, Lp(a) measurement is recommended in those with suspected familial hypercholesterolemia, premature ASCVD or have family history of premature ASCVD, and in very high-risk patients that are more likely to benefit from more intensive lipid-lowering therapies.

It should also be noted that many patients identified with high levels of atherosclerosis after undergoing coronary computed tomography angiography and coronary calcium scoring who lack conventional risk factors such as long-standing diabetes or smoking history very often have elevated Lp(a). Likewise, those with calcific aortic valve disease and aortic stenosis often have a higher prevalence of ASCVD attributable to Lp(a). However, waiting for disease to manifest before Lp(a) is measured is not an ideal approach for optimal clinical care.

Plasma Lp(a) level is simple to measure with a routine blood test (non-fasting) and since Lp(a) levels remain relatively consistent throughout life, a high-risk patient’s Lp(a) risk could be determined prior to the manifestation of ASCVD. The European Society of Cardiology⁸ and the Canadian Cardiovascular Society¹⁸ have recommended that Lp(a) be measured at least once in adults to identify those with high cardiovascular risk. Nonetheless, knowledge gaps on the part of providers with respect to understanding the nature of Lp(a)-associated risk and the current limited ability to specifically lower Lp(a) levels continue to discourage wider adoption of screening. 

Looking to the Future 

Increasingly, data point to the important role of Lp(a) in cardiovascular disease risk assessment. However, Lp(a) remains under-measured and under-estimated with respect to the prevalence of elevated Lp(a) in the population and the independent nature of the risk that accompanies high Lp(a) levels. The Phase 3 Pelacarsen trial using an ASO against LPA in a secondary prevention setting is expected to report outcome data in 2025. In the interim, we must seek to increase awareness of Lp(a) and the importance of measuring it in clinical practice including cascade screening of family members of patients presenting with elevated Lp(a) levels. Optimizing the management of other CVD risk factors should be aggressively pursued in individuals with elevated Lp(a). 

Dr. Shemisa has recieved honoraria from Merck, Boehringer Ingelheim, Janssen, and Bayer for speaking and honoraria from Novartis for being an advisory board member. Dr. Koshcinsky has receievd consulting fees from Novartis Canada and Moderna, and recieved honorarium from Vindico CME. 

References

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