Clinical Feature: Lipoprotein(a) – Fast Facts and Clinical Perspectives

What is the Structure of Lp(a)?

Lipoprotein(a) [Lp(a)] was first described as an antigenic variant of low-density lipoprotein (LDL) in 1963.¹ Indeed, Lp(a) contains an LDL-like moiety but is distinguished by the attached unique protein apolipoprotein(a) [apo(a)]. (Fig. 1) Apo(a) confers unique structural and functional properties to Lp(a) and likely plays a key role in the cardiovascular disease risk associated with elevated levels of this lipoprotein.² Apo(a) contains many repeated structural domains called kringles; these kringle domains are similar to several of the kringle domains in the proenzyme plasminogen.³ Plasminogen, when activated to plasmin, plays a key role in blood clot breakdown. Apo(a), on the other hand, lacks enzymatic activity because of several key mutations in its protease-like domain. It created tremendous excitement in the field that Apo(a), through its similarity to plasminogen, could interfere with the process of blood clot removal and contribute to atherosclerosis through its LDL-like moiety. This potential duality of function has intrigued basic scientists and clinicians alike since the structure of Lp(a) first was elucidated.

More recently, Lp(a) has been shown to contribute in a unique way to atherosclerotic cardiovascular disease (ASCVD), as well as calcific aortic valve disease (CAVD), through the presence of oxidized phospholipid (oxPL) on both the Apo(a) and LDL-like moieties (Fig. 1).^4,5 These oxPL are preferentially carried on Lp(a), compared to LDL.

How does Lp(a) contribute to ASCVD and CAVD?

There is strong evidence to suggest that elevated plasma Lp(a) levels (greater than 50 mg/dL or 125 nmol/L) are an independent – and possibly causal – risk factor for ASCVD.⁶ This evidence reflects data from large meta-analyses, Mendelian randomization studies, and genome-wide association studies (GWAS). GWAS data revealed the identity of two polymorphisms of the LPA gene, which encodes Apo(a), both of which are associated with elevated plasma levels and increased coronary heart disease risk.⁷ More recent studies also have implicated Lp(a) as a potent risk factor for CAVD; there is evidence to suggest that elevated Lp(a) concentrations are predictive of disease progression.⁸

The question of the mechanism(s) underlying the effect of Lp(a) on CVD has been a focus of investigation for many years, using a variety of approaches that range from in vitro studies to population-based investigations. The effect of oxPL in Lp(a) on harmful pro-inflammatory processes in the artery wall presents a potentially unifying theory as to how Lp(a) contributes to both ASCVD and CAVD. This modification likely underscores many of the alterations that Apo(a) and Lp(a) make to the phenotypes of vascular cells, including endothelial cells and monocyte/macrophages.9 Coupled with the contributions of the LDL component of Lp(a) to the atherosclerostic process in the vessel wall, such as increased macrophage foam cell formation, this underscores how Lp(a) can be a particularly potent risk factor for CVD. Additionally, the ability of Lp(a) to interfere with the breakdown of fibrin clots may contribute to the persistence of mural clots and the thrombotic events that accompany plaque rupture.¹⁰ 

The oxidative modification of Lp(a) has been associated with CAVD, likely through the ability of Lp(a) to bind to autotaxin and target this molecule to the site of aortic valve lesions.¹¹ Within the leaflets, autotaxin results in the generation of the proinflammatory lysophosphatidic acid from the oxPL on Lp(a).

When to measure Lp(a) levels

Since elevated levels occur in from 20% to 30% of all patients and levels do not markedly change, we predict that everyone eventually will have their Lp(a) levels checked as a standard test at an early age. This outcome will depend on the availability of properly standardized Lp(a) tests and acceptance of the concept that Lp(a) measurements provide clinical value. Until then, the recommendation from the European Atherosclerosis Society is to screen for Lp(a) in the following situations: premature CVD, familial hypercholesterolemia, family history of premature CVD or elevated Lp(a), recurrent CVD despite being on lipid-lowering therapy, >3% 10-year risk of fatal CVD (Europe) or >5% 10-year risk of fatal/ nonfatal coronary heart disease (United States) and aortic valve calcification or stenosis.¹² We also recommend measuring Lp(a) in patients who have a minor LDL-cholesterol (LDL-C) lowering response to statins or proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors. These patients may have an elevated Lp(a): these medications are unable to lower LDL-C since a considerable percentage of the LDL-C may be Lp(a) (PCSK9 inhibitors lower Lp(a) to a lesser extent than LDL, and statins may in fact slightly raise Lp(a) levels).¹³ Indeed, based on its structure, it is not surprising that Lp(a) may contribute significantly to measurements of LDL-C. Based on the following equation, LDL-C_measured = Lp(a)-C + LDL-C_true, three hypothetical scenarios shown in Table 1 illustrate the extent to which Lp(a) cholesterol can contribute to LDL cholesterol measurement.¹³

As can be readily seen in the PCSK9 era of unprecedented extents of LDL lowering, the contribution of Lp(a)-C to measured LDL-C may be extreme; it would be expected that, in cases such as this, the lack of expected response to LDL-lowering strategies based on LDL-C levels may be a flag for the presence of elevated Lp(a) levels.

When and how to treat an elevated Lp(a) in Primary Prevention

Meta-analyses show that the CV risk attributable to Lp(a) increases continuously starting at approximately 75 nmol/L (30 mg/dL);¹⁴ a level of 125 nmol/L (50 mg/ dL) is considered elevated by the EAS.¹² Lp(a) tests should (i) report particle concentrations in nmol/L, (ii) utilize a 5-point calibrator to minimize isoform-dependent bias, and (iii) be calibrated to the World Health Organization/ International Federation of Clinical Chemistry Lp(a) reference material.¹⁵ A one-time measurement of Lp(a) for patients with an intermediate CVD risk in the Bruneck study allowed a 40% reclassification of the patients into a category of either higher or lower risk of CVD.¹⁶ For these patients at a higher risk, it may be of benefit to address other treatable CVD risk factors more aggressively to possibly compensate for the increase risk associated with an elevated Lp(a). The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial demonstrated in primary prevention patients with high CV risk that an elevated Lp(a) level reduced the benefit of rosuvastatin therapy.¹⁷ Cholesteryl ester transfer protein (CETP) inhibitors consistently lower Lp(a) levels; even though the most recent study, Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL), using the CETP inhibitor anacetrapib significantly reduced CVD events, the company has decided not to pursue U.S. Food and Drug Administration (FDA) approval of the drug. The use of low-dose (82 mg/day) acetylsalicylic acid (ASA) for healthy individuals with a genetic variant in LPA (the gene encoding Apo(a)) associated with elevated Lp(a) in The Women’s Health Study resulted in a twofold lowering of CVD events.¹⁸ We believe that ASA should be considered in patients with elevated Lp(a).

When and how to treat Lp(a) in Secondary Prevention

The contribution of Lp(a) to secondary prevention when LDL levels are substantially lowered remains a point of controversy, with both positive and negative findings for a contribution of Lp(a) to risk in this setting.^19,20 These types of studies have methodological challenges associated with them, including index-event bias and issues with the methods used for Lp(a) measurement. Clearly this is an area that requires further study.

Currently, there does not exist an FDA-approved drug with an indication to lower Lp(a) levels. Past studies have shown aspirin and niacin reduce Lp(a) by about 30%, with the former demonstrating a reduction in cardiovascular events.²¹ PCSK9 inhibitors and mipomersen have shown modest reduction (30%) of Lp(a) but are prescribed for the reduction of LDL-C. Lipid-apheresis is the only presently available therapy providing consistent reduction of Lp(a) and CVD events (70%-80%) for patients with CVD and an elevated Lp(a);^22-24 in these prospective/ retrospective studies, the control groups were the same patients but prior to initiating apheresis. For the past 10 years the German Health association has allowed apheresis treatment for patients with an elevated Lp(a) level (>60 mg/dL) and ongoing CVD. More than 2,000 patients now are being treated once a week, with significant reduction in their future risk of CVD events. In the United States, very few patients receive apheresis for an elevated Lp(a). In a single U.S. center study, 15 patients were treated once every two weeks with apheresis and revealed similar CVD-event reductions as seen in the German trials. Very recent sub-analyses of the FOURIER²⁵ and ODYSSEY-Outcomes²⁶ trials showed that patients with the greatest reduction in Lp(a) had the greatest benefit, and in ODYSSEY-Outcomes this was independent of the extent of LDL-C lowering. However, both failed to show that high baseline Lp(a) predicted enhanced cardiovascular benefit from the respective drugs. It must be noted that these studies were not designed to enroll subjects specifically with elevated Lp(a) and the degree of Lp(a) lowering was modest.

Future therapy for the reduction of Lp(a)

Because of issues of cost, complexity and accessibility, lipid-apheresis is not a feasible future therapy for most patients with an elevated Lp(a) and CVD. Newer medical agents must be developed for the potentially sizable population of patients with CVD and elevated Lp(a). Presently, an ribonucleic acid (RNA) antisense medication to Lp(a) translation (IONIS-APO(a)_Rx) is in a Stage 2 dosing trial.²⁷ Following positive results, the drug most likely will move to a Phase 3 clinical outcome trial. Additionally, a comparable drug (RNA interference) will be initiating a Phase 1 trial in humans, and a third anti-Lp(a) drug is in early development. These investigational therapies offer hope for the future in treating Lp(a) and CVD.

Disclosure statement: Dr. Moriarty has received honoraria from Regeneron, Sanofi, Amgen, Duke University, Esperion, Kaneka, RegenXBio, Kastle, Amarin, Gemphire, Stage 2 Innovations and Ambry Genetics. He has received research grants from Stage 2 Innovations, the University of Pennsylvania, Zydus Discovery, Gemphire, Kowa, Akcea and the FH Foundation. He serves on the advisory board of Eliaz Therapeutics and Aegerion. He owns stock optionswith Eliaz Therapeutics. Dr. Koschinsky has received an honorarium and research grant from Pfizer, an honorarium and research contract from Eli Lilly and research contracts from Cardiovax and Ionis. Dr. Boffa has received a research contract from Ionis.

References can be found here.