Emerging Pharmacotherapy to Reduce Elevated Lipoprotein(a) Plasma Levels

Nathaniel Eraikhuemen; Dovena Lazaridis; Matthew T. Dutton


Am J Cardiovasc Drugs. 2021;21(3):255-265. 

In This Article

Abstract and Introduction


Lipoprotein(a) is a unique form of low-density lipoprotein. It is associated with a high incidence of premature atherosclerotic disease such as coronary artery disease, myocardial infarction, and stroke. Plasma levels of this lipoprotein and its activities are highly variable. This is because of a wide variability in the size of the apolipoprotein A moiety, which is determined by the number of repeats of cysteine-rich domains known as "kringles." Although the exact mechanism of lipoprotein(a)-induced atherogenicity is unknown, the lipoprotein has been found in the arterial walls of atherosclerotic plaques. It has been implicated in the formation of foam cells and lipid deposition in these plaques. Pharmacologic management of elevated levels of lipoprotein(a) with statins, fibrates, or bile acid sequestrants is ineffective. The newer and emerging lipid-lowering agents, such as the second-generation antisense oligonucleotides, cholesteryl ester transfer protein inhibitors, and proprotein convertase subtilisin/kexin type 9 inhibitors offer the most effective pharmacologic therapy.


Significant advances have been made in the treatment of dyslipidemia. However, many patients continue to experience clinical manifestations of atherosclerotic vascular diseases, such as myocardial infarction (MI), cerebrovascular diseases, and peripheral vascular disease.[1] Clinical dyslipidemias fall into four broad categories: high levels of low-density lipoprotein cholesterol (LDL-C), low levels of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and elevated lipoprotein(a) [Lp(a)].[2] Over time, more emphasis has been placed on pharmacologic and nonpharmacologic reduction of LDL-C as a method of reducing atherosclerotic vascular diseases. In addition, lifestyle modification and the treatment of modifiable diseases, such as hypertension and diabetes mellitus, have also been at the forefront of the management of dyslipidemia. Advances in our knowledge of non-LDL-C physiology and improved assay techniques have shed more light on the role of Lp(a) in the pathogenesis of atherosclerotic vascular diseases.[3] In this review, we focus on the emerging pharmacotherapeutic agents used to lower plasma levels of Lp(a).

Lp(a) was discovered in 1963 by the geneticist Kara Berg.[4] Initially described as a variant of LDL, Lp(a) is now widely recognized as a distinct plasma lipoprotein. Lp(a) is composed of two distinct parts: apolipoprotein-B (apoB) and apolipoprotein-A (apoA), a plasminogen-like glycoprotein (Figure 1). ApoB is structurally and physicochemically similar to LDL-C, and apoA consists of carbohydrate-rich proteins.[2,5,6] Both molecules are covalently linked by a disulfide bond to form a single macromolecule. The origin of unbound plasma apoA is unknown, but the synthesis of this subunit takes place in the liver and appears to be independent of other lipoprotein synthesis. The actual assembly of Lp(a) is believed to take place within the hepatocytes.[2,7] Although the size of the apoA moiety varies widely, it is mainly determined by the size and the number of repeats of cysteine-rich domains known as "kringles." Evidence from DNA sequencing suggests that the kringle IV repeat shares a high degree of structural homology with the fibrinolytic enzyme precursor plasminogen.[2,7] Plasminogen contains five kringles (KI–KV) and a protease domain. ApoA contains several subtypes of KIV repeat polymorphisms, so apoA protein size heterogeneity is extensive, resulting in different sizes of Lp(a) particles. Plasminogen is a protease zymogen; when activated, it cleaves fibrin to dissolve clots. Considering the striking molecular similarity between plasminogen and Lp(a), Lp(a)/apoA atherothrombotic properties are in part due to the competitive inhibition of tissue-type plasminogen activator-mediated binding, thus leading to a decrease in plasminogen activation, plasmin synthesis, and fibrinolysis.[8]

Figure 1.

Structure of lipoprotein(a). Lipoprotein(a) consists of apolipoprotein(a) covalently bonded to the apolipoprotein(b)-100 component of a low-density lipoprotein (LDL)-like moiety by a single disulfide bond. Also depicted are the kringles. Modified from Nordestgaard et al. [8]

Although the exact mechanism of Lp(a) atherogenicity is unknown, Lp(a) is a known preferential carrier of oxidized phospholipids in humans and has been shown to bind proinflammatory-oxidized phospholipids.[8]


Population studies have revealed that plasma levels of Lp(a) vary amongst humans, ranging from 20 to > 2000 mg/dL between racial groups, with almost 20% of the population at the extreme levels.[6] These levels are not affected by age or sex. There are no differences in the serum levels of Lp(a) between Caucasian men and premenopausal women. Among the Caucasian, Asian, and Indian populations, Lp(a) distribution is highly skewed to the left, whereas the distribution is almost normal among African American and perhaps African populations. These variations in the distributions must be considered when interpreting studies involving Lp(a). Additionally, particle size varies widely, ranging from 180 to > 600 kDa. The number of kringle IV repeat genes in Lp(a) is thought to determine the size, which is inversely related to an increased risk of cardiovascular diseases (CVDs).[6]

Lipoprotein(a) [Lp(a)]: A Risk Factor for Atherosclerotic and Thrombogenic Events

An elevated serum level of Lp(a) is an independent risk factor for CVD.[1,6,8,9] A residual risk of CVD remains in patients with low LDL-C goal, as demonstrated in a subgroup analysis of Caucasian participants in the JUPITER study.[6] In a meta-analysis of 29,069 patients with Lp(a) measurements, CVD risk was approximately linear with increased Lp(a) values.[10] Elevated Lp(a) of ≥ 30 mg/dL at baseline was associated with an increased hazard ratio of cardiovascular events independent of other cardiovascular risk factors.[10] Additionally, Willeit et al.[10] also reported that CVD risks were approximately linear with increased Lp(a) values in patients receiving statin treatment. Elevated Lp(a) of ≥ 50 mg/dL on treatment was associated with a linear increase of cardiovascular events, irrespective of statin therapy.[10] These data suggest that residual CVD risks remain in patients treated with maximally tolerated statin therapy and identifies elevated Lp(a) as one of the factors that may be modified to further reduce residual risk. Thus, statin-treated patients with elevated levels of Lp(a) represent a significant determinant of residual risks for CVD.[6,10] These findings also highlight the importance of lowering plasma levels of Lp(a). Moreover, two prospective population studies—EPIC-Norfolk (The European Prospective Investigation of Cancer in Norfolk) and the Copenhagen City Heart Study—concluded that Lp(a) and LDL-C are independently associated with CVD risk.[11] Additionally, the Canadian Cardiovascular Society's (CCS) guidelines for the management of dyslipidemia for the prevention of CVD in adults noted that Lp(a) is a marker of CVD risk.[12]

Although the actionable clinical threshold value for Lp(a) is difficult to define, the European Atherosclerosis Society has proposed an optimal Lp(a) level of < 80th percentile, which approximates < 50 mg/dL, in Caucasian patients without any cardiovascular risks.[8] Furthermore, the CCS has recommended that particular attention be given to individuals with Lp(a) levels > 30 mg/dL, for whom CVD risk is increased approximately twofold.[12]

Screening the general population for cardiovascular risk stratification is not recommended; however, Lp(a) screening should be considered in patients with premature coronary artery disease (CAD) and or in patients with dyslipidemia refractory to statins or bile acid sequestrants. Furthermore, other patient subgroups that may benefit from Lp(a) screening include those who may have particularly adverse clinical consequences secondary to elevated Lp(a) concentrations. These groups include patients with a history of coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, heart transplantation, and familial dyslipidemia.[13]