US Pharm. 2023;48(11):17-23.
ABSTRACT: Lipoprotein(a), or Lp(a), is a unique lipoprotein demonstrated to be a risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. Lp(a) is a genetic risk factor not responsive to changes in environment, lifestyle, or physiological conditions. Lp(a) serum concentrations >125 nmol/L are associated with increased ASCVD risk, but this threshold is not universally accepted. None of the available lipid-lowering drugs are indicated for the treatment of elevated Lp(a). There are currently four investigational RNA-based therapeutic agents that have substantially reduced Lp(a) in clinical trials; two of them are being evaluated for ASCVD risk reduction in adequately powered outcomes studies. Until agents specifically targeting elevated Lp(a) become available, intensive risk-factor modification is the general management strategy.
Lipoprotein(a), or Lp(a), is a unique lipoprotein similar to LDL cholesterol (LDL-C), but with an attached apolipoprotein(a), or apo(a), moiety.1,2 Elevated concentrations of Lp(a) are a causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS).1-3 Although >20% of the world’s population has elevated concentrations of Lp(a), this component is not routinely measured as part of the lipid profile even among patients with manifest ASCVD.3 A number of issues surrounding Lp(a) have limited its recognition and use as both a risk factor and a target of treatment in patients who are at risk for or have ASCVD. This review will highlight the current clinical status of Lp(a).
The functional role of Lp(a) has not been well established. Lp(a) contains one molecule of apo(a) bound by a covalent disulfide bond to the apolipoprotein B-100, or apo(b), component of LDL-C.4 The apo(b) component, largely composed of cholesterol, is atherogenic. The apo(a) component contains multiple loops of proteins known as kringle domains and one protease domain.5 There are >40 different sizes of Lp(a) particles, each with a different mass (i.e., isoforms).6 The protease domain is structurally related to plasminogen, but it is enzymatically inactive, which promotes thrombosis.7 In addition, Lp(a) binds to oxidized phospholipids, which promote inflammation and atherosclerosis.8 Therefore, Lp(a) is associated with inflammation, endothelial dysfunction, and osteogenic changes in valve tissue leading to calcification.9 As a result, elevated Lp(a) concentrations increase the risk of ASCVD, thromboembolism, and CAVS.
The laboratory measurement of Lp(a) has been challenging owing to its wide range of particle size and mass. Laboratory assays measure and report Lp(a) either as a mass (mg/dL) or as a concentration of particles (nmol/L). Guidelines recommend measuring Lp(a) in nmol/L.1 Commercially available assays specific to apo(a) are subject to substantial variability resulting from the broad range of apo(a) isoforms.1,3 Recent technological advances have established that the enzyme-linked immunosorbent assay is able to measure Lp(a) with less isoform variability.10 A second isoform-independent method using a novel liquid chromatography/mass spectrometry technique has also been developed.11 For Lp(a) measurement, it is recommended that assays be calibrated against the World Health Organization/International Federation of Clinical Chemistry and Laboratory Medicine secondary reference material.6,11
Lp(a) is a genetic risk factor for ASCVD and CAVS that is not impacted by changes in environmental, lifestyle, or physiological conditions such as age, diet, cigarette smoking, and gender.1 Meta-analyses, Mendelian randomization studies, and genome-wide association studies have shown that elevated Lp(a) concentrations increase the risk of ASCVD.1,2,6 Patients who have mild-to-moderate aortic stenosis and elevated Lp(a) concentrations experience more rapid clinical progression of aortic stenosis and have a greater need for valve replacement compared with patients who have lower Lp(a) concentrations.12
Lp(a) is the most prevalent inherited risk factor for ASCVD. As much as 90% of the variability in Lp(a) concentrations is attributable to variations in the gene responsible for the synthesis of apo(a).2 Ancestry plays a critical role in the variability of this gene and the resultant concentration of Lp(a). The median Lp(a) concentration in white, East Asian, and Hispanic populations is 10 mg/dL to 20 mg/dL, and concentrations may be twofold to threefold higher among black individuals of African descent and South Asian populations.2 Elevated Lp(a) is independently associated with ASCVD in all racial and ethnic groups. The pathophysiological mechanism of Lp(a) does not appear to differ among various ethnic groups. Lp(a) concentrations are typically established by age 5 years and remain constant throughout adulthood.
Clinical Risk Assessment
Traditional lipid screening does not include the measurement of Lp(a). Currently, the concentration of Lp(a) associated with increased ASCVD risk is generally accepted to be >125 nmol/L. Interindividual variance is >100-fold, with a range of 0 nmol/L to 500 nmol/L. A number of guidelines have been published in recent years that provide recommendations on Lp(a) risk thresholds and populations most likely to benefit from Lp(a) screening (TABLE 1).1,13-16
The Canadian and European guidelines recommend that Lp(a) screening be performed at least once in a person’s lifetime.15,16 The basis for this recommendation is the lack of change based on age and lifestyle modification. All of the other guidelines require specific and somewhat complex combinations of risk factors for ASCVD or CAVS in order to recommend testing. The most common risk factor is a personal and/or family history of premature ASCVD or CAVS.
The treatment of patients with elevated Lp(a) is complicated. Patients with established ASCVD typically are already receiving lipid-lowering therapy directed at LDL-C concentrations. In patients at high risk or very high risk for ASCVD, the finding of an elevated Lp(a) concentration is viewed as an additional risk enhancer.14 The known effect of drug therapy on Lp(a) concentration is derived from studies of drugs for other lipoprotein concentrations (TABLE 2).17 There are currently four investigational agents that have reduced Lp(a) by 70% to 100% in phase II/III clinical trials. Two of these agents are being evaluated for ASCVD risk reduction in adequately powered outcomes trials, with results expected in 2 to 3 years.
Statins tend to raise Lp(a) concentrations, but they remain the drugs of choice for ASCVD risk reduction.17 Ezetimibe has been found to produce a small but statistically significant decrease in Lp(a) concentration, although the clinical relevance of this is uncertain.1,2 The monoclonal proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran reduce Lp(a) concentrations.1-3 A post hoc analysis of an outcomes study with alirocumab found reductions in Lp(a) to be associated with lower rates of first major ASCVD events and venous thromboembolism independent of the LDL-C reduction.18 A subsequent analysis further supported these findings and suggested that each 5-mg/dL reduction in Lp(a) predicted a 2.5% relative reduction in ASCVD events.19 In patients with extremely high ASCVD risk and markedly elevated Lp(a), LDL apheresis can reduce Lp(a) by 70% acutely and by 25% to 40% long-term.20
Pelacarsen (TQJ230; previously known as AKCEA-APO(a)-LRX and IONIS-APO(a)-LRX) is an antisense oligonucleotide that leads to a reduction in the synthesis of Lp(a) by producing abnormal messenger RNA (mRNA).17,21 A phase II dose-ranging study randomized 286 patients with established cardiovascular disease and an elevated Lp(a) concentration (>150 nmol/L) in 5:1 fashion to pelacarsen at various SC doses every 2 to 4 weeks or saline placebo.22 Lp(a) concentrations were significantly reduced at all doses studied, but the largest reductions in Lp(a), 72% and 80%, occurred with the dosages of 60 mg every 4 weeks and 20 mg every week, respectively. At the highest dosage (80 mg monthly), 98% of patients attained Lp(a) concentrations <125 nmol/L. Adverse effects leading to drug discontinuation occurred in 5% of patients receiving pelacarsen versus 4% of patients receiving placebo. Injection-site reactions were the most commonly reported adverse effect (27% for pelacarsen, 6% for placebo).
A phase III outcomes study of pelacarsen (HORIZON trial) in patients with elevated Lp(a) and established ASCVD began in late 2019 and is estimated to be completed in 2025.23 This study has enrolled 8,323 patients with a history of ASCVD and Lp(a) >150 nmol/L. The study design involves randomizing patients to pelacarsen 80 mg SC weekly or placebo for up to 4 to 5 years. The primary outcome is time to the first event of a four-endpoint outcome (cardiovascular death, nonfatal myocardial infarction [MI], nonfatal stroke, or urgent coronary revascularization requiring hospitalization).
Olpasiran (formerly known as AMG 890 and ARO-LPA) is a small interfering RNA (siRNA) that inhibits the mRNA responsible for the synthesis of apo(a) in hepatocytes, which reduces the synthesis of Lp(a).17 Two phase I dose-ranging trials in healthy subjects with baseline Lp(a) concentrations >70 nmol/L evaluated single doses ranging from 3 mg to 225 mg, which were found to reduce concentrations of Lp(a) by 56% to 99%.17 The greatest reduction in Lp(a) occurred between 43 days and 71 days post dose.
OCEAN(a)-DOSE was a phase II dose-finding study of olpasiran in 281 patients with established ASCVD and Lp(a) >150 nmol/L.24 Patients were randomized to receive one of four olpasiran dosages (10 mg, 75 mg, or 225 mg every 12 weeks or 225 mg every 24 weeks) or matched placebo. After 36 weeks, Lp(a) reductions were 70% in patients receiving 10 mg every 12 weeks and roughly 100% for all other dosing regimens. The proportion of patients achieving Lp(a) <125 nmol/L was 67% in the lowest-dose group, and essentially 100% of patients in the other three olpasiran groups achieved that threshold. The incidence of adverse events leading to discontinuation of olpasiran or placebo was similar (2%) across trial groups. The most common side effects were injection-site reactions (17% for olpasiran and 11% for placebo). Injection-site and hypersensitivity reactions were more common at higher (>75 mg) olpasiran doses.24
An outcomes trial of olpasiran, OCEAN(a)-Outcomes, began at the end of 2022.25 An estimated 6,000 ASCVD patients with Lp(a) ≥200 nmol/L will be randomized to receive olpasiran 225 mg every 12 weeks or placebo. The expected duration of treatment is 4 years, and the estimated study-completion date is the end of 2026.
Two other siRNA drugs, SLN360 and LY3819469, are currently being investigated. Dose-ranging studies with these agents in subjects with elevated (>125-150 nmol/L) Lp(a) concentrations are in progress.17 Data from a study of SLN360 in 32 subjects without ASCVD evaluated single doses of 30 mg, 100 mg, 300 mg, or 600 mg versus placebo (six subjects in each group).26 The primary outcome of the study was safety. Almost all subjects had mild injection-site reactions, except for subjects receiving the 600-mg dose, which was also associated with a higher incidence of headache and increases in neutrophils and C-reactive protein. Reductions in Lp(a) concentrations were dose related (46%-98% decrease), with the greatest effect seen 30 to 60 days post dose. Studies involving SLN360 and LY3819469 are ongoing.
In summary, the key factors for Lp(a) that are relevant to clinical practice and the management of Lp(a) are as follows:
• Lp(a), which is considered another form of “bad” cholesterol that plays a role in atherosclerosis, thrombosis, and inflammation, is independently associated with ASVCD and CAVS.
• Approximately 20% of the general population has elevated Lp(a) concentrations (defined as >125 nmol/L, although this threshold is not universally accepted).
• Lp(a) concentrations are established in youth and are almost exclusively genetic; they are minimally affected by diet, exercise, and weight loss.
• Because Lp(a) is not a component of standard lipid panels, it is often missed, even in patients with severe and recurrent ASCVD.
• Pharmacists should suspect elevated Lp(a) in the presence of premature, recurrent, or unexplainable ASCVD; in patients with a family history of ASCVD; and in those with familial hypercholesterolemia.
• No currently available drug therapy is indicated for elevated Lp(a) concentration; statins can cause small increases in Lp(a), whereas PCSK9 inhibitors can reduce concentrations by approximately 25%.
• Investigational agents demonstrate Lp(a) reductions of 70% to 100%, with ASCVD-outcome trial results expected in a few years.1,13-16
Until agents specifically targeting elevated Lp(a) become available, intensive risk-factor modification is the general management strategy.
Despite efforts to reduce ASCVD risk via lipid-lowering therapy and management of other known risk factors, such as diabetes and hypertension, patients continue to experience MI, stroke, and other vascular events.1-3 This residual risk may be related to unrecognized elevated concentrations of Lp(a). Until drug therapy that reduces Lp(a) concentration and its associated risk becomes available, other questions surrounding Lp(a) continue to be investigated. These include which patients will benefit from routine Lp(a) screening; what threshold concentration of Lp(a) should result in treatment; how Lp(a) concentrations will be factored into risk assessment; and to what extent Lp(a) should be reduced for clinical benefit. Until these questions are answered, patients with known elevated Lp(a) concentrations should receive intensive risk-factor modification. This includes maximally reducing LDL-C and employing other interventions for controlling known ASCVD risk factors.
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