Recent studies have clarified the role of lipoprotein (a) [Lp(a)], relative to other lipoproteins, in atherogenesis. This article discusses several clinical aspects of Lp(a), including the association with cardiovascular disease risk, considerations regarding measurement, guideline recommendations, and emerging therapies.
Lp(a) is a low-density lipoprotein (LDL)-like lipoprotein with apolipoprotein (a) [apo(a)] covalently linked to apolipoprotein B via a disulfide bond. Conventional lipid assays cannot measure or estimate Lp(a), requiring a separate assay for its measurement.
Lp(a) is a risk factor for atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction and ischemic stroke, in both primary and secondary prevention populations, as well as for incident calcifying aortic stenosis. The increased risk associated with Lp(a) is attributed to a dyad of enhanced procoagulant effects of apo(a), with atherogenic and proinflammatory effects attributed to its apolipoprotein B-related oxidized phospholipids.
About 1 in 5 people have elevated Lp(a) levels (>50 mg/dL [or >125 nmol/L]). Lp(a) levels are 75% to 95% heritable , primarily determined by single nucleotide variants as well as kringle domain IV type 2 copy number variants in the LPA gene, which encodes apo(a). The LPA gene evolved from a duplication event of the plasminogen gene, which also has kringle domains .
Evidence supporting increased causal risk
Although placebo-controlled trials testing the hypothesis that lowering Lp(a) levels will reduce cardiovascular risk are ongoing, a large body of preclinical data supports this scientific premise.
Taking advantage of the exceptionally high heritability of Lp(a), Mendelian randomization methods are suitable for providing supporting evidence. To minimize potential confounding factors that may separately influence Lp(a) concentrations and cardiovascular disease risk, it is possible to examine the clinical risks conferred by random assignment of Lp(a)-generating alleles in LPA; These alleles are associated with various ASCVD and calcific aortic stenosis.
Proprotein convertase subtilisin/kexin type 9 (PCSK-9) monoclonal antibodies reduce the Lp(a) level by approximately 25%.
Post hoc analyzes of completed PCSK-9 monoclonal antibody cardiovascular outcomes trials suggest that Lp(a) level reduction from this drug class was associated with greater cardiovascular risk reduction beyond LDL cholesterol reduction. only.
Lp(a) measurement
Lp(a) levels are typically reported as the mass of the entire Lp(a) particle in mg/dL or as the number of apo(a) particles in nmol/L. Occasionally, Lp(a) may be expressed as cholesterol Lp(a) in mg/dL. Cross-reactivity of assay antibodies with kringle IV type 2 repeats may lead to an underestimation of Lp(a) concentrations in patients with smaller isoforms and an overestimation of concentrations in patients with larger isoforms.
Most clinical laboratories can at least identify high-risk patients (i.e., >50 mg/dL or >125 nmol/L).
However, because clinical trials now often include individuals with higher Lp(a) concentrations, better standardization and consistency will be necessary. Because Lp(a) is highly heritable , repeat Lp(a) testing is usually unnecessary in the absence of medications known to substantially change the Lp(a) level after initial measurement.
Genetic variants at the LPA locus may provide prognostic information similar to Lp(a) concentration, but have unclear incremental clinical utility when Lp(a) concentration is already available.
The failure of cholesterol-lowering medications to lower LDL may sometimes reflect imprecision of LDL cholesterol estimation due to elevated Lp(a) concentrations; To solve this problem, Lp(a) cholesterol must be subtracted from the calculated LDL cholesterol. If Lp(a) cholesterol is not analyzed directly, Lp(a) cholesterol can be estimated by multiplying 0.3 by the mass of Lp(a).
Guide recommendations
Current US guidelines suggest that Lp(a) may be used as a “risk-increasing factor” to support statin prescribing , along with other factors and shared decision-making, among primary prevention patients. ages 40 to 75 with an estimated 10-year ASCVD risk of 5.0% to 19.9%.
Although statins may moderately increase Lp(a), this phenomenon has not been associated with increased risk. Additionally, Lp(a) can be measured in patients with ASCVD that is apparently not explained by conventional risk factors.
European guidelines recommend a single broad measurement of Lp(a) for all adults to identify very high-risk individuals with Lp(a) greater than 180 mg/dL (or > 430 nmol/L), but the clinical efficacy of this strategy is currently unknown. These individuals may have a similar lifetime risk of ASCVD as those with heterozygous familial hypercholesterolemia, but, unlike LDL cholesterol, clinically effective Lp(a)-lowering therapies have not yet been demonstrated prospectively.
Although Lp(a) is thought to be prothrombotic , whether aspirin mitigates the risk of ASCVD associated with Lp(a) has not been well studied , and therefore aspirin alone is not currently recommended in guidelines for Lp (a) elevated.
Emerging therapies to reduce Lp(a) concentrations
There are currently no approved pharmacological therapies to reduce Lp(a) concentrations and the risk of ASCVD. Although PCSK-9 monoclonal antibodies reduce Lp(a), they are not approved for use in people meeting LDL cholesterol goals.
Niacin modestly reduces Lp(a), but may not further reduce ASCVD risk in addition to statins.
human genetics
Studies anticipate that considerable reduction of Lp(a) may be necessary to achieve significant improvement in clinical outcomes.
New drugs aimed at substantially reducing Lp(a) concentrations are currently in clinical development. In a 2020 Phase 2a trial, among 286 patients with ASCVD and elevated Lp(a), a hepatocyte-targeting antisense oligonucleotide targeting LPA mRNA led to an 80% decrease in Lp(a).
This agent, TQJ230, dosed at 80 mg subcutaneously monthly, is being compared with placebo in a pivotal phase 3 cardiovascular outcomes trial among 7,680 patients with prior myocardial infarction, stroke, or peripheral arterial disease and an Lp level ( a) greater than 70 mg/dl (NCT04023552).
Olpasiran, formerly AMG890, is a small interfering RNA targeting LPA mRNA that requires less frequent injections and is currently being studied in approximately 240 patients (NCT04270760).
Implications for clinical practice
Several lines of evidence suggest that Lp(a) concentrations are associated with ASCVD and calcific aortic stenosis beyond traditional risk factors, and that reducing Lp(a) concentrations may reduce these risks.
In the absence of prospectively validated strategies to address excess risk associated with Lp(a), high Lp(a) levels may prompt the prescription of statins and more aggressive LDL cholesterol targets in the primary prevention setting.
When evaluating LDL cholesterol goals for patients treated for primary and secondary prevention, Lp(a) concentrations could be considered to improve estimation of LDL cholesterol. Additionally, measurement of Lp(a) among patients treated for secondary prevention may facilitate participation in ongoing clinical trials.
