In this post, I link to and excerpt from the American College of Cardiology‘s Latest In Cardiology, Lipoprotein(a) in Clinical Practice, Jul 02, 2019 | Paul Scheel, MD; Joseph Meyer, MD; Roger S. Blumenthal, MD, FACC; Seth Shay Martin, MD, MHS, FACC Expert Analysis.
All that follows is from the above resource.
Editor’s Note: Commentary based on Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374-92.*
The traditional lipid profile has served as a mainstay of atherosclerotic cardiovascular disease (ASCVD) risk assessment for decades. This tool became even more important as targeted therapies, such as statins and more recently ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, became available. Even with these advances in lipid management, and more broadly in targeting traditional cardiovascular risk factors, ongoing risk in many patients points to a need to investigate other contributors as possible therapeutic targets. Lipoprotein(a) (Lp[a]) is a promising biomarker to help refine current strategies of ASCVD risk assessment, and it is estimated to be elevated in approximately 20% of the world’s population. Research on Lp(a) suggests it has added value in preventive medicine, and it is time for cardiologists and cardiovascular team members to consider using it routinely in their practice. Based on the mounting evidence, Wilson et al recently published a guideline on the clinical use of Lp(a) from the National Lipid Association, and herein we summarize key elements of their work.
What is Lipoprotein(a)?
Lipoprotein(a) is a low-density lipoprotein (LDL) particle with an added apolipoprotein(a) (apo[a]) attached to the apoplipoprotein(b) (apo[b]) component of the LDL particle via a disulfide bridge. The structure of Lp(a) is highly heterogeneous secondary to many different apo(a) isoforms within the population.
An individual’s Lp(a) level is 80-90% genetically determined in an autosomal codominant inheritance pattern with full expression by 1-2 years of age and adult-like levels achieved by approximately 5 years of age. Outside of acute inflammatory states, the Lp(a) level remains stable through an individual’s lifetime regardless of lifestyle.
High quality evidence supports a link between Lp(a) levels and a variety of cardiovascular related outcomes.
Table 1 shows the risk of elevated Lp(a) on a variety of cardiovascular conditions based on large prospective, population-based studies and that these associations were also seen in Mendelian randomization studies. Finally, genome wide association studies focusing on genetic variation and risk of disease found that high Lp(a) concentrations confer the highest risk of ASCVD and VAS independent of other known causes and risk factors.
Measurement and Target Levels of Lp(a)
One of the main obstacles to the clinical use of Lp(a) is that its measurement and target levels have not been standardized. Several available assays report results in mass (mg/dL) instead of concentration (nmol/L), the latter of which is preferred. Unlike other lipids and lipoproteins, direct conversion between these two units is not possible because of the variable number of repeated units in different apo(a) isoforms, which leads to over- or underestimation depending on the particle size.
Fortunately, all of these [problems] can be overcome by standardization of the assay and generated measurements. The guideline recommends reporting Lp(a) levels as concentration (nmol/L) using an assay calibrated against the WHO/International Federation of Clinical Chemistry and Laboratory Medicine secondary reference manual.
Based on the available studies, the guideline recommends a universal cut point of ≥100 nmol/L (approximately ≥50 mg/dL), which approximates the 80th percentile in the Caucasian U.S. populations. However, the use of this cut point remains a topic of debate amongst many experts in the lipid community and this likely stems from the lack of standardization and epidemiologic differences. This controversy is represented by the 2018 American Heart Association (ACC)/American Heart Association (AHA) Cholesterol Guidelines, which suggest high risk is ≥125 nmol/L (or ≥50 mg/dL). The cut off may change as additional studies are completed, recognizing that the cut off may vary based on risk, ethnicity, and comorbidities.
Which Patients Should Have Lp(a) Measured?
Assuming access to a WHO-standardized assay, select patients may benefit from Lp(a) testing after a shared decision-making discussion is completed. Based on this guideline, measuring Lp(a) may be reasonable in patients with a personal history of or first-degree relative with premature ASCVD (particularly if otherwise considered low-risk), and in severe hypercholesterolemia (LDL-C ≥190 mg/dL). Testing in these patients may trigger escalation of therapy, as described below. Additional indications where testing may be reasonable are listed in Table 2, most notably including patients where the LDL-C response to statins is less than anticipated, or in borderline-risk patients (5% to ≤ 7.5% 10-year ASCVD risk) who are particularly interested in reducing their ASCVD risk.
Studies like a JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) sub-analysis show Lp(a) is a strong predictor of risk when it remains elevated in patients who are already on a statin. However, no available data support that treating isolated, elevated Lp(a) leads to better clinical outcomes. If and when targeted Lp(a) treatment becomes available, it may be reasonable to start universal screening at a young age to determine if earlier preventive measures are indicated.
How Do You Treat Elevated Lp(a)?
Despite the observed associations between elevated Lp(a) and ASCVD, there has yet to be a randomized controlled trial to see if targeted lowering of Lp(a) improves clinical outcomes. However, the Lp(a)-lowering effect of currently available therapies has been investigated.
Of the current available preventive therapies, only a limited number are effective in reducing Lp(a).
Apheresis may be considered for select patients. It is highly effective at lowering Lp(a) levels but a costly and cumbersome procedure that may be difficult to obtain insurance coverage for. It is reserved for only the most refractory patients and should be pursued after optimally controlling known risk factors with proven therapies. In Germany, apheresis appeared to yield a 70% reduction in MACE in patients with recurrent ASCVD events with elevated Lp(a) regardless of LDL-C levels.
Based on the available data, the authors recommend initiating a moderate- to high-intensity statin therapy in adults aged 40-75 years with a 10-year ASCVD risk of 7.5% to ≤20% with a Lp(a) ≥100 nmol/L. As is already commonly done, high risk patients with LDL-C ≥70 mg/dL (non-HDL-C ≥100 mg/dL) and a Lp(a) ≥100 nmol/L on maximally tolerated statin should be considered for more intensive therapies (ezetimibe* and PCSK9 inhibitors**) to lower LDL-C.
Currently, novel therapies are being studied that selectively target Lp(a). A phase 2 trial of AKCEA apo(a)-LRx, an apo(a) antisense oligonucleotide, reduced Lp(a) up to 80%. A phase 3 study is being planned. Additionally, an oxPL antibody that binds and inactivates the pro-osteogenic activity of Lp(a) has promising in vitro data. These therapies, while promising, require additional research prior to becoming mainstream therapies.
Lipoprotein(a) represents an exciting new biomarker in the field of lipidology and preventive cardiology. Elevated Lp(a) is causally implicated in ASCVD, and testing in specific patients may help to tailor the appropriate intensity of preventive measures. However, because of the lack of standardization and heterogeneity of the available data, optimal cut-offs remain a source of intense debate. The current focus of clinical care is on traditional risk factor control in patients with high Lp(a) as targeted treatment options are limited. Novel Lp(a)-targeting therapies are actively being investigated, and if successful, they could become an important component of primary and secondary prevention.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Valvular Heart Disease, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Diet