Understanding Elevated Lipoprotein(a): A Focus on Cardiovascular Risk and Screening Recommendations

A panel discussion titled “Elevated Lipoprotein(a): Raise Your Game and Lower Your (Risk) Score?” presented at the American Heart Association (AHA) Scientific Sessions 2023, which convened in Philadelphia, Pennsylvania, from November 11 to 13, 2023, focused on elevated lipoprotein(a) as a risk for cardiovascular (CV) events, with speakers highlighting the need for awareness, testing, and personalized management strategies for patients with elevated lipoprotein(a).

Background, Prevalence, and Significance of Lp(a)

Lipoprotein(a), commonly referred to as “Lp little (a)” or “Lp(a),” is a type of lipoprotein particle found circulating in the blood. Lp(a) is an apolipoprotein(B) family member, but as presenter Leslie J. Donato, PhD, DABCC, associate professor and clinical chemist at Mayo Clinic, explained, the unique chemical feature of Lp(a) is the presence of the covalently bound apolipoprotein(a), or apo(a), to the core particle of this lipoprotein. Genetically, high expressers of the apo(a) protein will have high circulating concentrations of Lp(a) in their bloodstream.¹

High Lp(a) concentrations have been causally associated with poor CV outcomes, such as myocardial infarction (MI), stroke, and aortic stenosis, and the discussion panelists underscored the importance of screening for this often-overlooked risk factor.¹ Presenter Leslee J. Shaw, PhD, FACC, professor at Icahn School of Medicine at Mount Sinai, explained that elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD).² Through increased atherogenesis, inflammation, and thrombosis, elevated Lp(a) results in cholesterol accumulation in the arterial wall and downstream pro-inflammatory effects.² Despite the evidence demonstrating that elevated circulating concentrations of Lp(a) in the bloodstream are linked to increased risk for the development of ASCVD, Donato explained that many providers know little about this risk factor and subsequently don’t usually test for it. An estimated 20% of all individuals in the general population have increased Lp(a) concentration,³ but without adequate testing, those individuals are not being identified for intensive preventive measures.

Lipoprotein(a) Identified as a Causal and Independent Risk Factor for ASCVD

The presenters underlined the wealth of data implicating Lp(a) as a causal risk factor for CVD. Evidence such as epidemiologic meta-analyses, Mendelian randomization studies, and genome-wide association studies demonstrated that elevated Lp(a) levels play an additive and independent role in predicting CV risk.^3,4

In comparing individuals with low Lp(a) to individuals with elevated Lp(a), Donato explained that those with elevated Lp(a) have increased ASCVD risk, including increased risk of MI (3- to 4-fold), aortic valve stenosis (3-fold), ischemic stroke (1.6-fold), heart failure (1.5- to 2-fold), CV mortality (1.5-fold), and all-cause mortality (1.2-fold).^5-11

Presenter Nathan D. Wong, PhD, MPH, FACC, a professor and director at the University of California, Irvine, School of Medicine, emphasized the additive role of both elevated LDL and elevated Lp(a) in further predicting risk.¹² “We know from the Bruneck population study that Lp(a) was associated with a 37% increased risk of cardiovascular disease over about 15 years of follow-up. And noteworthy was that they were able to show that when you add Lp(a) to 2 standard risk factors, you correctly reclassify risk in nearly 40% of individuals,” said Wong. Additionally, he noted that higher levels of Lp(a) were directly related to the progression of coronary artery calcium, further compounding the increased CV risks of elevated Lp(a) concentrations.¹³

Evidence from imaging illustrated the effects of elevated Lp(a) on the progression of atherosclerosis. Shaw discussed the increase in the percent atheroma volume and necrotic core progression, markers associated with acute coronary rupture, as evidenced by studies utilizing intravascular ultrasound in patients with increased Lp(a) levels.^14,15 Studies with repeat coronary computed tomography angiography (CCTA) confirmed those findings, demonstrating that elevated Lp(a) was associated with increased progression of low-attenuation plaque volume in only 1 year of follow-up, a marked progression in such a short period.¹⁶ “This is the lowest of the low in terms of the density of the plaque that we can see on CT, and it is lipid-rich plaque. This is one that is highly volatile and highly prone to rupture,” said Shaw.

Study results also have shown that the increased risks of elevated Lp(a) levels persist despite lipid-lowering therapies and well-controlled LDL levels.^17,18 The presenters contended that elevated Lp(a) is the strongest risk factor for predicting future CVD events, even in statin-treated patients, and identified risk stratification based on Lp(a) levels as an opportunity to target higher-risk patients who could benefit from more intensive control of LDL-C and other risk factors.

Testing for Specific Populations

Lp(a) expression is genetic and can be detected within the first year of life, rising throughout childhood and reaching a stable plateau in adulthood.¹⁹ Guidelines vary by country and organization but recommend testing for individuals with a family history of premature ASCVD.^3,5,20-26 According to the American Heart Association (AHA) and American Association of Clinical Endocrinologists (AACE), other clinical considerations for testing include a personal history of premature ASCVD, moderate to severe ASCVD risk, and patients who are refractory to current lipid-lowering therapy.³ “If you live in Canada or the EU, their guidelines actually recommend at least once in a person’s lifetime. Individuals can be walking around with completely normal lipid panels and be unaware that they are a high expressor of Lp(a),” said Donato.^23,24

Underscoring the silent nature of this biomarker, presenter Maurice Williams, PhD, MPH, a medical science liaison with Novartis, shared his personal experience as a patient with undiagnosed elevated Lp(a) levels. Williams suffered a massive intraoperative heart attack during a lumbar fusion surgery, resulting in the placement of 6 coronary artery stents and a lengthy recovery period following a 7-day coma. He described how he was an active 50-year-old man who exercised regularly with well-controlled LDL on a low-dose statin. After the CV event, Williams requested testing for elevated Lp(a) and discovered his levels were significantly elevated at 217 mg/dL, placing him at extremely high risk. As his insurance did not cover the Lp(a) testing, Williams elected to pay out of pocket and was stunned to find it only cost $22 at his preferred laboratory. Cost can be a discouraging factor for many patients, and Williams was surprised that in his case, the price point was very accessible. Williams lamented not knowing about the availability of this relatively inexpensive test and being able to identify his risk sooner.

Presenter Emily E. Brown, MGC, CGC, a genetic counselor at The Johns Hopkins University School of Medicine, explained that despite the genetic component of elevated Lp(a) levels, testing is easily accessible as it can be measured with a simple blood test as opposed to a comprehensive genetic screening.²⁷ Clinicians have the opportunity to focus the conversation on shared clinical decision-making of whether patients want to know this information and how they can empower themselves with this guidance. In her experience, Brown explained that patients generally want to know about their Lp(a) levels and use the information to inform their health care decisions, including lifestyle modifications as well as considerations for financial planning.

Given the heritable nature of Lp(a) expression, with studies demonstrating about 90% heritability, Brown explained that cascade screening is recommended to test Lp(a) concentrations in immediate family members of persons with elevated Lp(a) levels.^28,29 By taking this approach, Brown emphasized the impact that testing can have on an entire family or multiple generations, allowing for early intervention, enabling them to understand their genetic risks, and personalizing their treatment recommendations.

Laboratory Perspectives: Measuring and Interpreting Lp(a) Results

A known limitation of the standard lipid panel is that the Lp(a) is included in the LDL-cholesterol value, unless it is accounted for by correcting the LDL-cholesterol and subtracting the Lp(a) mass.^30-32 For patients who are high expressers of Lp(a), Donato explained that the cholesterol in the Lp(a) is hidden within the LDL-cholesterol value, even in calculated LDL or the gold standard beta-quantification. There is no available assay in a standard lipid panel that can distinguish between the cholesterol within Lp(a) and the cholesterol within LDL, and clinical judgment must be applied.

Once the decision is made to test for Lp(a) in a patient, Donato explained there is a Current Procedural Terminology (CPT) code specific for the Lp(a) blood test (CPT 83695) as well as International Classification of Diseases–Tenth Edition codes associated with elevated Lp(a) in the patient (E78.41) and a family history of elevated Lp(a) (Z83.430).^33,34 The standard assay to measure Lp(a) in the clinical laboratory is an immunoassay; however, there are differences in the types of immunoassays that may be available to the clinician’s in-house laboratory or reference laboratory.

Historically, clinical trials utilized an assay measuring mass units in milligrams per deciliter (mg/dL), and these measurements have been documented in the literature to guide clinical decision-making.²⁷ Donato described the unique challenge in accurately measuring these mass units due to variances in the size of the apo(a) isoform from patient to patient based on their genetic composition.¹ As a consequence of this size heterogenicity, there are inherent inaccuracies in utilizing this methodology. More recently, laboratory science has recognized that assays that are calibrated in molar units of nanomoles per liter (nmol/L) are slightly more accurate, but these molar assays are not as readily accessible for testing and lack sufficient population health data for clinical cut points. Still, Donato stressed the importance of testing regardless of the type of immunoassay available and addressing elevated Lp(a) levels in either test result.

Wong noted that several guidelines, including the American College of Cardiology/AHA Cholesterol Management Guideline and the National Lipid Association (NLA) identified Lp(a) greater than 50 mg/dL, or greater than 100-125 nmol/L, to be a risk enhancement factor.^5,35 Donato explained that many practices take a more conservative approach. “We know that statistically significant risk starts a little lower than what is published in the guidelines. In my laboratory, and in many reference laboratories, they start flagging results at 30 mg/dL,” said Donato.

Impact on Treatment Decisions and Risk Modification

The speakers stressed the importance of individualized treatment based on the patient’s comprehensive CV risk profile, including factors such as family history, metabolic syndrome, and race/ethnicity, in addition to lipid levels and biomarkers such as elevated Lp(a).^35,36 “Beyond risk score in our risk assessment, guidelines recommend the consideration of several risk enhancement factors to further inform the treatment decision,” said Wong. He explained that elevated Lp(a) warrants more intensified risk-reduction efforts in those individuals whereby the decision may otherwise not be clear. For example, he noted that the risk-enhancing factor of high Lp(a) concentration favors initiating a statin in adults aged 40 to 75 years without diabetes and 10-year ASCVD risk between 5% and 20%.

Patients with elevated Lp(a) levels are at risk for progression of atherosclerosis.² Shaw noted that these patients are candidates for intensified preventive care and disease management. Further, as Wong explained earlier, studies demonstrated that residual risk remains even in patients on statin therapy, highlighting the importance of addressing elevated Lp(a) and targeting tight control of manageable CV risk factors.^17,18

In considering approaches to disease management, Brown drew parallels to Alzheimer disease; similar to elevated Lp(a), she noted that there are not any targeted drug therapies to prevent Alzheimer disease, but it is possible to prevent disease progression.³⁷ Modification of lifestyle factors, such as diet, exercise, and smoking cessation, and managing comorbidities such as diabetes and hypertension, can help mitigate overall CV risk for patients with high Lp(a) concentrations. Brown recognized the 2022 European Atherosclerosis Society (EAS) guidelines, citing the recommendation of managing LDL-C, glucose, blood pressure, and other lifestyle factors for patients with significantly elevated Lp(a).²⁵

Conclusion

Elevated Lp(a) is a highly prevalent and heritable risk factor for CV events, affecting an estimated 1 in 5 persons in the general population. Lp(a) is proatherogenic, prothrombotic, and proinflammatory, with studies demonstrating that elevated Lp(a) levels confer a higher risk for ASCVD events. This inherited biomarker is both an independent and causal risk factor, and the risk remains even in patients who have normal lipid panels or have statin-controlled LDL-cholesterol. Testing for elevated Lp(a) is simple, guideline-recommended, and provides valuable information for risk stratification. Lp(a) screening can inform treatment approaches and encourage shared clinical decision-making. Intensified preventive care for individuals with elevated Lp(a) involves a comprehensive approach that includes lifestyle modifications, management of other CV risk factors, and ongoing monitoring. This approach aims to mitigate the increased CV risk associated with elevated Lp(a) levels and improve overall CV health outcomes.

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