Heart disease is the leading cause of death globally, taking an estimated 17.9 million lives each year. Most people are aware of the major ways to reduce the risk of developing heart disease, i.e. eat a healthy diet, exercise regularly, get enough high quality sleep, maintain a healthy weight and body composition, and be sure that cholesterol, blood sugar, and blood pressure are all kept in check. Recently however, research has identified a new risk factor for heart disease: lipoprotein (a).
Lipoprotein(a), called “lipoprotein little a”, is a unique lipoprotein particle found in the blood. It is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. As a result, it has gained significant attention in recent years since levels are not measured on routine cholesterol blood tests.
In this article, we’ll discuss what Lp (a) is, testing, treatment, and more.
Note: Check out our podcast on this topic here, and the accompanying video here.
What is Lipoprotein(a)?
Lipoprotein(a), often abbreviated as Lp(a), is a protein produced in the liver that carries cholesterol around the body. Lp(a) is a variant of low-density lipoprotein (LDL), which is described in further detail here).
Both LDL and Lipoprotein(a) contain cholesterol and single molecule of apolipoprotein B-100 – abbreviated apoB. However, Lp(a) differs from LDL in that it also carries a unique and highly variable molecule called apolipoprotein(a) — abbreviated apo(a).
This additional molecule, apo(a), is the main difference between LDL and Lp(a).
Is Lipoprotein(a) Genetic?
Blood Lp(a) levels are mostly determined by genetics, with over 90% of the variance attributed to the LPA gene. As a result, Lp(a) levels are mostly established after age 5, and remain relatively stable throughout life. This distinguishes it from other lipid markers like LDL-cholesterol, which are often more responsive to lifestyle factors like diet.
Why Do Lipoprotein(a) Levels Matter?
Elevated Lp(a) levels increase the risk of heart disease even if all other risk factors are within the normal range. Lp(a) contributes to “residual” cardiovascular risk. This describes the risk that persists even after other established risk factors like LDL-cholesterol and blood pressure are optimally controlled. Focusing solely on traditional factors may leave part of a person’s risk unaddressed if their Lp(a) is high.
Approximately one in five individuals worldwide have elevated Lp(a) levels. This makes it a common contributor to heart disease worldwide, yet remains largely “hidden” due to a lack of widespread testing. On average, individuals of African ancestry tend to have the highest Lp(a) concentrations, often two to three times higher than those of European or Asian ancestry. Conversely, individuals of Chinese and Japanese ancestry typically have the lowest levels.
The current momentum in Lp(a) research is also driven by the development of potent Lp(a)-lowering treatments, which are now in late-stage clinical trials.
The Role of Lipoprotein(a) in Cardiovascular Disease
Lipoprotein(a) contributes to heart disease through many different ways. It promotes atherosclerosis, calcification, and inflammation. In addition to carrying cholesterol, it is also a preferential carrier of oxidized phospholipids (OxPL), which, when deposited into blood vessel walls, are key mediators of these harmful effects. Together, this increases the risk of plaque formation in the arteries.
In addition, high Lp(a) levels are linked to the risk of calcific aortic valve stenosis. This is a progressive condition characterized by calcification and stiffening of the aortic valve, ultimately leading to obstruction of blood flow out of the heart.
Finally, Lp(a) also has effects that promote blood clotting (pro-thrombotic) and prevent clot breakdown (anti-fibrinolytic). Tipping the balance towards clot formation increases the risk of events where atherosclerotic plaques rupture, causing heart attacks and strokes.
A large body of evidence has established Lp(a) as an independent causal risk factor for numerous cardiovascular diseases, including myocardial infarction (heart attack) and stroke. Much like with LDL-cholesterol, evidence shows that lifelong exposure to higher Lp(a) concentrations directly relates to the risk of cardiovascular disease. As an independent risk factor, even individuals with very low or optimally managed LDL-cholesterol levels remain at higher risk if their Lp(a) is elevated.
Who Should Check Their Lipoprotein(a) Level? (Screening)
The approach to Lp(a) screening has evolved over time, with international guidelines now advocating for broader testing. Current guidelines from the National Lipid Association and the European Atherosclerosis Society recommend that Lp(a) concentration should be measured at least once in all adults.
This measurement is preferably performed when an individual gets their first standard lipid panel (“cholesterol test”), as a means of identifying individuals at high cardiovascular risk early in life. For most people, a single measurement is sufficient due to the stability of Lp(a) levels throughout life, with exceptions made for specific conditions like kidney or liver disease, or infections, where levels might fluctuate.
General U.S. guidelines, such as those from the American College of Cardiology/American Heart Association (ACC/AHA), have historically remained more conservative, listing elevated Lp(a) as a “risk-enhancing factor” to be considered for testing only in select patients, rather than calling for universal screening.
How Is Lipoprotein(a) Tested?
Accurate measurement of Lp(a) in lab tests is challenging due to its complex structure, with variable apo(a) size. This variability means that two individuals can have the same mass concentration of Lp(a) but different numbers of Lp(a) particles, and vice versa, potentially leading to misclassification of risk.
Two main units are used for reporting Lp(a) levels:
- Nanomoles per liter (nmol/L): This unit measures the actual number of Lp(a) particles in the plasma. It is generally the preferred unit by most guidelines because it is less affected by the apo(a) size variability. Since each Lp(a) particle contains one molecule of apo(a), nmol/L provides a direct quantification of the particle burden.
- Milligrams per deciliter (mg/dL): This unit measures the total mass of the Lp(a) particle (protein and lipid components). While still used if nmol/L measurements are not available, it can be affected by apo(a) size. Larger apo(a) isoforms contribute more to mass, so a high mass concentration might not always equate to a high particle number.
A fixed conversion factor should not be used to convert Lp(a) values between mg/dL and nmol/L. Using a generic conversion factor (e.g., multiplying mg/dL by 2.0 to 2.5) can lead to significant inaccuracy and misclassification of risk.
Genetic testing for LPA gene variants or apo(a) size is not necessary or helpful compared with direct measurement of the Lp(a) particle concentration.
How do Lp(a), LDL, and ApoB Compare With One Another?
When comparing Lp(a) particles to standard LDL particles on a particle-for-particle basis, Lp(a) is significantly more harmful. This is due to the additional properties of apo(a) and its associated oxidized phospholipids, beyond the cholesterol content of the particle alone.
However, LDL particles are usually present in much greater quantities than Lp(a) particles. Therefore, while Lp(a) may be more dangerous per particle, the overall risk from elevated LDL levels is often greater due to their much higher total concentration in the blood.
Apolipoprotein B (apoB) measurement provides an estimate of the total number of atherogenic lipoprotein particles in circulation, including both LDL, Lp(a), and many others. To illustrate the difference in concentrations, in patients with a high Lp(a) level, Lp(a) typically accounts for less than 10% of the total circulating apoB-containing particles.
While apoB is an excellent marker of overall burden of harmful particles that can contribute to atherosclerosis, specific measurement of Lp(a) remains important, because Lp(a) has unique properties not shared by other apoB-containing particles, and its levels are not significantly lowered by standard LDL-C therapies like statins.
What is a Normal Lipoprotein(a) Level? (Risk Stratification)
A lipoprotein(a) level of less than 30 milligrams per deciliter (mg/dL) is “normal”, but interpreting Lp(a) levels requires understanding the spectrum of risk:
- ‘Rule out’ significant Lp(a)-mediated risk: <30 mg/dL (or <75 nmol/L)
- ‘Rule-in’ significant Lp(a)-mediated risk: >50 mg/dL (or >125 nmol/L)
- Interim ‘grey zone’: 30−50 mg/dL (or 75−125 nmol/L). Levels in this range are considered relevant in the presence of other cardiovascular risk factors and for overall risk stratification. For people in this category, particularly women after menopause, those who develop chronic kidney disease, or those with hypothyroidism, repeat measurement of Lp(a) may be useful.
Recall that the association between Lp(a) concentration and cardiovascular risk is a continuous gradient from lower to higher values. This means that risk increases progressively with higher Lp(a) levels, even below the defined “high-risk” thresholds. These cut-offs are primarily for practical guidance in clinical settings.
Elevated Lp(a) levels should always be interpreted within the broader context of an individual’s overall cardiovascular profile. This includes considering factors outlined in frameworks like the American Heart Association’s “Life’s Essential 8” or Barbell Medicine’s Health Priorities (healthy diet, physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure) and other traditional risk factors.
A high Lp(a) level has a more significant impact on a person’s cardiovascular risk if they also have multiple other risk factors. Conversely, an individual with a very high Lp(a) but no other major risk factors might still have a lower absolute risk in the short term compared to someone who has a normal Lp(a) but does have a heavy burden of other risk factors.
To aid in this assessment, the website lpaclinicalguidance.com offers an interactive tool, allowing users to input health information and Lp(a) levels to visualize how Lp(a) and modifying other risk factors impacts long-term risk estimates.
Consulting with a physician familiar with Lp(a) and cardiovascular disease can be beneficial to guide decision making in patients with borderline or elevated levels.
How Is Elevated Lipoprotein(a) Treated? (Management)
The current strategy for managing Lp(a)-associated risk is often described as a paradox: while we can easily identify this risk factor, targeted therapies to directly lower Lp(a) are not yet available.
While some have argued that we should not bother testing for something we cannot directly treat, others (including us) argue that identifying this risk factor can re-classify someone who otherwise appears to be at low- or moderate-risk, into a higher-risk category. In that situation, “compensatory risk reduction” by more aggressively managing all modifiable cardiovascular risk factors becomes more important.
Lifestyle Interventions For High Lp(a)
The general consensus among major scientific bodies is that lifestyle interventions, including dietary changes and exercise that can be effective for lowering LDL-c, do not have a significant direct impact on Lp(a) levels.
While a low-carbohydrate, high-saturated fat diet may modestly decrease Lp(a) levels, it typically leads to a more significant increase in other lipoproteins including LDL-c, leading to a net increase in risk. Therefore, such dietary approaches are not advisable for the primary goal of Lp(a) reduction.
Current observational studies generally show no consistent relationship between moderate exercise and serum Lp(a) levels in adults. However, exercise has well-established benefits for cardiovascular health and should be strongly recommended irrespective of an individual’s Lp(a) level.
Optimizing Other Heart Disease Risk Factors
As we do not yet have targeted Lp(a)-lowering drugs available, managing individuals with elevated Lp(a) mainly involves more aggressive management of all other modifiable cardiovascular risk factors. The primary objective is to lower the individual’s overall cardiovascular risk to mitigate the additional risk from their high Lp(a).
This typically involves a variety of health priorities:
- Aggressive apoB lowering: Achieving guideline-recommended, and often lower, apoB (or LDL-c) targets using lipid-lowering strategies.
- Optimal blood pressure control: Treating hypertension to target levels.
- Glycemic control: Managing diabetes or pre-diabetes effectively.
- Smoking cessation: Providing support and resources for quitting smoking.
- Healthy diet and weight management: Promoting adherence to healthy dietary patterns and maintaining a healthy body composition.
- Meeting or exceeding physical activity guidelines
The website lpaclinicalguidance.com provides a useful tool that can help visualize how much an individual might need to lower their LDL-C or systolic blood pressure to offset the estimated risk increase from their specific Lp(a) level. This can aid in shared decision-making and setting personalized targets for these modifiable risk factors.
The Role of Statins
Statins are very effective medications for lowering LDL-cholesterol and have unequivocally been shown to reduce the risk of cardiovascular events. However, statin therapy can, on average, slightly increase Lp(a) levels, typically by around 10-20%, although the response is variable among individuals.
However, recall our prior discussion that LDL particles are present in much greater quantities than Lp(a) particles. So, while Lp(a) may be more dangerous per particle, the overall cardiovascular risk attributable to elevated LDL levels is usually higher due to their much higher total concentration in the blood.
As a result, the net effect of statin therapy on overall cardiovascular risk remains beneficial, even in individuals with high Lp(a) and even if their Lp(a) levels increase modestly with treatment. This is because the large reduction in LDL particles from statins usually outweighs any potential negative impact from a small increase in Lp(a).
If LDL-cholesterol levels do not respond adequately while a patient is adherent to statin therapy, a high Lp(a) level could be a contributing factor. This is because Lp(a) particles contain cholesterol, and this Lp(a)-cholesterol content contributes to the measured LDL-cholesterol value in most lipid panels.
PCSK9 Inhibitors
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as evolocumab and alirocumab, are potent medications that dramatically lower LDL-c levels. In addition, PCSK9 inhibitors lower Lp(a) levels by approximately 20-30%, although there is considerable inter-individual variability in this response.
Cardiovascular trials of PCSK9 inhibitors (e.g., FOURIER and ODYSSEY OUTCOMES) found that the absolute risk reduction in cardiovascular events was greater in patients who had higher baseline Lp(a) levels, suggesting that the Lp(a) reduction may contribute to their overall benefit.
Aspirin
Lp(a) has pro-thrombotic properties, while aspirin’s anti-platelet effects inhibit thrombosis. This provides the rationale for its potential use as a risk-lowering (though not Lp(a)-lowering) strategy in this population. However, the role of aspirin for lowering cardiovascular risk in people with elevated Lp(a) is a subject of ongoing discussion and research, with no definitive consensus at this time.
A recent analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) suggested a potential benefit of aspirin in reducing cardiovascular risk in individuals with high Lp(a), but it also found an increased risk of major bleeding, a known side effect of aspirin. For patients with elevated Lp(a) who are considering aspirin, a careful risk-benefit discussion with their physician is warranted.
Lipoprotein Apheresis
Lipoprotein apheresis is a procedure similar to dialysis that physically removes apoB-containing lipoproteins (including LDL and Lp(a)) from the blood. It can achieve substantial rapid reductions in both LDL-cholesterol and Lp(a) levels. However, it is an invasive, time-consuming (typically requiring several hours per session, every 1-2 weeks), and expensive therapy. Its use is therefore reserved for a very select group of patients at extremely high cardiovascular risk.
Niacin
Certain therapies that can lower Lp(a) levels are not generally recommended for this purpose due to a lack of demonstrated net clinical benefit or concerns about side effects. For example, Niacin (nicotinic acid or vitamin B3) can reduce Lp(a) concentrations by 20-30%. However, large clinical outcome trials have evaluated the addition of niacin to statin therapy and failed to show an incremental benefit despite improvements in Lp(a) levels. This lack of benefit might be because the magnitude of Lp(a) reduction achieved was insufficient to produce meaningful risk reduction during the timeframe of the trial.
New Therapies Targeting Lp(a)
Several promising agents are now in late-stage clinical development and testing. The premise guiding the development of these new drugs is the “Lp(a) hypothesis”, which posits that specifically lowering plasma Lp(a) concentrations will lead to a clinically meaningful reduction in the risk of cardiovascular events like myocardial infarction, stroke, and progression of aortic valve stenosis.
Genetic studies have provided estimates that large reductions in Lp(a) levels – potentially in the range of >50−100 mg/dL (or >100−200 nmol/L) – may be required for clinically relevant impacts on cardiovascular risk, especially in trials of relatively short duration (e.g., 3-5 years). Several such large, randomized, placebo-controlled cardiovascular outcome trials are currently underway with novel Lp(a)-lowering drugs to test this hypothesis.
Take-Home Message
Lipoprotein(a) is a common, independent, causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis. Lp(a) is primarily a genetic risk factor, meaning its levels are not significantly modifiable by lifestyle changes that readily affect other lipids like LDL-cholesterol. This helps manage expectations and directs focus towards strategies that can make a difference.
Current international guidelines increasingly recommend screening for elevated Lp(a) at least once in an adult’s lifetime, identifying those at previously unrecognized cardiovascular risk. This recommendation is especially important for those with a family history of premature cardiovascular disease (heart attack or stroke at a young age).
While direct, approved therapies to specifically lower Lp(a) and reduce cardiovascular events are not yet available, the cornerstone of current management for individuals with high Lp(a) is the aggressive control of all other modifiable cardiovascular risk factors, especially for those who are “re-classified” from lower- or moderate-risk, to higher-risk based on their Lp(a) levels.
So, when a patient is found to have elevated Lp(a), the conversation should emphasize:
- The patient’s goals & preferences
- The genetic nature of the risk.
- Comprehensive risk assessment, including blood pressure, other blood lipids, insulin resistance, smoking, diet, exercise, sleep, and weight management
- Optimization of these other modifiable risk factors
- Consideration of currently available treatments known to impact Lp(a) levels and/or Lp(a)-mediated risk
- The hopeful outlook regarding emerging targeted Lp(a)-lowering therapies.
Shared decision-making between the patient and clinician is essential, especially when considering interventions with uncertain risk-benefit profiles for high Lp(a) (like aspirin) or when interpreting the effects of standard therapies (like statins).
Resources like lpaclinicalguidance.com can be valuable tools for patients and physicians to understand how specific Lp(a) levels might contribute to overall cardiovascular risk and the potential impact of modifying other risk factors.
Ongoing and future research still needs to determine whether direct Lp(a)-lowering therapies are safe and effective, as well as optimal Lp(a) target levels. If they do prove effective, the next steps will be defining the populations where these treatments offer the ideal balance of cost, potential benefits, and potential risks.
Consulting with a physician familiar with Lp(a) and cardiovascular disease can be beneficial to guide decision making. We at Barbell Medicine are available and happy to help.
References
- https://eas-congress.com/2024/congress/lpa-testing/
- https://www.tctmd.com/news/high-lpa-linked-ascvd-risk-even-when-ldl-cholesterol-low
- https://pubmed.ncbi.nlm.nih.gov/28183512
- https://www.lipid.org/sites/default/files/files/PIIS1933287424000333.pdf
- https://eas-society.org/page/lipoproteina-consensus-2022
- https://pubmed.ncbi.nlm.nih.gov/38924439
- https://pmc.ncbi.nlm.nih.gov/articles/PMC12087327
