#07 - Deep Dive: Lp(a) — what every doctor, and the 10-20% of the population at risk, needs to know
Dr. Peter Attia, interviewed by Bob Kaplan, delves into Lipoprotein(a) [Lp(a)], a critical but often overlooked cardiovascular risk factor. The discussion covers its structure, function, associated health problems, and current and future treatment options.
Deep Dive Analysis
10 Topic Outline
Introduction to Lp(a) and Listener Interest
Primer on Lipoproteins and Atherosclerosis
Defining Lp(a) and its Unique Structure
Understanding Lp(a) Measurement: Mass vs. Particle Number
Evolutionary Purpose and Physiological Functions of Lp(a)
Health Problems Associated with Elevated Lp(a)
Prevalence and Risk Quantification of Elevated Lp(a)
Current Therapies and Future Treatments for High Lp(a)
Impact of Lifestyle and Diet on Lp(a) and LDL-P
Importance of Testing and Physician Awareness for Lp(a)
6 Key Concepts
Lipoproteins
These are water-soluble macrostructures that package and transport hydrophobic molecules like cholesterol and triglycerides in the bloodstream. They are named based on their density, such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL).
ApoB100
This is an apolipoprotein that wraps around the spherical structure of LDL, VLDL, and IDL particles. Since each of these particles has one ApoB100, counting ApoB serves as a surrogate for quantifying the number of these atherogenic particles, which is a more accurate predictor of atherosclerotic risk than cholesterol concentration alone.
Lp(a) Particle Number
This is the preferred method for quantifying Lp(a) risk, as it directly counts the number of ApoA particles attached to LDLs. Unlike Lp(a) mass, it accounts for the variability in ApoA's molecular weight, providing a more consistent and accurate measure of risk.
Kringle Domains
These are repeated folding structures found in the ApoA component of Lp(a), resembling domains in plasminogen. Specifically, the Kringle 4-2 subsegment exhibits significant variability in the number of repeating units, which directly influences the overall mass of the Lp(a) particle.
Antisense Oligonucleotides (ASOs)
These are novel therapeutic molecules designed to specifically lower Lp(a) by disrupting the synthesis of ApoA in the liver. They act to prevent the creation of the ApoA protein, thereby reducing the number of Lp(a) particles in circulation.
Premature Cardiovascular Disease
This term loosely refers to a major adverse cardiac event (MACE) occurring before the age of 60. Elevated Lp(a) is often associated with premature heart disease, even in individuals without other classic risk factors.
7 Questions Answered
Lp(a) is a low-density lipoprotein (LDL) particle with an additional protein called apolipoprotein(a) or ApoA covalently attached to it. It's important because elevated levels are a significant, often overlooked, risk factor for cardiovascular disease, aortic stenosis, and venous thrombosis, affecting about 1 in 5 to 1 in 10 people.
Lp(a) is most ubiquitously measured by mass (e.g., milligrams per deciliter), but this can be misleading due to variability in the ApoA structure. The most accurate and preferred measurement is the Lp(a) particle number (nanomoles per liter), as it directly counts the number of Lp(a) particles, which correlates better with risk.
Elevated Lp(a) is primarily associated with enhanced atherosclerosis (hardening of the arteries), aortic stenosis (calcification and narrowing of the heart's aortic valve), and enhanced venous thrombosis (increased risk of blood clots).
No, Lp(a) levels are largely genetically determined and are not significantly modified by lifestyle interventions like diet or exercise. While other lipoproteins like triglycerides and LDL-P can be influenced by lifestyle, Lp(a) primarily depends on its synthesis in the liver.
Statins generally do not lower Lp(a) and can sometimes even cause a slight increase. Their primary role in patients with elevated Lp(a) is to reduce LDL particle number (ApoB) to a much lower target, thereby mitigating overall cardiovascular risk.
Currently, PCSK9 inhibitors can reduce Lp(a) by 30-50%, though they are not FDA-approved specifically for this purpose. Niacin has also been used historically but has a checkered history. The most promising future treatments are Antisense Oligonucleotides (ASOs), which directly disrupt ApoA synthesis and can reduce Lp(a) by 70-99%.
Lp(a) likely provided evolutionary advantages, such as promoting hypercoagulability (better blood clotting) to prevent bleeding to death from trauma or childbirth, and acting as a scavenger for oxidized phospholipids in a low oxidative environment.
18 Actionable Insights
1. Patients: Demand LP(a) Test
As a patient, demand to know your LP(a) levels, especially if you have a family history of atherosclerotic disease, as this is a non-negotiable step in understanding your risk.
2. Track LDL Particle Number (APO-B)
Prioritize knowing your LDL particle number (LDL-P) or APO-B, as these are more accurate predictors of atherosclerotic risk than traditional LDL cholesterol levels.
3. Best LP(a) Risk Measurement
For the most accurate assessment of LP(a) risk, request an LP(a) particle number test, or as a proxy, measure the amount of oxidized phospholipid normalized for APOB.
4. Lower LDLP with High LP(a)
If you have elevated LP(a), aim for an LDL particle number (LDLP) at the 10th percentile or lower, which often requires statin therapy, in addition to considering other risk factors.
5. Statins for APOB, Not LP(a)
If you have elevated LP(a), you should likely take a statin, but understand its purpose is to control APOB and lower LDL particle number, not to directly lower LP(a).
6. Screen Aortic Stenosis with High LP(a)
If you have elevated LP(a), especially at a young age, proactively screen for aortic stenosis using an echocardiogram (echo) at minimum, or preferably a cardiac MRI for more accurate assessment of the aortic valve.
7. DVT Prevention for High LP(a)
If you have elevated LP(a) and are taking long flights, discuss deep vein thrombosis (DVT) prophylaxis with your doctor, which may include pharmacologic agents or over-the-counter options like “flight tabs” to reduce risk.
8. Swap Saturated for Monounsaturated Fats
If you are on a high-fat diet (e.g., ketogenic) and experience a significant increase in LDL particle number, consider replacing saturated fats with monounsaturated fats (like those from olives, olive oil, macadamia nuts) to potentially lower LDL-P, even while maintaining a high-fat intake.
9. Monitor Oxidized LDL and LPPLA2
Monitor your oxidized LDL levels (aiming for below 40) and LPPLA2 as these are important local markers of vascular inflammation, providing a clearer picture than general inflammatory markers like CRP.
10. Diet to Lower Triglycerides
You can significantly lower triglycerides, which are highly sensitive to dietary intervention, through specific dietary changes, potentially within a month.
11. Understand LDL Beyond “Bad Cholesterol”
Avoid misunderstanding “LDL cholesterol” as simply “bad cholesterol” by understanding that LDL stands for “low-density lipoprotein,” indicating it’s a macro structure carrying cholesterol, not cholesterol itself.
12. Combine LP(a) Mass & Cholesterol
If LP(a) particle number is unavailable, consider assessing both LP(a) mass and LP(a) cholesterol; if both are high, it indicates high particle number and risk, if both are low, risk is low, and if one is high and one is low, further follow-up may be needed.
13. Physicians: Learn About LP(a)
Physicians on the front lines of medicine, including family physicians and GYNs, should understand LP(a) to effectively help patients lower their cardiovascular disease risk.
14. Physicians: Deepen LP(a) Knowledge
If you are a physician and this is your first introduction to LP(a), commit to learning more about it to better serve your patients and understand cardiovascular risk factors.
15. Utilize Show Notes for Technical Podcasts
For technical podcasts, review the show notes either before or after listening, as visual aids like pictures can significantly enhance understanding of complex topics.
16. Seek Professional Medical Advice
Always seek professional medical advice, diagnosis, or treatment from your healthcare professionals for any medical conditions, and do not use podcast content as a substitute.
17. Give Feedback on Podcast Format
If you find the interview format helpful, provide feedback to the hosts, as they are open to doing more such episodes on general topics.
18. Subscribe to Peter Attia’s Email
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4 Key Quotes
A 60% increase in risk on something that is going to kill a third of people is a big effing problem.
Peter Attia
I'm still shocked at how many doctors don't understand this.
Peter Attia
The further from the shore, the deeper the water. And so the more you dig into this, the more you learn, the less, you know, in a sense, it's that you've sort of exposed yourself to a lot of unknowns.
Bob Kaplan
If you're listening to this as a patient, you should demand that your LP little a be known. It's non-negotiable, especially if you have a family history of atherosclerotic disease.
Peter Attia
2 Protocols
Screening for Aortic Stenosis in Elevated Lp(a) Patients
Peter Attia- Perform an echocardiogram (echo) at a minimum.
- Preferably conduct a cardiac MRI for more accurate assessment of aortic valve morphology and pressure gradient.
Dietary Adjustment for High LDL-P on Ketogenic Diet
Peter Attia- Identify patients on a ketogenic diet with significantly elevated LDL-P (e.g., >3500 nmol/L) and potentially increased oxidized LDL and CRP.
- Replace high amounts of saturated fat in the diet with monounsaturated fats (e.g., olives, olive oil, macadamia nuts).
- Maintain a high-fat diet if desired, but shift the fat composition.
- Re-test lipid panel after approximately eight weeks to assess changes in LDL-P.