#129 - Tom Dayspring, M.D.: The latest insights into cardiovascular disease and lipidology
Dr. Tom Dayspring, a world-renowned lipidologist, returns to discuss updates in lipidology, emphasizing ApoB and Lp(a) as key drivers of atherosclerosis. The episode covers risk assessment, lab interpretation, therapeutic targets, and new lipid-lowering drugs.
Deep Dive Analysis
13 Topic Outline
Introduction to Updated Lipidology and Cardiovascular Disease
The Growing Consensus on Atherogenic Lipoproteins and ApoB
Understanding ApoB: Biology, Metrics, and Clinical Utility
Optimal ApoB Levels and the 'Lower is Better' Principle
Atherosclerosis Pathogenesis: Particle Number, Quality, and Endothelial Dysfunction
HDL Cholesterol: Why it's a Less Informative Metric
Lipoprotein(a) [Lp(a)]: A Critical Genetic Risk Factor
Advanced Risk Assessment: Lp(a) and Oxidized Phospholipids
LDL Triglycerides as a Marker for Atherogenic Particles
Current State of Statin Therapy and New Guidelines
Bempedoic Acid: A New Cholesterol Synthesis Inhibitor
Evolving Data on Omega-3 Fatty Acids: EPA vs. EPA+DHA
Fibrates: An Underappreciated Treatment for Hypertriglyceridemia
5 Key Concepts
Apolipoprotein B (ApoB)
ApoB is the main structural protein that wraps around hydrophobic lipids, forming water-soluble lipoprotein particles. These ApoB-containing lipoproteins (VLDL, IDL, LDL, Lp(a)) are considered atherogenic because they are the vehicles that transport sterols into the artery wall, initiating the pathological process of atherosclerosis.
Atherogenic Lipoproteins
These are lipoproteins that contain ApoB, including very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and lipoprotein(a) (Lp(a)). They are the primary drivers of atherosclerotic vascular disease by trafficking sterols into the artery wall where they can become pathological.
HDL Cholesterol vs. HDL Functionality
HDL cholesterol is a measurement of the collective cholesterol mass within all high-density lipoprotein particles in plasma. This metric is largely uninformative about cardiovascular risk because it does not reflect the diverse and complex functions of HDL particles, such as cholesterol efflux or immunomodulation, and attempts to raise it have not shown clinical benefit.
Lipoprotein(a) [Lp(a)]
Lp(a) is an LDL particle that has an additional protein, apoprotein(a) (ApoA), co-attached to its ApoB structural protein. It is a significant genetically determined risk factor for atherosclerosis, with potential thrombogenic properties and a strong affinity for binding oxidized phospholipids, making it a highly injurious particle.
ATP Citrate Lyase Inhibitor (Bempedoic Acid)
Bempedoic acid is a pro-drug that, once activated in the liver, inhibits ATP citrate lyase, an enzyme in an early step of cholesterol synthesis. This inhibition depletes hepatic cholesterol pools, leading to increased expression of LDL receptors on liver cells, which in turn enhances the clearance of ApoB-containing lipoproteins from the blood.
9 Questions Answered
ApoB immunoassay is more standardized and consistent across different laboratories compared to the various LDL-P technologies (NMR, ion mobility), making it a more reliable metric for tracking over time, and it is increasingly included in major clinical guidelines.
With currently FDA-approved pharmacologic methods for lowering ApoB, there is no signal of harm, and clinical trials demonstrate continued incremental event reduction even at very low ApoB levels, as cells can synthesize their own cholesterol for essential functions.
Observational studies linking high HDL cholesterol to better outcomes were often not adjusted for other confounding factors, and numerous clinical trials designed to raise HDL cholesterol have consistently failed to show cardiovascular benefit, and in some cases, have even shown harm.
Lp(a) is an LDL particle with an additional protein, apoprotein(a), attached, making it a significant genetic driver of atherosclerosis. It is dangerous due to its potential thrombogenic properties and its high affinity for carrying oxidized phospholipids, which are injurious to cells.
European guidelines recommend that everyone should have their Lp(a) measured once in adulthood, as it is a genetically determined marker that remains stable over a lifetime and provides crucial information for a thorough cardiovascular risk assessment.
Statins can sometimes increase the synthesis of certain ApoA isoforms, potentially raising Lp(a) slightly, whereas PCSK9 inhibitors improve the clearance of Lp(a) particles by upregulating LDL receptors and possibly other ApoA clearing receptors.
High LDL triglycerides indicate a higher presence of small, dense LDL particles, which are more atherogenic. This often signifies insulin resistance, increased remnant lipoproteins, and dysfunctional HDLs, all contributing to increased cardiovascular risk.
Bempedoic acid is a pro-drug that, once activated in the liver, inhibits ATP citrate lyase, an enzyme in the cholesterol synthesis pathway. This action depletes hepatic cholesterol pools, leading to increased LDL receptor expression and enhanced clearance of ApoB-containing lipoproteins.
High-dose EPA (4 grams/day) has demonstrated significant residual risk reduction in high-risk patients on statins with elevated triglycerides (e.g., in the REDUCE-IT trial). In contrast, trials with combined EPA and DHA have not shown similar benefits, leading to a preference for EPA-only in evidence-based practice for this specific indication.
23 Actionable Insights
1. Prefer ApoB for Atherogenic Lipoproteins
Use ApoB as the primary marker for atherogenic lipoproteins because it is a more standardized immunoassay, is referenced in all contemporary guidelines, and may have fewer false positives compared to other LDL particle count methods.
2. Target Physiologic ApoB Levels
Strive to achieve ApoB concentrations under 50 milligrams per deciliter, as this level is associated with the most significant risk reduction in clinical trials and is comparable to newborn levels.
3. Comprehensive Cardiovascular Risk Management
Even after optimizing ApoB levels, thoroughly examine and treat all other factors that might be injuring the endothelium or arterial wall, as atherosclerosis is a multi-factorial disease.
4. One-Time LP(a) Test for Adults
Get an LP(a) test once as an adult, as it is a genetically determined marker that does not change significantly over time and helps in thorough cardiovascular risk assessment.
5. Maximize Risk Reduction for High LP(a)
For elevated and problematic LP(a), maximally lower all other ApoB, optimize metabolic parameters (glucose, insulin, blood pressure), and control factors like uric acid and homocysteine.
6. Avoid Commercial HDL Panels
Do not waste money, time, or brain energy on commercial HDL function panels (e.g., HDL size, ApoA1, ceramides) as they are not useful bedside metrics and lack proven clinical relevance.
7. Key Lipid & Metabolic Markers
Focus on VLDL cholesterol (as a proxy for remnants), ApoB, LP(a), and metabolic markers such as glucose, insulin, homocysteine, uric acid, and aggressive blood pressure management for comprehensive risk assessment.
8. Consistent Biomarker Tracking
To accurately track health biomarkers like ApoB, consistently use the same metric and assay, ideally from the same lab, to ensure results are comparable over time.
9. Utilize CAC & LP(a) for Statin Decisions
When deliberating statin therapy, especially with patient hesitancy, utilize adjunctive diagnostics like coronary artery calcium (CAC) scoring and LP(a) testing, alongside family history and other risk factors, to inform the decision.
10. Start Statins Low, Add Adjuncts
For statin therapy, consider starting with a lower dose and optimizing ApoB lowering with a second drug like ezetimibe or bempedoic acid, rather than immediately using maximum statin doses, unless in acute high-risk scenarios.
11. Bempedoic Acid for Statin Intolerance
Consider bempedoic acid as an ApoB-lowering option, especially for individuals with statin intolerance or muscle aches, as it is hepatoselective and does not have uptake in muscle cells.
12. High-Dose EPA for High Risk
For high-risk individuals seeking evidence-based omega-3 therapy, consider using 4 grams per day of EPA-only to reduce macrovascular outcomes, especially when combined with a statin.
13. Consider Fibrates for Triglycerides
Fibrates, particularly fenofibric acid, are underused and should be considered for individuals with triglyceride-rich lipoproteins and clear signs of insulin resistance or diabetes, as they show benefits for both macrovascular and microvascular endpoints.
14. Prefer Fenofibric Acid
If a fibric acid is indicated, prefer fenofibric acid (e.g., Trilipix) as it is considered the purest fibric acid and is not a pro-drug.
15. Avoid Niacin for Lipid Management
Niacin is no longer recommended in any major lipid guidelines for general lipid management due to lack of proven cardiovascular benefit and is considered a ‘dead drug’ by most lipidologists.
16. Don’t Fear Low Plasma Cholesterol
Do not be concerned about very low plasma LDL cholesterol levels (e.g., 30 mg/dL) as cells can synthesize their own cholesterol and are not deprived, given that plasma cholesterol is a tiny fraction of total body cholesterol.
17. Advocate for Affordable ApoB Test
Given the low cost of ApoB assays (e.g., $3-4), patients should advocate for this test as there is no economic excuse for physicians to avoid ordering it over more expensive or less standardized lipid metrics.
18. Assess Oxidized Phospholipids with LP(a)
If LP(a) is elevated, consider measuring oxidized phospholipids on ApoB (OxPL-ApoB) to determine if the LP(a) particles are carrying injurious oxidized lipids, indicating a higher risk.
19. LP(a) Not a Direct Therapy Goal
While LP(a) is a critical risk factor, it is not currently an acceptable direct goal of therapy because there is no trial data supporting its direct modulation as a primary treatment target.
20. Calculate VLDL-C from Direct Measures
To obtain an accurate VLDL cholesterol measurement, subtract directly measured LDL cholesterol and HDL cholesterol from total cholesterol; do not use a calculated LDL cholesterol for this purpose.
21. EPA-DHA for Lower Triglycerides
While 4 grams/day of EPA is evidence-based for high triglycerides, for individuals with triglycerides below 150 mg/dL but still having residual ApoB risk, using EPA-DHA combinations is still a reasonable consideration.
22. Supplement DHA if Deficient
If taking 4 grams of EPA daily and the omega-3 index still indicates DHA deficiency, consider supplementing with additional DHA to ensure adequate levels.
23. Individualize Atherosclerosis Risk Assessment
When assessing atherosclerosis risk, individualize the approach by considering multiple factors beyond just particle number, such as endothelial function and particle quality, as it is a multi-factorial disease.
6 Key Quotes
Atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease.
Tom Dayspring
There's one cholesterol molecule. I don't care whether it's in your cell, whether it's in any lipoprotein in your brain. If I drew you the structure of cholesterol, it's identical. So how dare we put an adjective on it like that's good and that's bad?
Tom Dayspring
This LDL biology stuff is trivial. All you got to do is lower it. It's the HDL biology that is really complicated.
Peter Attia
Don't have high LP little a if somehow you can avoid that, which you can't. Don't have a terrible family history of coronary artery disease. And I don't know how you avoid that. But if you want the worst scenario, don't have both LP little a.
Tom Dayspring
Our default position is that all generics are crap until proven otherwise.
Peter Attia
Niacin is a dead drug.
Tom Dayspring