#22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V: HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins
Dr. Thomas Dayspring, a lipidology expert, and Peter Attia explore the complexities of HDL, reverse cholesterol transport, and lipid metabolism. They delve into apolipoproteins, the limitations of traditional cholesterol metrics, and the outcomes of CETP inhibitor trials, emphasizing a nuanced understanding of lipid biology.
Deep Dive Analysis
17 Topic Outline
Introduction to Part III: HDL and CETP Inhibitors
Defining Direct vs. Indirect Reverse Cholesterol Transport
Challenges with Traditional HDL Cholesterol Metrics
The Complex Lipid Transportation System
Formation and Clearance of Remnant Lipoproteins
Role of Apolipoprotein E (ApoE) in Particle Clearance
Impact of Apolipoprotein C3 (ApoC3) on Atherogenicity
VLDL to LDL Conversion and Insulin Resistance
Non-HDL Cholesterol as a Remnant Marker
Lipoprotein Exchange: Particles Having Sex
HDL's Role in Cholesterol Transfer to LDL
The Misleading 'Good' and 'Bad' Cholesterol Labels
Limitations of Framingham and Mesa Studies
Case Study: Dysfunctional High HDL Cholesterol
Rationale for CETP Inhibitors
Failure of Early CETP Inhibitor Trials (Torcetrapib, Dalcetrapib)
Outcomes of Later CETP Inhibitor Trials (Evacetrapib, Anacetrapib)
5 Key Concepts
Reverse Cholesterol Transport (RCT)
RCT is the process by which the body removes excess cholesterol from peripheral cells. It can be 'direct' where HDL brings cholesterol directly to the liver or intestine, or 'indirect' where HDL transfers cholesterol to ApoB particles, which then transport it to the liver or intestine for clearance.
Remnant Lipoproteins
These are smaller, triglyceride-depleted VLDL or chylomicron particles that remain after delivering energy (triglycerides) and phospholipids to cells. They are typically cleared rapidly by receptors in the liver.
Apolipoprotein C3 (ApoC3)
ApoC3 is an apolipoprotein that, when present on VLDLs, IDLs, and LDLs, significantly increases their plasma residence time. Its presence makes these particles intensely more atherogenic, especially in insulin-resistant individuals.
Cholesteryl Ester Transfer Protein (CETP)
CETP is a protein, primarily carried on HDLs, that facilitates the exchange of core lipids (triglycerides and cholesterol esters) between different lipoproteins. This exchange can occur between HDL particles (homotypic) or between HDL and ApoB particles (heterotypic).
HDL Functionality
The actual effectiveness of HDL particles in cholesterol efflux and transport is far more complex than just their cholesterol content or particle number. It depends on their specific protein signature and phospholipid makeup, which dictate their specific roles in the lipid transportation system.
7 Questions Answered
Their primary functional purpose is to deliver energy in the form of triglycerides to adipocytes and myocytes, and phospholipids to cells, not to deliver cholesterol to peripheral cells.
Cholesterol is included for structural purposes, making these particles spherical so they can efficiently carry more triglycerides, rather than for direct delivery to peripheral cells.
HDL cholesterol levels do not reflect the complex movement and functionality of cholesterol within the body; high levels can sometimes indicate dysfunctional HDL particles that are not effectively clearing cholesterol, and low levels can be protective if the HDL is highly functional.
ApoE acts as a strong ligand for the LDL receptor, greatly amplifying the efficacy of LDL clearance from circulation, leading to lower LDL particle levels and reduced risk of heart disease.
In individuals who are not insulin resistant and do not have significant triglyceride issues, a large percentage of ApoB particles from the liver are directly LDLs, and the VLDLs produced are smaller and cleared rapidly, with less conversion to LDLs.
Non-HDL cholesterol is used as a marker for potentially atherogenic cholesterol, including remnants, but it is a crude estimation. There can be significant discordance between non-HDL cholesterol and actual ApoB or LDL particle numbers, which are more precise metrics for assessing risk.
While some CETP inhibitors did raise HDL cholesterol, they either had off-target toxicities (like torcetrapib) or showed no clinical benefit in reducing cardiovascular events (like dalcetrapib and evacetrapib), suggesting that simply raising HDL-C does not equate to improved cardiovascular outcomes.
16 Actionable Insights
1. Normalize ApoB/LDL Particle Number
The ultimate goal in lipid management is to normalize ApoB or LDL particle number, as this addresses the primary drivers of atherosclerosis and helps manage remnant lipoproteins.
2. Use Particle Numbers for Decisions
For proper clinical decisions, especially in patients of concern, utilize particle numbers (ApoB or LDL particle number) instead of solely relying on non-HDL cholesterol, due to significant discordance between these metrics.
3. Avoid “Good/Bad” Cholesterol Terms
Refrain from using the terms “good cholesterol” and “bad cholesterol” when discussing lipids with patients, as these terms are misleading, lack scientific meaning, and can miseducate patients about their actual risk based on blood measurements.
4. Avoid Crude Cholesterol Metrics
Do not rely on LDL cholesterol, total cholesterol, or HDL cholesterol as sole metrics for understanding cholesterol flux and trafficking, as they provide zero information about the complex movement of cholesterol.
5. Interpret HDL-C with Caution
Be cautious when interpreting HDL cholesterol levels; low HDL-C doesn’t clarify if cholesterol pickup is failing or delivery is efficient, and high HDL-C doesn’t clarify if pickup is high or drop-off is deficient.
6. Re-evaluate Old HDL-C Data
When reviewing historical epidemiological data that links low HDL cholesterol to risk, recognize that these studies often did not adjust for ApoB or LDL-P, and if they had, low HDL cholesterol would likely cease to be an independent risk factor.
7. Discard “Reverse Cholesterol Transport” Term
Stop using the term “reverse cholesterol transport” because it is an oversimplification of an immensely complex system, and there are currently no biomarkers to accurately evaluate this process in individual patients.
8. Target VLDL Cholesterol
Aim to keep VLDL cholesterol levels below 15 milligrams per deciliter, especially in insulin-resistant patients, as this marker can indicate the presence of remnant lipoproteins contributing to pathology.
9. Manage Risk Factors for Dysfunctional HDL
For individuals with very high HDL cholesterol but accelerated atherosclerosis (indicating dysfunctional HDL), the primary strategy is to lower ApoB and aggressively manage all other identifiable cardiovascular risk factors.
10. Consider Apo C3 as Risk Marker
Apo C3 is overexpressed in insulin-resistant situations and its presence on lipoproteins significantly increases their plasma residence time and atherogenicity, making it a potential future clinical assay for identifying problematic remnant lipoproteins.
11. Apply Lipid Knowledge to Nutrition
When prescribing or considering nutritional therapies, it is very important to understand the complexities of lipid transportation and particle functionality, as this knowledge should inform dietary recommendations.
12. Understand Absolute vs. Relative Risk
When evaluating changes in lipid markers, especially in insulin-resistant patients, always consider the absolute increase in particle numbers, not just the relative percentage increase, as absolute changes often dominate the overall risk picture.
13. Critically Evaluate Old Information
When reviewing older scientific or medical information, especially in rapidly evolving fields like lipidology, be aware that understanding and recommendations can change significantly over time.
14. Prioritize Safety and Alternatives
When considering new therapeutic approaches, especially those with unknown long-term effects or residual presence in the body, prioritize therapies with established safety profiles and consider if existing or emerging alternatives offer comparable or superior benefits without the same risks.
15. Exercise Caution with New Drugs
Be extremely cautious with new pharmaceutical interventions, especially those that significantly alter biological systems, as unforeseen long-term side effects or toxicities can emerge, as seen with past drugs like Vioxx.
16. Seek Direct, Honest Feedback
Actively seek out mentors or colleagues who are not afraid to directly correct your misunderstandings or challenge your assumptions, as learning from such individuals can significantly deepen your understanding.
5 Key Quotes
Our metrics of these pathways are going to be LDL cholesterol, maybe total cholesterol, or HDL cholesterol. And that's where the whole thing falls apart. Because those metrics have zero to do with describing the complex flux and trafficking of all these pools of cholesterol.
Thomas Dayspring
What if that HDL pulled cholesterol out of your cell because it was overproducing too much and he gave it to an LDL and said, buddy, take off. The liver's got that LDL receptor. It's going to clear you. And that LDL particle raced back to the liver. And for some reason, there was no LDL receptors or there weren't enough of them there. Where's that LDL going? He might wind his way back into circulation.
Thomas Dayspring
If you want to use those darn adjectives with a patient, I guess what's going to determine what's good or bad cholesterol is what is that lipoprotein going to do with its cholesterol molecule?
Thomas Dayspring
Before you declare, make any statements based on, based on an HDL metric, please make sure you have an LDL particle or APOB metric in front of you also, and pretty much base what you're going to advise a patient on risk and assessment based on that.
Thomas Dayspring
The HDL story is one where the more time goes on, the less I know. I mean, there are a few things in lipidology that humble me more than my complete and utter buffoonery and ignorance when it comes to understanding high-density lipoproteins.
Peter Attia