← The Peter Attia Drive

#22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V: HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins

Oct 17, 2018 1h 4m 17 insights
<p>In this five-part series, Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology, and one of Peter's most important clinical mentors, shares his wealth of knowledge on the subject of lipids. In Part III, Peter and Tom dig into HDL, why "reverse cholesterol transport" is a lot more nuanced than what most of us are taught, lipid transport, apolipoproteins, and more. In addition, this episode highlights the complexity of HDL and a discussion about the CETP inhibitor trials.</p> <p>We discuss:</p> <ul> <li>Reverse cholesterol transport [1:40];</li> <li>Lipid transportation, apolipoproteins, VLDL, IDL, and LDL particles [11:00];</li> <li>Remnant lipoproteins and apoC-III [16:45];</li> <li>Particles having sex: lipid exchange [28:00];</li> <li>Cholesteryl Ester Transfer Protein (CETP) and CETP inhibitors [40:45];</li> <li>2006 CETP inhibitor trial: torcetrapib (Pfizer) [54:45];</li> <li>2012 CETP inhibitor trial: dalcetrapib (Hoffmann–La Roche) [56:15];</li> <li>2017 CETP inhibitor trials: evacetrapib (Eli Lilly) and anacetrapib (Merck) [58:00]; and</li> <li>More.</li> </ul> <p> <span> Learn more at <a href="http://www.peterattiamd.com/"><span><u>www.PeterAttiaMD.com</u></span></a></span></p> <p> <span>Connect with Peter on <a href=""> <span> <u>Facebook</u></span></a> | <a href=""> <span> <u>Twitter</u></span></a> | <a href=""> <span> <u>Instagram</u></span></a>.</span></p>
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.

17. Engage with Podcast Resources

To deepen your understanding and stay updated, visit peteratiamd.com/podcast for show notes and links, sign up for the weekly email for updates and interesting papers, and follow Peter Attia on social media for questions and comments.