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Peter Attia MD#22 – Tom Dayspring Part III of V: reverse cholesterol transport, CETP inhibitors, & apolipoproteins
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At a glance
WHAT IT’S REALLY ABOUT
Rethinking HDL, Reverse Cholesterol Transport, and Why CETP Inhibitors Failed
- Dayspring argues the old picture of HDL simply carrying cholesterol back to the liver is far too simple, since cholesterol also moves via the intestine, red blood cells, albumin and LDL particles.
- He and Attia contend that serum HDL cholesterol and LDL cholesterol say nothing about cholesterol flux, and that apoB or LDL particle number should be checked before drawing risk conclusions from HDL.
- The discussion covers how apoB particles transform and clear, with apoE speeding clearance and apoC3 slowing it, and why apoC3 is a promising future marker and drug target.
- The CETP inhibitor story is traced from torcetrapib's termination through dalcetrapib's futility and evacetrapib's early stop to Merck's anacetrapib, which cut events and lowered apoB but was not commercialized.
IDEAS WORTH REMEMBERING
5 ideasReverse cholesterol transport is far more complex than HDL returning cholesterol to the liver.
Dayspring says HDL can deliver cholesterol to the liver by several routes or to the intestine, and can also hand it to apoB particles, so he would rather talk about total lipid transport.
HDL cholesterol in the blood tells you nothing about cholesterol flux.
Both speakers note that a low or high HDL-C could reflect picking up a lot of cholesterol or failing to drop it off, so it cannot be read as a measure of transport function.
'Good cholesterol' is a misleading term.
Dayspring points out that a cholesterol molecule passed from HDL to LDL is the same molecule, and its fate depends on whether the LDL is cleared by the liver or enters the artery wall.
Low HDL-C as a risk factor may largely reflect apoB.
Dayspring says the early epidemiologic studies never adjusted for apoB or LDL particle count, and he believes low HDL-C would lose independent risk status if they had; Attia adds that HDL-C and triglycerides are proxies for apoB.
In insulin resistance, the rise in particle number comes mainly from LDL, not VLDL.
Using the Garvey paper, the speakers explain that LDL particles rise by hundreds of nmol/L while VLDL rises by tens, so a larger relative VLDL increase is a smaller absolute change.
WORDS WORTH SAVING
5 quotesI mean, there are 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
So spare me the nonsense. Stop using it. It's absurd term. It has no meaning. You're miseducating patients if you tell them it's good cholesterol
— Tom Dayspring
So, uh, before you declare, make any statements 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.
— Tom Dayspring
And a serum HDL cholesterol tells you nada about that process.
— Tom Dayspring
It's like the HDL was a quarterback, it passed it to the tight end who ran it across the goal line. Who gets the credit, the quarterback or the tight end or both of them?
— Tom Dayspring
High quality AI-generated summary created from speaker-labeled transcript.
