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Peter Attia MD#22 – Tom Dayspring Part III of V: reverse cholesterol transport, CETP inhibitors, & apolipoproteins
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CHAPTERS
- 0:04 – 7:35
Direct vs. Indirect Reverse Cholesterol Transport: Where Cholesterol Goes
Peter Attia opens by asking for a definition of direct versus indirect RCT. Tom Dayspring explains the classic view of cholesterol leaving cells via HDL and returning to the liver or stool, and why that picture is too simple.
- •The liver makes about 20% of the body's cholesterol; peripheral cells make the rest
- •Classic teaching: HDL carries cholesterol back to the liver for use or excretion in bile
- •Most bile salts are reabsorbed by the ileum, so this is not the most efficient route out
- •Forward versus reverse transport was judged with LDL-C and HDL-C, which say nothing about flux
- 7:35 – 10:59
Multiple Pathways Back: SR-B1, Intestine, Red Blood Cells and Albumin
Dayspring describes the newer understanding that HDL can return cholesterol through several routes, including the intestine. Red blood cells and albumin also carry and accept cholesterol. Peter wonders aloud about red blood cells in familial hypercholesterolemia.
- •Three routes back to liver: SR-B1 delipidation, holoparticle uptake, and free diffusion
- •Transintestinal cholesterol efflux lets HDL dump cholesterol without reaching the liver
- •Red blood cells carry more cholesterol than lipoproteins; albumin can bind 17 cholesterol molecules
- •Phytosterols in red blood cell membranes cause hemolytic anemia in sitosterolemia
- 10:59 – 18:41
Chylomicrons, VLDL, IDL and LDL: Remnants and ApoE Clearance
Before discussing CETP, Dayspring lays out how apoB particles function and transform. VLDLs and chylomicrons deliver triglycerides and phospholipids, not cholesterol, and become remnants cleared by the liver. ApoE speeds clearance while apoC3 slows it.
- •VLDL and chylomicron purpose is delivering energy and phospholipids, not cholesterol
- •Remnants are cleared quickly via apoE; IDL and LDL follow as particles shrink
- •ApoE on LDL gives it a half-life like an IDL, but only about 3-4% of people have it
- •ApoC3 prolongs residence time and makes LDL more atherogenic; an apoC3 antisense drug is in trials
- 18:41 – 25:15
Insulin Resistance, LDL-P vs. VLDL, and Non-HDL Cholesterol
The two discuss how insulin resistance raises apoB, and argue that the rise is driven mostly by LDL particles rather than VLDL. They also address the limits of non-HDL-C and VLDL-C as remnant markers.
- •In non-insulin-resistant people about 40% of apoB particles from the liver are LDL
- •Large VLDLs appear mainly in triglyceride-rich states, most commonly insulin resistance
- •Relative increases in VLDL particle number can mislead; the absolute LDL-P increase dominates
- •Non-HDL-C is a free calculation but is discordant with apoB or LDL-P in many people
- •Peter no longer treats VLDL-C as a precise remnant estimate; the same therapy lowers both
- 25:15 – 32:45
Why Particles Exchange Lipids: ApoD/CETP and "Good Cholesterol"
Dayspring explains that lipoproteins constantly exchange core lipids, with HDL passing cholesterol ester to apoB particles. He argues the good-versus-bad cholesterol language is meaningless.
- •VLDL and chylomicron cholesterol is there to make particles spherical so they can carry triglyceride
- •Homotypic and heterotypic transfer occur between HDL and apoB particles, and between apoB particles
- •LCAT esterifies cholesterol in HDL before transfer to LDL
- •30-60% of LDL cholesterol arrives via HDL
- •A cholesterol molecule is not good or bad; it depends on what the carrying lipoprotein does with it
- 32:45 – 36:30
Low HDL-C in Framingham Is a Proxy for ApoB
Dayspring and Peter argue that epidemiologic findings on low HDL-C were never adjusted for apoB or LDL-P. They note that HDL-C and triglycerides are proxies for apoB, and discuss Framingham and MESA.
- •Early studies of low HDL-C were not adjusted for apoB or LDL particle counts
- •Framingham found HDL-C and triglycerides more predictive than calculated LDL-C; these are proxies for apoB
- •Insulin-resistant patients with that pattern have very high apoB
- •MESA is multi-ethnic and has shown apoB or LDL-P matters in discordant people
- •Check apoB or LDL-P before drawing conclusions from an HDL metric
- 36:30 – 40:45
Very High HDL-C and Dysfunctional HDL: The Case Study
Peter recounts a case of a woman with HDL-C around 130-140 and accelerated atherosclerosis. Dayspring explains that such cholesterol-rich HDL can be dysfunctional, and discusses Probucol and the SR-B1 gene.
- •The woman had HDL-C of about 130-140 mg/dL and LDL-C about 110, yet had accelerated atherosclerosis
- •Dayspring suggests huge cholesterol-rich HDLs that aren't cleared may carry wrong phospholipids and protective proteins
- •The only real approach is lowering apoB and other risk factors
- •Probucol induces the scavenger receptor and lowers HDL, with some arteriographic benefit
- •A gene affecting scavenger receptor function is linked to high HDL-C and coronary atherosclerosis
- 40:45 – 48:13
Defining Direct and Indirect RCT and the Limits of HDL Measurement
Peter summarizes that neither low nor high HDL-C can be interpreted without knowing flux. Dayspring then defines direct RCT as HDL delivering cholesterol itself and indirect RCT as passing it via apoB particles, and says HDL-C reveals nothing about either.
- •Low or high HDL-C cannot show whether HDL is picking up or dropping off cholesterol
- •CETP is the apoD discussed earlier; the quarterback analogy compares HDL passing cholesterol to LDL
- •Direct RCT is HDL delivering to liver, intestine or steroid-producing organs; indirect is via apoB particles
- •Total RCT is the sum of direct and indirect, and serum HDL-C tells nothing about it
- •HDL subpopulations and their protein and lipid signatures may determine where they act; functional assays are lacking
- 48:13 – 52:40
ApoA-1 Milano and the Rationale for CETP Inhibition
Peter asks why CETP inhibition seemed promising and why it failed. Dayspring covers the ApoA-1 Milano story, failed apoA-1 infusion trials, and the genetic model suggesting high HDL-C from CETP variants was protective.
- •ApoA-1 Milano carriers had very low HDL-C yet longevity, suggesting HDL function matters more than HDL-C
- •Infusing ApoA-1 or truncated versions after acute coronary syndrome failed in every trial
- •Inhibiting CETP leaves cholesterol in HDL and sends HDL-C up
- •Mendelian randomization came later and suggested high HDL-C is not protective
- •PCSK9 inhibitors were pursued because the genetic model was convincing
- 52:40 – 1:00:34
The CETP Inhibitor Trials: Torcetrapib, Dalcetrapib, Evacetrapib, Anacetrapib
Dayspring walks through the sequence of CETP inhibitor trials. Pfizer's torcetrapib was stopped in 2006, dalcetrapib showed futility, Lilly's evacetrapib was dropped, and Merck's anacetrapib met its endpoint but was shelved.
- •Pfizer terminated torcetrapib, which appeared to have off-target effects on electrolytes and hormones
- •Dalcetrapib was weak, raised HDL-C 20-30%, and showed futility
- •Lilly's potent evacetrapib was abandoned after futility
- •Merck's anacetrapib reduced coronary events and lowered apoB, suggesting apoB lowering rather than HDL-C raising was the benefit
- •Merck did not commercialize it because the drug stays in the body for years
- 1:00:34 – 1:04:18
Merck, Vioxx and Pharma Risk Aversion
Peter and Dayspring discuss why Merck may have shelved its CETP inhibitor despite a successful trial. Peter brings up Vioxx as an example of the legal and regulatory risk companies face.
- •Peter doubts the FDA would have been the obstacle; Dayspring cites the long tissue residence time
- •Peter describes Vioxx as a drug withdrawn after a signal of higher MI risk in some patients
- •Peter argues a subset of patients was deprived of a good drug and that Merck is sensitive to such history
- •Dayspring notes one adverse outcome can lead to huge lawsuits and recalls older arrhythmia drugs that killed patients
