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Peter Attia MD#129 - Tom Dayspring, M.D.: The latest insights into cardiovascular disease and lipidology
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CHAPTERS
- 0:11 – 5:06
Preview of Topics and Tom Dayspring's Background
Peter Attia introduces Tom Dayspring and previews the three areas the conversation will cover: atherogenic lipoproteins and ApoB, risk assessment, and therapies. He then welcomes Tom back two years after their long lipid series.
- •Tom's earlier five-part series was among the show's most popular despite being technical
- •Three themes: atherogenic lipoproteins, risk assessment, and therapies
- •Therapy topics include PCSK9 inhibitors, omega-3s (EPA versus DHA) and bempedoic acid
- •Tom now works inside Attia's practice, mainly on research and cardiovascular consults
- 5:06 – 9:59
What Has Changed in Lipidology Over Two Years
Tom says the field has caught up with what he has long argued: atherogenic lipoproteins drive clinical atherosclerosis, and guidelines now reflect this. He names the areas of change: triglycerides, the fading usefulness of HDL cholesterol, Lp(a), and pharmacology.
- •Guidelines now embrace atherogenic lipoproteins and ApoB
- •Sterols enter the artery wall inside ApoB-containing lipoproteins
- •Triglycerides have taken center stage
- •HDL cholesterol has lost informativeness while Lp(a) has gained significance
- 9:59 – 21:47
ApoB Biology and Why It Beats LDL-P
Tom explains how lipids travel on apoproteins and how ApoB-100 and ApoB-48 differ. He notes that 90 to 95% of ApoB particles are LDL. Peter explains why he switched from LDL-P to ApoB in his practice, and both discuss consistency across labs and low cost.
- •ApoB is the main structural protein of VLDL, IDL, LDL and Lp(a); HDL uses ApoA-1
- •Plasma residence time explains why LDL particles dominate the ApoB count
- •Peter went through three NMR/electrophoresis technologies in eight years
- •The ApoB immunoassay is standardized and costs only a few dollars
- •Tom says to pick one metric, and stick with it
- 21:47 – 26:26
Is ApoB Causal? Exceptions and Particle Quality
Peter raises a patient with very high ApoB but a zero calcium score, and the pair discuss why particle number is not the whole story. Tom emphasizes particle quality and the multifactorial nature of atherosclerosis.
- •Endothelial injury from smoking and hypertension plus ApoB particles drives atherogenesis
- •Not every person with high ApoB develops disease, so risk is individualized
- •Particle quality, including proteins and lipidome, may explain differences
- •Treating ApoB is not the end; other injurious factors are examined too
- 26:26 – 37:06
How Low Can ApoB Go? Cholesterol Pools in the Body
Peter asks about the dose-response of lowering ApoB far below current norms. Tom says lower is better with no signal of harm so far, and that most benefit comes from the first 50% reduction. They then explain that plasma lipoprotein cholesterol is a small part of body cholesterol, with red blood cells and cell membranes holding far more, and discuss why foam cells, not red blood cells, drive plaque.
- •Guidelines suggest an initial 50% reduction in higher-risk people
- •Tom suggests ApoB under about 50 mg/dL is physiologic, like newborns
- •No harm signal with currently approved ApoB-lowering drugs
- •Cholesterol in lipoproteins does not reflect cellular or red blood cell cholesterol
- •Histology points to foam cells from oxidized lipoproteins, not red blood cell cholesterol
- 37:06 – 53:03
Why HDL Cholesterol Is a Poor Metric
Peter and Tom trace how HDL cholesterol gained prominence through observational data and why it has faded. Trials raising HDL have been neutral at best, and Tom likens HDL particles to varied fire engines whose function can't be measured.
- •Observational HDL data was never adjusted; low HDL often reflects high ApoB
- •Trials and Mendelian randomization of HDL raising have been neutral
- •Average HDL carries about 45 cholesterol molecules versus 1,500 to 2,000 in LDL
- •HDL functionality likely can't be assayed affordably
- •Both advise against paying for advanced HDL panels
- 53:03 – 1:02:36
Lp(a): The Genetic Driver and What It Is
Peter introduces Lp(a) as a major genetic driver of atherosclerosis that many people don't know they have. Tom explains it is an LDL particle carrying apo(a), discusses variability in risk, oxidized phospholipids, and the recommendation to test once.
- •Roughly one in ten people have elevated Lp(a)
- •Lp(a) is an LDL particle with an extra apo(a) protein attached
- •Oxidized phospholipids on ApoB may identify more dangerous Lp(a)
- •European guidelines suggest everyone be tested once in life
- •A study showed that high Lp(a) combined with bad family history is the worst scenario
- 1:02:36 – 1:13:15
Lp(a) Therapies: ASO Drugs, Statins and PCSK9 Inhibitors
They discuss current strategy for high Lp(a), mainly lowering ApoB and other risk factors, and antisense drugs in early trials. Tom explains why statins may slightly raise Lp(a) in some people while PCSK9 inhibitors lower it, and why Lp(a) isn't a therapeutic goal.
- •Antisense drugs to block apo(a) synthesis are in early trials with a phase three trial starting
- •Initial trials are limited to people with prior events and very high Lp(a)
- •Statins may raise Lp(a) in those with small isoforms, but benefit outweighs this
- •PCSK9 inhibitors lowered Lp(a) 0 to 60-70% in Peter's patients, median about a third
- •Lp(a) is not an accepted treatment goal because trial data are lacking
- 1:13:15 – 1:21:36
LDL Triglycerides, Non-HDL Cholesterol and VLDL Cholesterol
Peter asks about the experimental LDL triglyceride test. Tom explains what triglyceride-enriched LDL implies, including small LDL and insulin resistance. They then compare non-HDL cholesterol to ApoB and explain how to get VLDL cholesterol as a proxy for remnants.
- •LDL triglyceride is an easy assay, but not widely available
- •Triglyceride-rich LDL leads to small LDL and dysfunctional HDL, and often signals insulin resistance
- •Non-HDL cholesterol is still discordant with ApoB in 20-30% of some populations, and risk follows ApoB
- •VLDL cholesterol requires a directly measured LDL, not Friedewald-calculated
- 1:21:36 – 1:30:51
Statins: Choosing Agents and a Lower-Dose Approach
Tom and Peter discuss why no new statins are appearing and how guidelines now favor more selective statin use. They compare agents by drug interactions and potency, and Tom explains why he prefers starting lower and adding other ApoB-lowering drugs.
- •Payers favor cheap generics, so there's little incentive for a new statin
- •Newer guidelines use CAC, Lp(a) and family history to guide statin decisions
- •Pravastatin and pitavastatin have fewer drug interactions; rosuvastatin is a potent hydrophilic option
- •Guidelines recommend maximum-dose potent statins, but Tom believes the benefit comes from ApoB reduction
- •Peter's practice uses a tightly controlled list of four statins and prefers branded
- 1:30:51 – 1:38:20
Bempedoic Acid, Ezetimibe and Add-On ApoB Lowering
Tom explains where statins, ezetimibe and bempedoic acid act on cholesterol handling and why bempedoic acid is liver-selective. They cover its modest monotherapy potency, muscle-symptom data, FDA use and the combination pill with ezetimibe.
- •Statins inhibit HMG-CoA reductase; bempedoic acid inhibits ATP citrate lyase earlier in the pathway
- •Bempedoic acid is a prodrug taken up only by the liver, not muscle
- •Monotherapy lowers LDL-C about 10-18% and ApoB about 10-12%
- •Muscle aches aren't zero, but are less than with statins
- •A combination of bempedoic acid and ezetimibe exists, and there are now four ApoB options
- 1:38:20 – 1:50:12
EPA vs. EPA/DHA: REDUCE-IT and the Stopped Epanova Trial
Peter asks how thinking about EPA and DHA has changed. Tom walks through the Japan EPA trial, REDUCE-IT's nearly 30% residual risk reduction with four grams of EPA, and the stopped EPA/DHA Epanova trial. He gives his take on what to prescribe.
- •Triglyceride-lowering needs high omega-3 doses, around 4 grams a day
- •REDUCE-IT enrolled high-risk people on statins with triglycerides above about 137-150
- •The Epanova EPA/DHA trial was stopped for futility and remains unpublished
- •Tom would choose 4 g/day of EPA for evidence-based use in that risk group
- •He favors the omega-3 index to guide whether DHA is also needed
- 1:50:12 – 2:00:03
Fibrates, Niacin and Closing Thoughts
Tom argues fibrates are underused for triglyceride-rich lipoprotein problems, including insulin resistance and diabetes, and recommends fenofibric acid. Peter shares a patient whose ApoB dropped dramatically on Trilipix alone. Tom says niacin is out of guidelines, and they close with future topics such as genetics.
- •Fibrates show macrovascular and microvascular benefits in the right patients
- •Fenofibric acid (Trilipix) is the pure form; pemafibrate is in outcome trials
- •Peter's patient went from triglycerides ~400 to ~100 and ApoB from ~200 to 80-100 on Trilipix
- •Tom calls niacin a dead drug absent from guidelines
- •Genetic testing for lipid disorders and FH was left for a future episode
