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Peter Attia MD#24 – Tom Dayspring, M.D., FACP, FNLA – Part V of V: Lp(a), inflammation, oxLDL, remnants, and more
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CHAPTERS
- 0:04 – 3:08
Episode Preview and Why Statins Don't Lower Lp(a)
Peter Attia previews the final episode of the lipidology series and then raises why statins don't lower Lp(a). Tom Dayspring suggests the LDL receptor clears Lp(a) and that liver production of apo(a) is the main determinant of its levels.
- •Preview of topics: Lp(a), inflammation, oxLDL, remnants, red blood cells, Lp-PLA2, ADMA and SDMA
- •Attia sets aside niacin's modest Lp(a) lowering and asks why statins don't lower Lp(a)
- •Dayspring believes the LDL receptor is the main clearance route for Lp(a)
- •Data suggest apo(a) production in the liver, not clearance, drives Lp(a) concentration
- 3:08 – 12:38
What Lp(a) Is and How It's Measured
Dayspring explains that Lp(a) is an LDL-like particle with apo(a) attached and why Lp mass is a weak metric. He describes an electrophoretic Lp(a) particle count and why statins leave Lp(a) particles largely unchanged.
- •Lp(a) is an LDL-like particle carrying apoprotein little a, not to be confused with apoA1 on HDL
- •Lp(a) mass weighs the entire particle, and apo(a) size varies, making it a poor metric
- •NMR can't count Lp(a) particles, so an electrophoresis-plus-apoB antibody assay (Lp(a)-P) is used
- •Statins lower LDLs without apo(a) but barely move Lp(a) particle count
- •Attia gives an example of 600 Lp(a) particles among 1,600 LDL particles
- 12:38 – 17:22
Therapies for Lp(a): Niacin, PCSK9 Inhibitors, and Apo(a) Synthesis Inhibitors
The pair discuss options for lowering Lp(a). Dayspring is skeptical of niacin, notes that PCSK9 inhibitors lower Lp(a) but can't prove an Lp(a)-specific benefit, and explains how apo(a) may camouflage the LDL receptor binding domain.
- •Niacin lowers Lp(a) about 20% and PCSK9 inhibitors about 30–50% (Attia's figure), with individual variation
- •A PCSK9 inhibitor's benefit can't be separated from its LDL and remnant lowering
- •An antisense apo(a) synthesis inhibitor is under investigation and enrolling for phase three
- •Niacin enlarges HDL but doesn't raise HDL particle count
- •Apo(a) may camouflage the LDL receptor binding domain on apoB, slowing clearance
- 17:22 – 20:47
Inflammation as a Target: IL-1, Methotrexate, and Colchicine
Attia raises recent trials targeting inflammation, including an IL-1 inhibitor and low-dose methotrexate. Dayspring notes colchicine's outcome trial and the cost and cancer-risk downsides of the IL-1 drug, and both stress stratifying patients by their driver.
- •Methotrexate and colchicine outcome trials are expected to report within a year
- •The IL-1 inhibitor showed outcome benefit but costs about $30,000 and slightly raised cancers
- •Attia argues for personalized treatment based on markers like CRP and fibrinogen
- •Inflammation is necessary but not sufficient, and the immune system shouldn't be shut down
- 20:47 – 25:56
Oxidative Markers: oxLDL, MPO, and F2-Isoprostanes
Asked about markers of endothelial dysfunction and oxidation, Dayspring explains what oxLDL assays actually measure and mentions myeloperoxidase and urinary F2-isoprostanes. He uses these mainly to motivate nutritional changes.
- •Oxidative-marker trials have never been adjusted for apoB or LDL particle count
- •Plasma oxLDL reflects minimally oxidized apoB aldehydes, not truly oxidized LDL from the artery wall
- •Myeloperoxidase is made by granulocytes, and F2-isoprostanes are measured in a small urine sample
- •Dayspring uses these markers to push nutritional therapy
- 25:56 – 34:36
Lp-PLA2 and Oxidized Phospholipids on Lp(a)
Dayspring says he wouldn't use Lp-PLA2 as a general pro-oxidative marker because Mendelian randomization and inhibitor trials show no outcome benefit. He and Attia then explain why Lp-PLA2 may still add information in Lp(a) patients, tying it to oxidized phospholipids carried on Lp(a).
- •Lp-PLA2 inhibitor trials lowered activity drastically with no outcome reduction
- •Attia stopped using MPO but finds Lp-PLA2 somewhat useful in people with high Lp(a)
- •Lp-PLA2 generates oxidized phospholipids and lysolecithin in the artery wall
- •Kringle lysine-rich segments on apo(a) bind oxidized lipids
- •Oxidized phospholipid on apoB, mostly carried by Lp(a), identifies who to worry about, but the assay isn't widely available
- 34:36 – 44:01
ADMA, SDMA, Homocysteine, and Kidney Function
Attia asks about asymmetric and symmetric dimethylarginine. Dayspring explains their link to nitric oxide and endothelial function, and they discuss homocysteine, renal function, and using cystatin C alongside creatinine.
- •ADMA and SDMA lower arginine availability and thus nitric oxide production
- •Homocysteine impairs clearance of ADMA and SDMA, offering a plausible mechanism
- •SDMA is cleared by the kidney and rises in renal disease, while ADMA is not
- •Cystatin C isn't affected by muscle mass, and a combined creatinine-cystatin eGFR is the most informative
- •Mild renal impairment and albuminuria are often ignored but signal vascular risk
- 44:01 – 47:29
What Remnants Really Are
Dayspring explains that every lipoprotein class has remnants and that particle number drives atherogenesis. He discusses the limits of estimating remnants from VLDL cholesterol and the role of large VLDL-P as an insulin-resistance marker.
- •Remnants are smaller parts of their sister particles within a density class
- •Most cholesterol entering the artery wall is still delivered by LDL due to particle count
- •VLDL cholesterol estimates from triglycerides/5 or non-HDL minus LDL are only crude remnant proxies
- •ApoB-lowering drugs clear all apoB particles including remnants
- •Large VLDL-P is mainly an insulin-resistance marker, not a treatment goal
- 47:29 – 56:23
ApoC-III and Its Role in Remnant Pathology
Dayspring explains how apoC-III slows clearance of triglyceride-rich particles and describes the CARE trial post hoc analysis showing pravastatin helped only people with apoC-III-enriched LDL. Attia notes apoC-III hypofunction as a strong longevity gene.
- •VLDLs with high apoE and low apoC-III are cleared quickly and aren't pathological
- •ApoC-III delays clearance, enabling more CETP exchange and cholesterol enrichment
- •In CARE, only people with apoC-III-enriched LDL got event reduction from pravastatin's triglyceride lowering
- •An apoC-III antisense drug is in development
- •DHA, not EPA, lowered apoC-III in a recent trial
- 56:23 – 1:07:45
Omega-3s: EPA vs. DHA, Red Blood Cell Levels, and Formulations
The two discuss omega-3 therapy, including the mainstream view that it is useless, measuring red blood cell omega-3 levels, and the vehicle of supplements. Dayspring points to an upcoming high-dose EPA outcome trial and the Vascepa and AstraZeneca free fatty acid story.
- •High-dose prescription EPA can lower apoB an additional 8–10%
- •Red blood cell omega-3 levels are preferable to plasma free fatty acids
- •Supplements differ in esterification, which affects how much omega-3 you get
- •Dayspring expects an EPA outcome trial to report at the American Heart Association in November
- •Attia and Dayspring both plan to wait for the data
- 1:07:45 – 1:10:26
Why Red Blood Cells Don't Cause Atherosclerosis
Attia asks why red blood cells, which carry more cholesterol per cell than lipoproteins, don't cause atherosclerosis. Dayspring answers that they're too large to enter the artery wall and aren't oxidized there, while apoB particles are far more numerous.
- •Red blood cells aren't invading the arterial wall or subject to oxidative uptake by macrophages
- •They are gigantic, though some enter plaque via the vasa vasorum
- •ApoB particles vastly outnumber red blood cells
- •Remnants can enter the wall too, but LDL particles are far more numerous
- 1:10:26 – 1:16:44
Remembering Earl: A Friend Lost to Untreated Cholesterol
Dayspring tells the story of his high school friend Earl, a firefighter who ignored advice to see him about high cholesterol and died of a heart attack in his mid-50s. Attia reflects on why delaying heart disease matters.
- •Earl introduced Dayspring to ice hockey and shared his love of firefighting
- •He avoided doctors and never came in despite repeated reminders
- •He died of a sudden heart attack at home in his mid-50s
- •Dayspring sees it as a needless, preventable death, and Attia frames the goal as delaying disease
- 1:16:44 – 1:29:46
Closing Reflections on Learning, First Principles, and Biology
Dayspring urges continued study and thanks the experts who taught him, while Attia tells a story about first-principles thinking in engineering versus biology. They close with thanks and where to find Dayspring.
- •Dayspring says none of this comes easy and has spent his career learning from experts
- •Attia describes learning first-principles derivation in engineering
- •Attia found he couldn't first-principles his way through biology without a large base of facts
- •Dayspring remains an optimist about teaching lipids
- •Dayspring's Twitter handle is shared, and both thank each other
