#129 - Tom Dayspring, M.D.: The latest insights into cardiovascular disease and lipidology

Episode Summary

Executive Summary: Peter Attia and Tom Dayspring review major updates in lipidology: ApoB is now the preferred marker of atherogenic lipoproteins, HDL-C is largely unhelpful, and LP(a) is increasingly recognized as a major inherited risk factor. They also discuss newer therapies—PCSK9 inhibitors, bempedoic acid, omega-3s, and fibrates—and emphasize individualized cardiovascular risk assessment beyond LDL-C alone.

Main Topics: ApoB as the central atherogenic marker (Priority: 5/5): The conversation reaffirms that ApoB-containing lipoproteins are the causal drivers of atherosclerosis and that ApoB is now the most practical, standardized, and guideline-aligned way to quantify particle burden. Why HDL cholesterol is no longer a useful target (Priority: 5/5): Dayspring explains that HDL-C measures cholesterol mass, not HDL function, and that attempts to raise HDL-C have not improved outcomes; HDL biology is too complex for current bedside testing. LP(a) as a major inherited risk factor (Priority: 5/5): The discussion highlights LP(a) as a genetically determined, underdiagnosed contributor to premature cardiovascular disease, with emerging interest in oxidized phospholipids and antisense therapies. Risk assessment and individualized treatment (Priority: 4/5): They emphasize combining ApoB, LP(a), CAC scoring, family history, blood pressure, and metabolic markers to decide who needs therapy and how aggressively to treat. Therapeutic evolution: statins, ezetimibe, PCSK9s, bempedoic acid (Priority: 4/5): The episode reviews how modern lipid-lowering therapy now allows much deeper ApoB reduction, including hepatic-selective options and combination strategies for statin-intolerant or high-risk patients. Triglycerides, remnants, and omega-3 controversy (Priority: 4/5): They discuss triglyceride-rich lipoproteins as contributors to residual risk, the role of fibrates, and the mixed evidence for EPA-only versus EPA+DHA omega-3 formulations. Particle quality beyond particle number (Priority: 3/5): Beyond concentration, they discuss how triglyceride enrichment, oxidized lipids, and attached proteins may alter a lipoprotein’s atherogenicity, especially for HDL and LP(a).

Key Arguments: ApoB-containing lipoproteins are the causal vehicle for atherosclerosis; ApoB is a better clinical surrogate than LDL-P because it is standardized, inexpensive, and guideline-supported. Most ApoB particles in circulation are LDL particles, but VLDL remnants, IDL, and LP(a) also contribute; particle number matters more than cholesterol content. HDL-C is a poor bedside metric because it measures cholesterol mass, not HDL function; raising HDL-C has not reduced cardiovascular events. LP(a) is genetically determined and should be measured at least once in adulthood; high LP(a) plus family history or CAC meaningfully increases concern. Residual risk persists even after statins; deeper ApoB lowering with ezetimibe, PCSK9 inhibitors, and bempedoic acid can further reduce events. Triglyceride-rich lipoproteins and small dense LDL are important in insulin resistance and may be better addressed with fibrates or high-dose omega-3s in selected patients. Omega-3 evidence favors high-dose EPA in high-risk patients with elevated triglycerides, while EPA+DHA remains controversial after a futility stop in a major trial. Bempedoic acid is attractive because it is hepatoselective and can be combined with statins and ezetimibe to lower ApoB further, especially in statin-intolerant patients.

Data Points: ApoB particle composition: 90–95% LDL particles - Dayspring explains that most circulating ApoB particles are LDL, even though ApoB also includes VLDL remnants, IDL, and LP(a). LDL particle residence time: 2–5 days - Used to explain why LDL dominates ApoB burden and atherogenic exposure. VLDL half-life: 2–6 hours - Illustrates that VLDL is more transient than LDL in plasma. IDL residence time: 1–2 hours - Described as a short-lived intermediate particle with limited contribution in most people. Chylomicron residence time: minutes to a few hours - Used to distinguish postprandial particles from the main ApoB-driven risk particles. Average HDL cholesterol molecules per particle: ~45 molecules - Illustrates why HDL-C is a crude measure of HDL biology. Average LDL cholesterol molecules per particle: ~1,500–2,000 molecules - Contrasts LDL and HDL cholesterol content per particle. LP(a) prevalence: ~1 in 10 people - Attia notes that elevated LP(a) is common and often unrecognized. ApoB assay cost: ~$3–$4 - Used to argue that cost is no longer a valid reason to avoid ApoB testing. Omega-3 dose for triglyceride lowering: 4,000 mg/day - Dayspring emphasizes that meaningful triglyceride lowering requires high-dose omega-3 therapy. Reduce-It effect size: ~30% residual risk reduction - High-dose EPA added to statin therapy in high-risk patients with elevated triglycerides. Bempedoic acid LDL-C lowering: ~10–18% - Monotherapy effect described as modest but clinically useful, especially in combination therapy. Bempedoic acid ApoB lowering: ~10–12% - Approximate ApoB reduction with monotherapy. Triglyceride threshold in Reduce-It: >137 mg/dL (often 150 mg/dL cutoff) - Eligibility criterion for the EPA outcome trial. ApoB goal concept: <50 mg/dL - Dayspring suggests physiologic ApoB levels are roughly in this range, similar to newborns. PCSK9 effect on LP(a): 0–70% reduction, median about one-third - Attia reports wide variability in LP(a) response to PCSK9 inhibitors in practice. Statin effect on LP(a): Minimal; may slightly increase in some isoforms - Dayspring notes statins do not meaningfully lower LP(a) and can raise it slightly in some people. Fibrate example response: Triglycerides 400→100 mg/dL; ApoB high 100s/200→80–100 mg/dL - Attia describes a patient whose triglycerides and ApoB improved substantially on trilipix.

Pivotal Quotes: "Atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease." — Tom Dayspring: Core thesis of the episode: ApoB-containing particles drive atherosclerosis. "HDL cholesterol is useless as a bedside metric." — Tom Dayspring: Explaining why HDL-C does not capture HDL function or predict benefit from HDL-raising therapies. "If you want to be evidence-based and you're in that type of risk category, I think you got to go with EPA four grams a day." — Tom Dayspring: Practical recommendation on omega-3 therapy after reviewing trial data.

Implications: Listeners should shift from LDL-C/HDL-C thinking to ApoB-centered risk assessment, measure LP(a) once, and use combination therapy more strategically. The field is moving toward deeper, more individualized prevention and away from simplistic cholesterol targets.