#22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V: HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins

Episode Summary

Executive Summary: The episode dismantles simplistic ideas about HDL as “good cholesterol” and explains cholesterol trafficking as a dynamic system involving HDL, LDL, VLDL, chylomicrons, apo proteins, and transfer proteins. The speakers argue that HDL-C is a poor proxy for reverse cholesterol transport, and that CETP-inhibitor failures reflect biology’s complexity rather than a simple drug-class failure.

Main Topics: Reverse cholesterol transport: direct vs indirect (Priority: 5/5): The discussion reframes reverse cholesterol transport as both direct HDL-mediated cholesterol return and indirect transfer via apoB particles that are later cleared by liver or intestine. Why HDL-C is a misleading biomarker (Priority: 5/5): HDL cholesterol level is presented as an unreliable surrogate for HDL function, cholesterol flux, or cardiovascular protection. ApoB particles, remnants, and apoE/apoC3 (Priority: 5/5): The speakers explain how VLDL, chylomicrons, IDL, and LDL interconvert, how apoE speeds clearance, and how apoC3 prolongs residence time and increases atherogenicity. CETP inhibitors and drug-trial failures (Priority: 5/5): The episode reviews why early CETP inhibitors were expected to work, why some failed, and why one later trial succeeded on events but still was not commercialized. HDL functionality and genetic outliers (Priority: 4/5): Rare cases such as very high HDL with atherosclerosis, or low HDL with longevity, are used to show that HDL composition and function matter more than HDL-C quantity. Clinical implications for lipid testing (Priority: 5/5): The speakers argue for prioritizing apoB/LDL particle number over HDL-C or non-HDL-C when assessing risk and guiding therapy.

Key Arguments: HDL-C does not measure reverse cholesterol transport; it is only a crude concentration metric and tells you little about flux or function. Cholesterol trafficking is bidirectional and highly dynamic: HDL can donate cholesterol to apoB particles, which may then be cleared by the liver or intestine. Most cholesterol in the body is made outside the liver; peripheral cells must export excess cholesterol or risk dysfunction. ApoE on lipoproteins accelerates clearance, while apoC3 prolongs particle residence time and likely increases atherogenic risk. VLDL and chylomicrons primarily transport triglycerides and phospholipids, not cholesterol to peripheral tissues; cholesterol is largely structural. CETP inhibition can raise HDL-C dramatically, but raising the metric does not guarantee improved HDL function or better outcomes. The success or failure of CETP inhibitors likely depends more on apoB lowering and off-target effects than on HDL-C changes. Non-HDL-C is a rough proxy for atherogenic particles, but apoB or LDL particle number is more informative when discordance exists. Genetic and functional HDL abnormalities can produce very high HDL-C with accelerated atherosclerosis, showing that HDL quantity can be misleading. Future lipidology may require functional, proteomic, or lipidomic assays rather than relying on HDL-C alone.

Data Points: Liver contribution to body cholesterol: ~20% - Speaker states the liver makes about 20% of cholesterol in the body; the rest is made in peripheral cells. Ileal bile salt reabsorption: 90% to 95% - The ileum reabsorbs most bile salts, limiting cholesterol loss through bile unless sequestrants are used. ApoE on LDL particles: ~3% to 4% in an average population - ApoE-containing LDLs are cleared much faster; the speaker estimates only a small fraction of LDL particles carry apoE on average. Cholesterol molecules bound per albumin molecule: 17 - Albumin can bind multiple cholesterol molecules and participate in cholesterol exchange. HDL cholesterol in APOA1 Milano cases: 5 to 10 mg/dL - Rare Italian APOA1 Milano carriers had very low HDL-C yet longevity, illustrating that HDL-C alone is not protective. Woman’s HDL cholesterol in case example: 130 to 140 mg/dL - A case study described a woman with extremely high HDL-C but accelerated atherosclerosis. Typical female HDL cholesterol: ~60 mg/dL - Used as a comparison to show how unusual the case patient’s HDL-C was. CETP inhibitor HDL-C increase (dalcetrapib): 20% to 30% - The weaker CETP inhibitor raised HDL-C modestly but did not show clear clinical benefit. CETP inhibitor HDL-C increase (potent agents): 80% to 100% - More potent CETP inhibitors produced much larger HDL-C increases. VLDL particle number in insulin resistance example: 30 to 90 - Illustrative example showing VLDL particle number may rise, but less dramatically than LDL particle number. LDL particle number in insulin resistance example: 1,000 to 3,000 - Illustrative example showing LDL-P can dominate the increase in apoB burden in insulin resistance. Fraction of LDL cholesterol arriving via HDL transfer: 30% to 60% - The speakers note that a substantial portion of LDL cholesterol may come from HDL via CETP-mediated transfer.

Pivotal Quotes: "HDL cholesterol tells you nada about that process." — Tom Dayspring: On why HDL-C is a poor marker for reverse cholesterol transport or HDL function. "The HDL story is one where the more time goes on, the less I know." — Tom Dayspring: Reflecting on how HDL biology has become increasingly complex and humbling. "I would rather just talk about lipid transport. It’s every particle is part of the system." — Tom Dayspring: Summarizing the move away from simplistic reverse cholesterol transport language.

Implications: Listeners should not equate high HDL-C with protection or low HDL-C with failure. Risk assessment should emphasize apoB/LDL particle burden and particle biology, while future therapies will likely depend on functional assays and better mechanistic understanding.