#240 ‒ The confusion around HDL and its link to cardiovascular disease | Dan Rader, M.D.

Episode Summary

Executive Summary: Peter Atiyah and Dan Rader unpack HDL biology from formation to function, emphasizing that HDL cholesterol is not a reliable causal protector against ASCVD. They explain HDL’s complex metabolism, why CETP and niacin trials failed, how HDL function (cholesterol efflux) may matter more than HDL-C, and emerging links to brain health and neurodegeneration.

Main Topics: HDL biology and lipoprotein architecture (Priority: 5/5): HDL is introduced as a lipid-transport particle built around APOA1, distinct from APOB lipoproteins. The discussion covers HDL genesis, maturation via ABCA1 and LCAT, and why HDL metabolism is far more dynamic and complex than LDL/APOB metabolism. HDL measurements and nomenclature (Priority: 4/5): The episode clarifies confusing terminology: HDL is a particle, while HDL-C, APOA1, and HDL particle number are different lab metrics. It also distinguishes APOA1 from APO little a and explains why HDL2/HDL3 and NMR subclasses are not directly tied to APOA numbering. Why raising HDL-C failed clinically (Priority: 5/5): The hosts review CETP inhibitor trials and niacin, showing that pharmacologically raising HDL-C did not reduce cardiovascular events and sometimes caused harm. This supports the conclusion that HDL-C itself is not causally protective. Reverse cholesterol transport and HDL function (Priority: 5/5): A major theme is HDL’s functional role in cholesterol efflux from macrophages and reverse cholesterol transport. The conversation argues that HDL function, not HDL-C concentration, is the biologically relevant concept for atherosclerosis risk. Genetics, rare disorders, and paradoxical high HDL (Priority: 4/5): Rare conditions such as Tangier disease, LCAT deficiency, and SRB1 deficiency reveal key HDL pathways and show that very high HDL-C can coexist with increased ASCVD risk when HDL handling is impaired. HDL beyond cardiovascular disease (Priority: 3/5): The discussion expands to HDL/APOA1 in the brain, including possible roles in neurodegenerative disease, APOE interactions, endothelial nitric oxide, and insulin sensitivity, suggesting HDL biology may matter beyond atherosclerosis.

Key Arguments: HDL is a transport platform, not just a cholesterol number; its proteins and lipids exchange dynamically with cells and other lipoproteins. HDL-C is not causally protective against ASCVD; Mendelian randomization and failed drug trials support this. CETP inhibition reliably raises HDL-C, but outcome trials were neutral or harmful, showing that more HDL-C does not equal better outcomes. Niacin raises HDL-C and lowers triglycerides/ApoB modestly, but large trials failed to show meaningful cardiovascular benefit. HDL function, especially cholesterol efflux capacity from macrophages, is more predictive of risk than HDL-C alone. Rare genetic disorders demonstrate that very high HDL-C can be dysfunctional and associated with increased cardiovascular risk. HDL may have additional biologic roles in nitric oxide signaling, muscle insulin sensitivity, and brain lipid transport, but these are still emerging and not yet clinically actionable. APOA1 in blood and CSF may be relevant to neurodegeneration, but the relationship is not yet ready for routine clinical use.

Data Points: HDL particle size vs LDL: HDL is about one-fifth to one-tenth the size of LDL - Rader explains the physical difference between HDL and LDL particles. APOA1 molecules per HDL particle: About 1 to 4, sometimes more - APOA1 is not a single-copy structural protein like APOB. Tangier disease HDL-C: Virtually undetectable / about 1 mg/dL - ABCA1 deficiency prevents nascent HDL formation. LCAT deficiency HDL-C: About 10 mg/dL - Failure to esterify cholesterol prevents mature HDL formation. Mice HDL cholesterol proportion: About 90% or more of plasma cholesterol in HDL - Mice lack CETP and rely heavily on HDL for cholesterol transport. CETP deficiency HDL-C: Often over 100 mg/dL - Human genetic CETP deficiency produces very high HDL-C. CETP inhibitor trial effect: 9% reduction in cardiovascular events - One CETP inhibitor trial showed only modest benefit despite lowering LDL/ApoB. Niacin HDL-C effect: Can rise from about 50 to 90 mg/dL - Pharmacologic niacin can markedly raise HDL-C in some patients. APOE4 prevalence: About 25% of people - APOE4 is described as a common major genetic risk factor for Alzheimer’s disease. APOE2 effect on Alzheimer’s risk: About 20% relative risk reduction - APOE2 is protective for Alzheimer’s but can worsen remnant lipoprotein disorders. HDL efflux assay outcome: Predictive of incident cardiovascular events over 10+ years - The EPIC-Norfolk study showed cholesterol efflux capacity predicted hard outcomes.

Pivotal Quotes: "HDL cholesterol itself is not directly and causally protective against atherosclerotic cardiovascular disease." — Dan Rader: Summarizing the evidence from genetics and failed drug trials. "HDL cholesterol is sort of like an HbA1c for cardiovascular risk factors." — Dan Rader: Explaining HDL-C as an integrator of triglyceride metabolism and insulin resistance rather than a causal mediator. "High HDL is never a reason not to treat someone who would have otherwise merited treatment." — Dan Rader: Clinical guidance on not using high HDL-C to dismiss ASCVD risk.

Implications: Listeners should not treat high HDL-C as protective reassurance. Future risk assessment may rely more on HDL function assays than HDL-C, while HDL-targeted therapies will likely matter only if they improve efflux/function, not just HDL levels.