Why is Peter Attia skeptical of Dave Feldman's 'energy model' for high LDL in lean mass hyper-responders?

Peter Attia is skeptical primarily due to the 'mass balance' problem, arguing that Dave's model doesn't adequately explain the increased quantity of cholesterol in LDL particles. He also points out that in insulin-sensitive individuals (like many hyper-responders), VLDL production is typically lower, not higher, which contradicts the idea of VLDL conversion driving high LDL-P.

What advanced lipid tests does Peter Attia recommend to understand LDL particle number better?

Peter recommends getting a 'sterol panel' which measures cholesterol synthesis (via desmosterol) and absorption (via phytosterols), in addition to a particle count test (like ApoB or LDL-P). These markers help differentiate whether high LDL is due to overproduction, impaired clearance, or issues with cholesterol recycling.

What is the distinction between LDL cholesterol (LDL-C) and LDL particle number (LDL-P)?

LDL-C measures the amount of cholesterol carried within LDL particles, while LDL-P measures the total number of these particles. LDL-P is generally considered a more accurate predictor of cardiovascular risk than LDL-C because it accounts for the number of atherogenic particles, regardless of their cholesterol content.

How does the progression of atherosclerosis typically occur?

Atherosclerosis begins when lipoproteins diffuse into the sub-endothelial space of arteries. If proteoglycans bind to and retain LDL particles, they can become oxidized. This oxidized LDL then triggers an inflammatory response in the endothelium, leading to plaque formation. HDL particles, by contrast, always exit the sub-endothelial space.

Can high LDL cholesterol be considered benign or even beneficial in some cases?

Dave Feldman explores if high LDL, specifically in lean mass hyper-responders with high HDL and low triglycerides, could be benign or even beneficial, suggesting it might relate to efficient energy trafficking. Peter Attia acknowledges potential benefits for non-cardiovascular functions (e.g., immune response, hormone synthesis), but asserts there's no evidence for cardiovascular protection from high LDL.

What is the role of ApoC3 in lipoprotein metabolism and atherosclerosis?

ApoC3 is an apolipoprotein that increases the residence time of VLDL and LDL particles in circulation, making them more atherogenic. High ApoC3 levels, often associated with insulin resistance, are considered detrimental, and drugs targeting ApoC3 are in clinical trials to enhance lipoprotein clearance.

How do statins and PCSK9 inhibitors affect cholesterol and what are their clinical implications?

Statins lower LDL by inhibiting cholesterol synthesis in the liver, which upregulates LDL receptors and increases LDL clearance. PCSK9 inhibitors (like Repatha) prevent the degradation of LDL receptors, also leading to increased LDL clearance. Both are effective in reducing cardiovascular events, but Peter Attia cautions against excessive cholesterol synthesis suppression with statins due to potential side effects like neurodegenerative concerns in susceptible individuals.

What is the 'lifetime exposure model' of atherosclerosis?

The lifetime exposure model, discussed in relation to Alan Sniderman's work, emphasizes that atherosclerosis is a cumulative disease, meaning the risk increases with the duration and magnitude of exposure to atherogenic lipoproteins (like LDL-P) over a person's entire life, making short-term studies potentially underestimate risk.

How does carbohydrate intake influence LDL levels in Dave Feldman's self-experiments?

Dave Feldman found that increasing net carbohydrate intake above a threshold, around 90 grams per day, for about three days could substantially drop his LDL-C. This suggests that LDL levels are sensitive to carbohydrate intake in addition to fat intake, which he is exploring as part of his 'energy model'.

Are there natural conditions where elevated biomarkers might offer protective effects against cardiovascular disease?

Yes, an example is Gilbert's Syndrome, where slightly elevated unconjugated bilirubin (1.6-2.0 mg/dL) is associated with a reduced risk of cardiovascular disease. This is thought to be due to bilirubin's antioxidant properties, though very high bilirubin levels are toxic. This illustrates that biological responses are often non-linear and U-shaped.

Why is Peter Attia concerned about the low-carb community's approach to lipid science?

Peter expresses concern that some in the low-carb community, having successfully challenged mainstream nutritional advice, may apply the same dismissive skepticism to well-established lipid science, including Nobel Prize-winning work. He believes this leads to a dangerous oversimplification that 'LDL doesn't matter' for everyone.

Key Moments

#19 – Dave Feldman: stress testing the lipid energy model

Peter Attia MD

People & Blogs6 min read191 min video

Jan 1, 2020|14,693 views|223|138

low-carbohydrate diets lipids cholesterol lipid energy model Hyper-responders LDL atherosclerosis LDL-P HDL

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Key Moments

TL;DR

Dave Feldman challenges conventional LDL-C beliefs, exploring the 'lean mass hyper-responder' phenotype and the lipid energy model.

Key Insights

Dave Feldman, a software engineer turned citizen scientist, became known for his research into cholesterol changes on ketogenic diets.

He proposes a 'lipid energy model' where high LDL-C in 'lean mass hyper-responders' (lean, athletic, low-carb individuals) is due to increased fat energy trafficking, not necessarily atherosclerosis risk.

Peter Attia, while respecting Feldman's work, remains unconvinced, citing mass balance issues (unexplained increase in cholesterol mass), VLDL production inconsistencies in insulin-sensitive individuals, and the disregard for genetic evidence in Mendelian randomization.

The 'lean mass hyper-responder' phenotype is characterized by LDL-C > 200 mg/dL, HDL-C > 80 mg/dL, and triglycerides < 70 mg/dL.

Attia emphasizes that LDL is 'necessary but not sufficient' for atherosclerosis, akin to oxygen for fire, and criticizes the dismissal of extensive lipid research by some low-carb proponents.

Feldman's self-experimentation shows he can manipulate his LDL-C and LDL-P significantly by altering dietary fat and carbohydrate intake, suggesting a dynamic relationship with energy metabolism.

ORIGINS OF A SELF-EXPERIMENTER AND THE LEAN MASS HYPER-RESPONDER PHENOTYPE

Dave Feldman, originally a software engineer, transitioned into n=1 experimentation after experiencing a substantial increase in his cholesterol levels while following a low-carbohydrate diet. This personal experience spurred his deep dive into lipid metabolism. Collaborating with others who observed similar phenomena, Feldman identified a distinct pattern he termed 'lean mass hyper-responders.' These individuals are typically lean, athletic, and maintain a very low-carbohydrate dietary intake, yet exhibit remarkably high LDL cholesterol (LDL-C) and LDL particle numbers (LDL-P). He outlines specific criteria for this phenotype: LDL-C above 200 mg/dL, HDL-C above 80 mg/dL, and triglycerides below 70 mg/dL, a combination that challenges conventional lipid interpretations regarding cardiovascular risk.

THE LIPID ENERGY MODEL: TRAFFICKING FAT FOR FUEL

Feldman's central hypothesis, the 'lipid energy model,' proposes that in lean mass hyper-responders, elevated LDL levels are primarily a reflection of enhanced fat energy distribution rather than a sign of pathology. Drawing parallels to network engineering, he views lipoproteins as 'boats' efficiently trafficking fat-based energy to various tissues. He postulates that in a fat-adapted, low-carb state, the body, particularly the liver, increases VLDL (very-low-density lipoprotein) secretion to replenish energy stores and supply fatty acids to muscles and other organs. This increased VLDL production, according to his model, subsequently leads to a higher number of LDL particles as VLDLs remodel while shedding triglycerides, effectively making LDL a 'ride-sharing' vehicle for cholesterol in an energetically optimized system.

ATTIA'S SKEPTICISM: MASS BALANCE, KINETICS, AND GENETIC EVIDENCE

Peter Attia expresses significant skepticism towards Feldman's lipid energy model. He identifies three primary areas of concern. Firstly, Attia questions the mass balance: if LDL is merely trafficking existing cholesterol, where does the significantly greater mass of cholesterol in hyper-responders' LDL particles originate? He suggests it must involve increased de novo cholesterol synthesis, a point Feldman initially did not emphasize. Secondly, Attia challenges the idea that VLDL production drives high LDL in insulin-sensitive individuals, noting that standard metabolic models show insulin sensitivity reduces, not increases, hepatic triglyceride export, thus decreasing VLDL to LDL conversion. Lastly, Attia finds it problematic to exclude genetic studies from the discussion, particularly Mendelian randomization, which offers robust evidence for LDL's causal role in atherosclerosis by observing individuals with lifelong genetically altered lipid profiles.

THE COMPOSITION OF LIPOPROTEINS AND CHOLESTEROL METABOLISM

The discussion delves into the intricate nature of lipoproteins and their cargo. Attia clarifies that while chylomicrons primarily transport exogenous fat, and HDL is crucial for reverse cholesterol transport and immune function, the VLDL-IDL-LDL pathway (marked by ApoB100) is the main lineage relevant to atherosclerosis. He highlights that about 40% of LDL particles are directly secreted by the liver, not solely derived from VLDL remodeling. Attia stresses that clinicians need a 'sterol panel' (measuring desmosterol for synthesis and phytosterols for absorption) to understand the underlying causes of high LDL-P, asserting that increased desmosterol often indicates elevated cholesterol synthesis, which he believes is a key driver in hyper-responders.

CLINICAL CASES AND THE CHALLENGE OF INTERPRETATION

Attia presents a case study of a lean, low-carb patient with exceptionally high LDL-C (362 mg/dL), HDL-C (94 mg/dL), and LDL-P (>3500 nmol/L), alongside concerning inflammatory markers (high Lp-PLA2, oxidized LDL). Despite the patient's otherwise pristine metabolic health, Attia argues for an increased risk of cardiovascular disease based on the sheer burden of ApoB-containing particles. He attributes this patient's lipid profile to dramatically upregulated cholesterol synthesis and absorption, evidenced by high desmosterol and phytosterol levels, rather than purely energy trafficking. This divergence in interpretation highlights the core debate: whether high LDL in this specific phenotype is a benign adaptation or a silent risk factor.

TRANSIENT EFFECTS AND DIETARY MANIPULATIONS

Feldman describes his ability to rapidly manipulate his own LDL-C and LDL-P through dietary changes. He notes that consuming high amounts of dietary fat for three days can paradoxically lower his LDL-C and LDL-P, while introducing a specific carbohydrate threshold (around 90 net carbs/day) also causes significant drops. He attributes these changes to alterations in glycogen stores within the liver, theorizing that higher liver glycogen reduces VLDL secretion and subsequent LDL formation, thereby impacting circulating LDL levels. Attia acknowledges the interesting nature of these 'perturbations' but questions their long-term clinical relevance, emphasizing that transient, extreme dietary shifts may not reflect sustained metabolic states relevant to chronic disease development.

THE LIFETIME EXPOSURE PROBLEM AND CAUSALITY

Both agree on the 'lifetime exposure problem' in atherosclerosis, where observational and interventional studies typically run for only a few years, while the disease develops over decades. Attia highlights Mendelian randomization as a powerful tool to infer causality, as it studies genetic variations that lead to lifelong differences in LDL levels, showing a clear, unambiguous link between lower lifetime LDL and reduced cardiovascular risk. Feldman, however, calls for direct observational data from non-genetic, non-drug-treated populations with his specific high HDL/low triglyceride/high LDL phenotype, aiming to find datasets that show a lack of increased cardiovascular risk, a challenge Attia views as potentially biased by exclusion criteria and a misunderstanding of what constitutes 'proof' in science.

LDL: NECESSARY BUT NOT SUFFICIENT

Attia firmly states that LDL is 'necessary but not sufficient' for atherosclerosis. He uses the analogy of oxygen being necessary for fire: you can have oxygen without fire, but no fire without oxygen. Similarly, he argues, without LDL particles, there would be little to no atherosclerosis, though other factors like endothelial health and inflammation are also crucial. He criticizes the 'LDL denial' within some low-carb communities, suggesting they dismiss established lipid science with the same skepticism applied to flawed dietary guidelines, overlooking Nobel-Prize-winning research. Attia stresses that while low-carb diets offer significant metabolic benefits, they do not automatically negate the well-established role of elevated LDL in cardiovascular disease.

THE QUEST FOR DATA AND THE PROBABILITY OF RISK

Feldman expresses a strong desire to access large datasets like Framingham Offspring or MESA to perform regression analyses that stratify individuals by high HDL-C, low triglycerides, and high LDL-C (or ideally LDL-P). His goal is to find evidence that, within this specific metabolic profile, high LDL does not correlate with increased cardiovascular disease risk. Attia acknowledges this scientific curiosity but maintains that such a single analysis, even if supportive of Feldman's hypothesis, would not unilaterally overturn decades of medical science. He reasserts that the collective body of evidence establishes a strong probability that elevated LDL and ApoB-containing particles contribute causally to atherosclerosis, calling for a measured approach to risk assessment rather than a complete dismissal based on a specific dietary pattern.

Mentioned in This Episode

●Supplements

●Software & Apps

●Organizations

●Drugs & Medications

●Studies Cited

●Concepts

●People Referenced

Common Questions

A 'lean mass hyper-responder' is an individual, often lean and athletic, who experiences a significant increase in LDL cholesterol and LDL particle number (LDL-P) on a ketogenic or low-carbohydrate, high-fat diet, typically with high HDL cholesterol and low triglycerides. This response is not universal among low-carb dieters, with some estimates suggesting it affects 5-30% of individuals.

Topics

Health & Longevity Neuroscience & the Brain Nutrition & Diet Ketogenic Diets Atherosclerosis Prevention Lipid Metabolism Low Carbohydrate Diets Cholesterol Synthesis LDL Particle Number Cardiovascular Risk

Mentioned in this video

Drugs & Medications

Zetia

A cholesterol absorption inhibitor medication (ezetimibe) used to lower LDL cholesterol, particularly effective in patients with high cholesterol absorption.

Repatha

A PCSK9 inhibitor drug that helps lower LDL cholesterol by preventing the degradation of LDL receptors, thus increasing LDL clearance from the liver.

Lipitor

A statin medication (atorvastatin) used to lower LDL cholesterol. It increases LDL clearance by decreasing liver cholesterol synthesis.

Organizations

Albert Einstein College of Medicine

Research institution where work was done to identify longevity genes, including hypo-functioning ApoC3 variants.

KetoGains

A ketogenic community related to strength training, where Dave Feldman observes different LDL responses compared to aerobic exercise types.

Studies & Research

MESA Data

The Multi-Ethnic Study of Atherosclerosis, a large-scale study that provides data on cardiovascular risk factors, including Kaplan-Meier curves for LDL-C and LDL-P, which Dave Feldman is interested in for his research.

Quebec Heart Study

A study mentioned for its stratification of cardiovascular risk based on ApoB, LDL-C, HDL-C, and triglycerides, which Peter Attia refers to as providing evidence that ApoB is more predictive than LDL-C alone.

Framingham Offspring Study

A long-term, ongoing cardiovascular study that has provided extensive data on lipid markers and heart disease risk, mentioned as a potential dataset for analyzing LDL categories.

Supplements

Tocopherol

An antioxidant mentioned in the context of LDL particles, with some discussion around its role in the antioxidant defense system.

condition

atherosclerosis

A disease characterized by the buildup of plaque in arteries. The podcast discusses its genesis and the debated causal role of LDL, as well as its progression and detection methods like CIMT and CAC.

Concepts

Ketogenic Diet

A low-carbohydrate, high-fat diet that can lead to significant increases in LDL cholesterol and LDL particle number in a subset of individuals, coined 'lean mass hyper-responders.'

PCSK9

A protein that regulates LDL receptor degradation. Hyper-functioning PCSK9 leads to fewer LDL receptors and higher LDL levels, while hypo-functioning PCSK9 leads to more LDL receptors and lower LDL levels.

Niemann-Pick C1-like 1 (NPC1L1) transporter

A protein responsible for the absorption of cholesterol and phytosterols from the diet into the enterocytes (intestinal cells). Deficiencies can lead to increased cholesterol.

ATP-binding cassette G5/G8

A transporter protein in enterocytes that effluxes excess cholesterol and phytosterols back into the intestinal lumen. Deficiencies can lead to hypercholesterolemia.

Lipopolysaccharide

A component of bacterial cell walls, used in studies to induce an inflammatory response, leading to increased fatty acid synthesis and lipolysis in the liver.

Software & Apps

Carotid Intima-Media Thickness

A type of ultrasound used to measure the thickness of the inner two layers (intima and media) of the carotid arteries, used to gauge advanced atherosclerotic disease.

Coronary Artery Calcium (CAC) Score

A non-invasive CT scan that detects calcification in the coronary arteries, used to gauge advanced atherosclerotic disease.

Cholesterol Code

Dave Feldman's website where he shares his research, hypotheses, and collects data from individuals, particularly 'hyper-responders' on low-carb diets.

Oxidized LDL

A laboratory test that measures a small subset of LDL particles that have been oxidized and escaped the arterial intima, serving as an indirect marker of oxidative damage and inflammatory response in the endothelium related to atherosclerosis.

People

Dave Feldman

Dave Feldman is known for his work on 'lean mass hyper-responders' who experience very high LDL cholesterol and/or LDL particle number on ketogenic or low-carbohydrate diets. He is somewhat skeptical of the LDL causal paradigm in atherosclerosis and conducts extensive self-experimentation.

Tom Dayspring

A prominent lipid mentor for Peter Attia, who contributes commentary and clarifications on technical lipidology topics in the show notes. He is also credited with coining the term 'hyper-responder' in the context of low-carb diets.

Peter Attia

Host of The Drive podcast and a physician who focuses on optimizing performance, health, and longevity. He engages in deep discussions on topics like lipidology and challenges prevailing medical views.

Alan Sniderman

A researcher known for his lifetime exposure model of atherosclerosis, which emphasizes the cumulative effect of LDL exposure over time.