#19 - Dave Feldman: stress testing the lipid energy model
This episode features Dave Feldman, a software engineer and n=1 experimenter, discussing his "lean mass hyper-responder" hypothesis for low-carb dieters with high LDL-C/P. Peter Attia challenges this model, emphasizing the causal role of LDL in atherosclerosis and discussing alternative explanations and testing.
Deep Dive Analysis
17 Topic Outline
Peter's Initial Synthesis and Skepticism of Dave's Model
Dave Feldman's Journey to Cholesterol Research
Standard vs. Advanced Lipid and Sterol Panels
Understanding Lipoprotein Lineages and Function
The Lean Mass Hyper-Responder (LMHR) Phenotype
Atherosclerosis Progression and Diagnostic Markers
LDL's Causal Role vs. All-Cause Mortality in Studies
The "Zero LDL" Hypothesis and Trade-offs
Genetic Insights into Lipid Metabolism (PCSK9, ApoC3)
Dave's Challenge: Non-Genetic Studies on LMHR Phenotype
Energy Metabolism and Lipid Flux Hypotheses
Case Study: A Patient with High LDL-P on Low Carb
Peter's Hypothesis: Upregulated Cholesterol Synthesis in LMHR
Dave's Carb-Swap Experiments and Glycogen Threshold
Dave's Carotid Intima-Media Thickness (CIMT) Data
The Quality of Evidence in Nutrition vs. Lipidology
Challenges in Accessing and Interpreting Lipid Data
8 Key Concepts
Lean Mass Hyper-Responder (LMHR) Phenotype
A subset of people on low-carbohydrate diets who are typically lean, athletic, and metabolically flexible, exhibiting very high LDL cholesterol (200+ mg/dL), very high HDL cholesterol (80+ mg/dL), and very low triglycerides (70- mg/dL). This pattern is observed across various APOE types.
Sterol Panel
A blood test that measures molecules like desmosterol and phytosterols to provide insight into cholesterol synthesis and reabsorption in the body. Desmosterol indicates endogenous cholesterol synthesis, while phytosterols indicate exogenous sterol absorption.
LDL Clearance
The process by which low-density lipoprotein (LDL) particles are removed from circulation, primarily by the liver. This process is regulated and can be influenced by factors like statins or changes in cholesterol concentration.
Apolipoprotein C3 (ApoC3)
A protein found on lipoproteins, particularly VLDL and LDL, that increases their residence time in circulation. High ApoC3 levels are associated with increased risk for atherosclerosis, and inhibiting it is a therapeutic target.
Necessary but Not Sufficient
A logical relationship where one factor (e.g., LDL) is required for an outcome (e.g., atherosclerosis) to occur, but its presence alone is not enough to guarantee the outcome. Other factors (e.g., endothelial dysfunction, inflammation) must also be present.
Energy Model (Dave Feldman's Hypothesis)
The idea that in lean, fat-adapted individuals on a low-carb diet, high LDL particle numbers are primarily driven by increased VLDL secretion to traffic more triglycerides for energy, rather than an issue of cholesterol synthesis or clearance. This model suggests the high LDL might be a benign or even beneficial adaptation.
Mass Balance
A fundamental principle in physical models stating that the total amount of a substance (e.g., cholesterol) within a system must be accounted for by its inputs, outputs, production, and degradation. Peter Attia uses this to question Dave's energy model regarding the increased cholesterol in LMHRs.
Remnant Cholesterol
Cholesterol carried in lipoproteins other than LDL and HDL, primarily VLDL and IDL. It can be estimated by subtracting HDL-C and LDL-C from total cholesterol, particularly in a fasted state. Peter Attia notes that while it tracks with triglycerides, its clinical relevance as a standalone marker for pathology is limited without more specific assays.
10 Questions Answered
It describes individuals on ketogenic or low-carbohydrate diets who are typically lean and fit, and exhibit very high LDL-C (200+ mg/dL), high HDL-C (80+ mg/dL), and low triglycerides (70- mg/dL).
LDL-P is influenced by the amount of triglyceride and cholesterol ester it carries (cargo-related), cholesterol synthesis (measured by desmosterol), cholesterol reabsorption (measured by phytosterols), and LDL clearance (primarily hepatic).
It begins with lipoproteins (like LDL) entering the subendothelial space, binding to proteoglycans, becoming retained and oxidized, which then triggers an inflammatory response in the endothelium.
No, LDL cholesterol (LDL-C) is considered a 'crappy predictor' of cardiovascular disease; LDL particle number (LDL-P) and ApoB are better predictors.
Yes, the overwhelming body of evidence suggests that LDL is necessary but not sufficient for atherosclerosis; if there were no LDL particles, there would be little to no atherosclerosis.
While high LDL can offer some benefits (e.g., in infection), from a cardiovascular standpoint, there is no known 'good reason' to have high LDL. The discussion explores whether the LMHR phenotype might be an exception, but Peter Attia remains unconvinced.
ApoC3 increases the residence time of VLDL and LDL particles in circulation, contributing to their atherogenicity. Inhibiting ApoC3 is a therapeutic target.
In a subset of susceptible individuals (hyper-responders), high intake of saturated fat on a low-carb diet can upregulate cholesterol synthesis, leading to significantly elevated LDL-C and LDL-P. This effect can be reversed by substituting saturated fats with monounsaturated fats.
Under non-pathologic states, the half-life of an LDL particle is about one day, though it can be longer in pathologic conditions.
Mendelian randomization studies, which examine genetic variations that naturally alter LDL levels over a lifetime, provide strong evidence for LDL's causal role in atherosclerosis by acting as 'natural experiments' that avoid confounding factors present in observational or short-term drug trials.
34 Actionable Insights
1. Proactive Diabetes Prevention
If you have elevated fasting glucose or a family history of type 2 diabetes, proactively research and implement strategies to manage blood glucose levels rather than just monitoring.
2. Avoid Echo Chambers
Actively seek out information and perspectives that challenge your existing beliefs from every side, rather than staying within an echo chamber, to foster a more complete understanding.
3. Embrace Scientific Skepticism
Approach scientific inquiry with skepticism and prioritize the pursuit of truth over advocacy for a particular viewpoint or diet, as this fosters genuine understanding.
4. Contextualize Scientific Literature
When evaluating scientific literature, especially in complex fields like lipidology, recognize that the quality and depth of evidence can vary significantly, and avoid applying the same dismissive lens used for less robust fields like past dietary guidelines.
5. Consult Top Field Experts
To gain the deepest and most accurate understanding of complex scientific topics, seek out and engage with the leading experts in that specific field, who may not be found in popular online forums or general conferences.
6. Personalize Health Decisions
Recognize that population-level health data can obscure individual nuances; seek personalized advice to understand what specific health strategies are most relevant and beneficial for your unique situation.
7. Prioritize Healthspan & Lifespan
When pursuing longevity, consider both increasing lifespan (delaying death) and improving healthspan (quality of life), as patients often prioritize the latter.
8. Indecision Is a Decision
Understand that choosing not to act or decide on a course of action is itself a decision, with its own set of consequences and implications.
9. Address Multiple CVD Risk Factors
Understand that atherosclerosis is driven by multiple factors (lipoproteins, endothelial damage, inflammation), and improving any single risk factor like blood pressure or smoking cessation can lead to better cardiac outcomes.
10. LDL Necessary for Atherosclerosis
Understand that LDL is a necessary, though not sufficient, factor for atherosclerosis development; without LDL over a lifetime, there would be little to no atherosclerosis.
11. Clarify Health Goals & Trade-offs
Clearly define your health concerns, such as reducing cardiovascular disease risk, and consider potential trade-offs, like whether interventions might increase the risk of other conditions like cancer or neurodegenerative disease.
12. Avoid Health Confirmation Bias
Be wary of confirmation bias in health and diet, recognizing that even beneficial interventions can have downsides or not be universally optimal, and avoid overly simplistic ‘black and white’ thinking.
13. Integrate New Data Thoughtfully
When new research emerges, integrate it thoughtfully into the existing body of scientific knowledge to refine understanding, rather than immediately dismissing decades of established data.
14. Actively Fill Knowledge Gaps
Recognize and acknowledge personal knowledge gaps, and actively pursue learning and information to fill them as quickly as possible.
15. MUFA for Keto Hyper-Responders
For individuals on a ketogenic diet experiencing a ‘hyper-response’ with very high LDL, replacing saturated fats with monounsaturated fats (e.g., olive oil, macadamia nuts) may significantly lower LDL without changing total fat intake.
16. Pre-Low-Carb Lipid Test
Before starting a low-carb diet, get a particle count test to establish a baseline, as this can help in understanding subsequent changes in lipid profiles.
17. Baseline Sterol Panel
Obtain a sterol panel (measuring desmosterol for synthesis and phytosterols for absorption) at baseline to understand the underlying drivers of LDL particle number.
18. Consider Cholesterol Synthesis
For lean mass hyper-responders, consider that increased endogenous cholesterol synthesis, rather than just energy trafficking, may be the primary driver of their elevated LDL levels.
19. Carb Threshold for LDL-C
Experiment with carbohydrate intake, as increasing net carbs to a certain threshold (e.g., around 90g/day for 3 days for one individual) may lead to a substantial drop in LDL-C for some individuals.
20. Caloric/Fat Deprivation for LDL
Caloric deprivation (fasting) and fat deprivation appear to be general principles that lead to a reduction in LDL levels.
21. Statin Diabetes Risk Awareness
Be aware that while statins do not cause Alzheimer’s disease, they can slightly increase the risk of diabetes in a susceptible subset of patients over time, emphasizing the need for individualized assessment of medication side effects.
22. Understand LDL’s Role
Understand that the primary purpose of the LDL particle is to transport cholesterol, including its role in reverse cholesterol transport from the periphery back to the liver.
23. HDL’s Diverse Immune Roles
Appreciate that HDL particles play critical roles not only in reverse cholesterol transport but also in immune function, carrying immunoglobulins and other proteins.
24. Liver as Body’s Energostat
Appreciate the liver’s central and robust role as the body’s ’energostat,’ constantly sensing and regulating circulating energy and metabolites, likely through ATP levels.
25. Understand Chylomicron & HDL Roles
Recognize that chylomicrons primarily deliver fat-based energy from the gut, while HDL particles are generally involved in support operations not directly related to energy delivery.
26. Understand LDL Half-Life
Understand that the normal half-life of an LDL particle is about a day, but it can be pathologically extended by factors like ApoC3, increasing residence time.
27. Insulin Impacts Lipoprotein Residence
Understand that ApoC3 levels tend to correlate with insulin, meaning hyperinsulinemia (e.g., in type 2 diabetes) can increase the residence time of VLDL and LDL particles, potentially increasing their burden.
28. Monitor ApoC3 as Therapeutic Target
Stay informed about emerging therapeutic targets in lipid management, such as antisense oligonucleotides aimed at impairing ApoC3, which could impact lipoprotein residence time.
29. CIMT/CAC for Advanced Disease
Recognize that Carotid Intima-Media Thickness (CIMT) and Coronary Artery Calcium (CAC) scores are indicators of advanced atherosclerotic disease, not early biomarkers of risk, and should be interpreted accordingly.
30. Assess Quality of Life Impact
When evaluating health risks and interventions, consider not only the risk of death but also the potential impact of events like heart attacks or procedures on long-term quality of life and functional capacity.
31. Recognize Biological Non-linearity
Understand that many biological phenomena and their effects are not linear, meaning that increasing or decreasing a factor may have different outcomes at different levels.
32. Share All Symptoms, Stay Open
When dealing with novel or unusual health phenotypes, share all observed symptoms and remain open to the possibility of as-yet-undetermined risks, even with cautious optimism.
33. Weigh Efficacy & Cost in Healthcare
When making healthcare decisions, differentiate between the efficacy of a treatment and its cost or value, recognizing that the latter often involves individual or insurance-based decisions.
34. Skip the Introduction if Preferred
If you prefer to skip the lengthy introduction, fast forward approximately five minutes into the episode.
8 Key Quotes
Ultimately, I am not convinced by Dave's model.
Peter Attia
I'm not a formally trained biochemist. I'm not a medical professional. I regularly feel like I need to emphasize that.
Dave Feldman
Lipoproteins are a boat. This is going to be one-on-one, but let's kind of do that for the listener for a second. They're lipid carrying proteins.
Dave Feldman
If the concern is if you are less likely to die of heart disease, you are more likely to die of something else, then we should state that explicitly.
Peter Attia
Science is based on skepticism and certainty is forever elusive. So science gets better and gets sharper through this type of discussion.
Peter Attia
I am on a journey of science, not of advocacy.
Dave Feldman
The body of literature implicating LDL as having a causal role, a necessary but not sufficient role in the pathogenesis of atherosclerosis is on a different level from the body of literature that gave us the food pyramid.
Peter Attia
HDL-C is just categorically not a useful metric. It is like a first order term on a, like, no, no, it's not even that. Like in engineer speak, it's the fourth order term on a fifth order polynomial, Dave. That hurts, Peter. That hurts.
Peter Attia
2 Protocols
Dave Feldman's Carb-Swap Experiment (to lower LDL-C)
Dave Feldman- Maintain a very fixed diet, sleep schedule, and other lifestyle factors.
- Introduce a certain threshold of carbohydrates (around 90 net carbs per day for Dave Feldman) for about three days.
- Observe a substantial drop in LDL-C.
Peter Attia's Protocol for Hyper-Responder Patient (to lower LDL-P while staying in ketosis)
Peter Attia- Reduce saturated fat intake to approximately 25 grams per day.
- Substitute saturated fats with monounsaturated fats (e.g., olive oil, macadamia nuts).
- Maintain ketosis.
- Observe a significant drop in LDL-P (e.g., from >3500 to ~1300 nmol/L over eight weeks).