Debate: ApoB and All Cause Mortality - Nick Norwitz vs Dave Feldman

Dave and Nick discuss the larger questions and evidence around ApoB lipoproteins (such as LDL) and overall mortality.

[@annieyu3592]

Please do keep up the complex, civilised discussions that don’t patronise us laypeople - I for one am gradually learning the terminology and concepts you discuss even if I don’t get every nuance (yet). Greatly appreciate the way you seek to learn from people who will debate with you from different viewpoints and challenge you (intelligently) on the data and mechanisms. So valuable in this polarised world.

[@joannsmith9]

Guys. IF YOU ARE CORRECT-you may not need the ones who get to the bottom of this-but if and when someone does prove your theory-they will be standing on your shoulders and will owe everything to you -we will all be indebted to you wonderful young men. I love you both I love your brains too

[@ericolander9920]

Watching these two talking has been a fascinating learning experience for me. And loads of fun to boot!

[@AnneMB955]

Love these discussions guys. Was hoping to be there for the live. Always interested in how I can improve my knowledge and take steps to chase better health than both my parents.

[@nicknorwitzPhD]

Love it!

[@milenasenov6228]

Is it possible for someone with very high LDL to have low Apob values? My LDL literally exploded after I went on a VLCHD diet, as well as Apo b, Trg are almost zero mmol/l, hdl increased. Insulin, glucose, hs Crp, ferritin, homocysteine are at lowest level ever...

[@DK-pr9ny]

Great discussion guys! Was hoping to hear more about PCSK9 inhibitors. Also, Nick needs a better mic. 😉

[@pvl256]

Amen to the loss of trust, from being patronized to, and from "main stream" medicine creating a walled garden to defend rather than staying curious and being open to exploring new hypotheses.

[@nicknorwitzPhD]

"Stay curious!"

[@johnf.hebert1409]

Timestamped summary 🗣 00:00 Both Nick Norwitz and Dave Feldman have similar opinions on lipids, but they disagree on the relevance of ApoB and all-cause mortality, with Nick emphasizing the association of ApoB containing lipoproteins with all-cause mortality and the potential trade-offs of lowering ApoB. Expand 🔍 07:24 Low LDL cholesterol may be associated with greater all-cause mortality, but the relationship between ApoB and all-cause mortality is complex and influenced by confounding factors, making it difficult to isolate the true effect. Expand 📊 15:56 Metabolic vulnerability is a better predictor of mortality than ApoB, and nutritional factors can change the relationship between ApoB and all-cause mortality, with a linearized graph suggesting that lowering ApoB could be good for reducing all-cause mortality. Expand 🗣 24:02 The debate focuses on the uncertainty in lipidology and the relationship between ApoB and all-cause mortality, with a discussion on the impact of genetic abnormalities on LDL levels and cardiovascular disease. Expand 📊 35:56 Lowering ApoB levels may have cardiovascular benefits, but the complexity of real-world interventions and genetic differences must be considered in individual risk assessments for intervention. Expand 🔑 43:21 Insulin resistance syndrome leads to higher levels of apob and ldlp, impacting cardiovascular disease, but recognizing causal directionality and understanding unique population risks is crucial. Expand 📊 53:05 Melan randomization studies are interesting but can vary in results, the importance of uniform data analysis models and the challenges of obtaining and sharing data for studies on ApoB and all-cause mortality, frustration with the application of genetic ideology for differences in LDL apop versus metabolic response, and the importance of asking relevant questions and avoiding false dichotomies in scientific research. Expand 🗣 01:03:39 Progress in ApoB and all-cause mortality discussions, potential for more debates and discussions on the channel, and advocating for a discussion between Simon and Sean. Expand

[@rayfih]

Love your discussions so much! You are both such incredible human beings and super generous to share all your wisdom and insights with the collective. I'd love to pay it forward and support you both with some quantum coaching to help make that awesome roundtable discussion idea with Peter Attia et al a reality! 🤩

[@kingpossie]

Good stuff guys - keep it coming. ❤❤❤ from the. Netherlands 🇳🇱

[@nicknorwitzPhD]

We will!

[@stevelanghorn1407]

Appreciate the fact that neither of you seem influenced by some of the more “biased” social-media pressures. The fact that you stay science-focused, open-minded & free of “tribal-thinking” is what keeps me listening and taking you both seriously…in a very positive way. Keep going with your excellent work!

[@nicknorwitzPhD]

Appreciate you!

[@Torquilina]

What we need is better understanding of the underlying mechanisms rather than attempting to make deductions from observed effects. These indicators could be body defence mechanisms , could be good, or deleterious in themselves. People may have low ldl because they don’t need it. High ldl May be good as a defence. Maybe it is all IR? Sir George Mathewson.

[@Torquilina]

Malcolm Kendrick’s explanation I find more convincing. Read The Clot Thickens. GM

[@SLPCaires]

I would LOVE to hear you both talk to Bart Kay. In particular as it relates to the contentious statistical `techniques` mentioned in this debate.

[@lindabirmingham603]

I suspect Bart would do a video review on this devate.. I would be in attendance!

[@christinaperez254]

I'm afraid they wouldn't hold a candle.... Bart Kay is a legend comparatively. While delving into interesting "models" and "theories", ones that must be explored and not ignored.... These two are babies next to Bart.

[@888jucu]

@@christinaperez254Bart hasn't even proven he has ever been a professor in his life. If your whole story starts with a lie its hard for sensible people to take him seriously hence you rarely see him have deep dive discussions. All Bart is good at is doing take down videos where he gets pedantic on semantics and straw mans to make himself look like a genius. Many people can see through Bart but there are the gullible who love him 👍

[@user-zd7xp2sf7c]

@@888jucu starts with a lie?

[@vapidVGM]

I have to wonder why people have Bart Kay in such high regard. Is it because he talks in an extremely authoritative and condescending way? He's troll and full of BS

[@philthompson1097]

Mendelian Obfuscation and behind the curtain statistical adjustments - spraying the turd with gold paint.

[@Damcarnivore]

I hope the person that brought up Mendelian studies wasn’t referring to that horrible one that claimed ldl caused heart disease when they didn’t even take samples of the ldl levels

[@CipovPeter]

Hello Dave, thanks for your discussion. Got couple of comments/questions 1) I liked that you picked chinese study, Mr Cromwell presented on CoSci, I liked analogy with signal / noise. It showed me there could be even more populations with different treatments for high apoB. (malnourished population in this case) I consider this very novel/valueable topic to me. Is there any connection with keto-rash and malnutrition? 2) I value your style of presenting topics without point fingering, trolling, hate speech. This field is already heated too much and it drives attention from PROBLEM to IMHO fierce fight about unimportant technicalities. As I see The problem for the majority is not in nuances of lipid model or precision of apoB. Hard reality is doctors do not have deeper knowledge than "higher chol worse". My GP uses only total cholesterol for the risk model :-( ApoB is NOT measured in the majority of labs in the country. No demand. And a big elephant in the room. BAD, BAD lifestyle habits of their patients. I did not realize how bad myself, until I have changed my diet 5 years ago. Now I see it in every family meeting. Nearly all elders are after some chirurgical operation (knees) due to too much weight, are on pills taming diabetes 2, are obese. some after non fatal MI I could keep going on. They have never seen a gym, even run out, walk sporadically. Some are smoking, some overeating all day long, and drinking a lot of alcohol. You can talk to them but the only answer they give you, "recommend me the better pill". Lifestyle changes are ridiculed. What's worse, their kids are on a good path to meet the same destiny. I consider this dire. I value your effort moving the needle forward here, by providing unbiased information. Not polarizing people with meaningless facts but explaining context and creating safe space, inclusion. Btw. I have donated a bit ;-)

[@dbzgtcrazy]

That roundtable idea sounds awesome but microphones need to be very controlled. Attia would have a problem keeping his mouth shut while others are speaking, based on historical evidence.

[@paulasamec8715]

😂

[@annahurt575]

David and Nick. There appears to be a typo in the thumbnail I am seeing for this. Unless this is a debate about the morality of ApoB. :). Cheers.

[@mase3087]

What is lower apoB? Meaning isn’t our reference point from people on the standard American diet? In other words isn’t the reference range built from a metabolic unhealthy population?

[@markleblanc451]

Yes I agree wholeheartedly. Do we need to look at this through 2 different lenses? In the context of LMHR, ApoB is nothing but noise without an iota of causality. In the context of SAD diet, yes it is a problem.

[@paulasamec8715]

@@markleblanc451That means that eventually it - ApoB- is NOT the trigger, but a consequence of the metabolic Syndrom or some other disease!

[@ericzarahn9343]

I think the mechanism you two were discussing vis-a-vis the J-shape vs. linear hazard ratio curves is not signal:noise but confounding.

[@susanbeever5708]

ApoB does 1 thing: transports lipids in a lipophobic liquid. The environment is huge, it is metabolic syndrome that causes inflammation, hypertension and more. LMHR do not have metabolic syndrome. Look at all of the receptors involved in atherosclerosis from glp-1 to glp-1 receptor and TRPV1, TRPV4 etc. and how they transduce and transmit signals and cellular changes at the plasma membrane, mitochondrial membrane, endothelial junctions, vascular smooth muscle cells and LP(a) that attaches to apoB. Look at drugs that up-regulate these receptors along with carbs/sugar. Look at how these receptors interact with each other and what other receptors control these receptors. In other words, only looking at epidemiological studies does nothing to prove the causal mechanism of action. In a study on children on oxcarbazepine that up-regulates TRPV1 and TRPV4 LP(a) was significantly increased. Don’t you think that’s worth looking in to?

[@kenadams5504]

I just abstain from carbs .

[@Martihorn]

I am LMHR. My labs show normal fasting glucose 4.1 and A1C 5.4, but I still consider myself prediabetic (like years ago) because if I eat high carb anything my glucose shoots up to 300 and doesn’t come down for hours and hours. No cheating for me. It is too costly.

[@kenadams5504]

@@Martihorn The longer you do keto for, the more your metabolic health and the Underlying Pathologies will improve .In time , your glucose will spike less and remain elevated for less time ,(after eating carbs).

[@susanbeever5708]

@@Martihorn it’s so good that you are monitoring your system. I’m wondering what you mean by “glucose anything”. What amount of carbohydrates and or sugar and over what period of time? If you periodically, every 9-12 months run 6 hour oral glucose tolerance tests with insulin and c-peptide curves you will be able to see what your system is doing over time. Remember that carbohydrates stimulate insulin production and various drugs stimulate TRPV1 that stimulates insulin production after carbs convert to sugar and stimulate glp-1 and then the glp-1 receptor and then TRPV1 on lymphatic sensory neurons. Additionally, resting your system by not eating 16 hours overnight allows your system to rest, do maintenance and heal. You’ll see changes in your test curve over time.

[@Martihorn]

@@susanbeever5708 I seldom eat more than the regular 20 carbs per day but a few times I ate high carb foods and my glucose spiked really high. I just don’t do that anymore.

[@biowm]

Thanks for the nuanced discussion, all v balanced and reasonable 👍

[@richardbray8004]

Check with Bart Kay.

[@rsdaarud]

Dave, Im seeing changes in your brows and fullness in the thyroid. Are your thyroid function tests normal? Sorry to get personal but 38 years of primary care are hard to leave behind! Thanks for the apo B discussion.

[@pvl256]

I'm not reading his presentation that way - at all. He's confident - there's a difference between that and arrogance.

[@MartoDriftz]

Think you misunderstood the point of OPs comment. It's more regarding Dave's health or his potentially negative issues.​@@pvl256

[@nicknorwitzPhD]

It's okay... I have enough eyebrow for the both of us (and the lower T3 between us too, if I'm correct)

[@rsdaarud]

😂😂 Ditto here! Glad the thyroids are pulling their weight.

[@jerome4276]

Its true that the outer third of eyebrows missing are indicative of hypothyroidism. Dave should at least get his TSH measured.

[@anthonylawrence5842]

Where would Eurythrocite Sedimentation Rate fit as a cardio risk measure?

[@lennonzamora5387]

Gotta go with the engineer (and Bart Kay) in this particular instance but both are doing God's work for the nutrition workd as far as I'm concerned.

[@Dr_Boult]

@nic I don't belive that MVX would be constant in a person that undergoes a intervention/dietary change designed to reduce Apob. Diet can clearly change lucine, isolucine etc. and will probably impact small HDL particles, hence the assumption that lowering apob will not impact MVX is dubious at best.

[@DebiDalio]

What I would really like to know is does reducing LDL/ApoB to a really low number to avoid CVD increase the risk of dementia?

[@pureabsolute4618]

Hmmm.. I don't blame you guys, as much as the "meta science".. but there seems to be an occam's razor issue here. If the "Source" of the increase in LDL/ApoB changes the risk / plaque progression, then it is the source that is the issue, and not the ApoB. Why is there an assumption that ApoB is the cause? I've seen the statements from the Nature publication of that ApoB study, and there are severe limitations with respect to proving causality. For example, if ApoB is associated with death, and LDL is not, and there is a 1/1 relationship between the particles, that implies that the size of the LDL particle is the issue, and not the fact that there are more LDL particles. So what causes small LDL particles? AAAAND, it also implies that the VLDL are good particles - their offsetting nature with respect to the small LDL particles.

[@davidzip8841]

I would lose roundly if I debated someone knowledgeable in the area, so I’ll debate Nick!

[@dougsoderberg-uh9fw]

regardless of lipid profile where is the atheroma in the vein side of this closed system?

[@georgemoonman2830]

Yes, I just learned this recently too, if LDL/ApoB are in any way causitive for atherosclerosis then why don't we get it in veins.

[@paulasamec8715]

I’d suggest that genetics play a role as far as your ancestors may have developed different tolerance to carb consumption, e.g. if they primarily lived in a cold climate their tolerance for carbs may be very low in contrast to those who lived in the the warmer equatorial areas. In the end your health depends on your environment, meaning your food consumption, lifestyle etc. which influences your health, your genes however, determine the tolerance to carbs and the severity of the insulin resistance. ApoB levels , high or low, may be genetically predetermined in a given environment, but only playing a secondary role, namely that of firemen in a fire!

[@Kjuken69]

You can study single biomarkers til you drop, you will never find the answer of one marker that the body makes who increase anything related to arterie disease. It's the sum of extremely many factors. And the most important is your own imune systems. Your blood wessels own imune system! The only thing you can do, is to use your own head on what are logic and what's not.

[@Damcarnivore]

There is a purpose for epidemiology but the numbers rarely get close enough to show anything close to show causality. You can’t say it’s the best we have therefore we should accept it.

[@divadyrdnal]

Nick mentioned “some method to lower just Apob” , how is that done as I thought LDL/Apob were coupled together?

[@trail.blazer]

Apparently exercise can lower ApoB without lowering LDL.

[@nicknorwitzPhD]

I meant LDL/ApoB as an isolated change apart from other effects of the intervention. For example, if you are an LMHR are eat Oreos and lower LDL and ApoB... there are DEFINITELY other effects

[@pbziegler]

So my question is this--At 82 years of age can either of you or anyone tell me for certain that some number on a blood test proves I will die in the next 10 years from a heart attack? That is, what scientific evidence can you produce that establishes as a certainty that a number or physical condition will CAUSE me to have a heart attack in the next ten years? True that my age is a risk factor and there may be other risk factors but that doesn't make them causal.

[@runemartinguldberg9056]

Obsessing about ApoB. Ok. But have an eye to what happen in the process when cells block glucose entry to avoid poisoning damage. High glucose level are temporary store in the blood system. Endothelia is designed to take more beating and have a faster turnover. Glucose levels never seen in history before since the Egyptians thought it was sexy with man boobs. Regenerating endothelia is dysregulated with all this glycation going on.

[@russbrown6453]

Let's get Arlo's opinion...

[@rob2848]

What does Apo B got to do with our morality?

[@AnneMB955]

Funny. 🤭

[@jdogi1]

I don't do academia, but one thing seems clear. Nick needs Dr Cornwall for something... I won't bother to figure out what's behind it. I have better things to do with my time.

[@antonbelsky]

Check with Saladino.

[@ymvgee3762]

All Cause MORALITY would be grate! ( see your titel of your post )

[@rweaver6]

The thumbnail says "... all cause morality", missing t.

[@AZ89231]

Round table…

[@uaeio]

Why do you think this should be longer than 20 minutes?

[@ghost9-9ghost]

Narcissism and ego......I've seen these pretentious youtubers film themselves for TWO HOURS where they basically say "you need both strength training and cardiovasuclar" These are the new generation of "scientists" ....theye been molded to be absolutely narcissistic.

[@Arthurjshurley]

Please stop bringing up your Oreo versus Staten Study. The Oreo versus Stan Study didn't count for taking exogenous ketones as the reducing factor. If you add another fuel source, then other ones are less needed such as cholesterol carrying fat.

[@witoldoleksiewicz4155]

Nick You should really take "correlation is not causacation" to heart, especially as a PhD. To say that smoking decreases RISK of parkinsons desease is just a mistake, is like saying "eating less ice cream decreases the risk of drowning.

[@JD-mz1rl]

Classic example, buying ashtrays increases risk of lung cancer

[@jamesdellaneve9005]

He was using it as a poor example. Likely a co-variable.

[@jdogi1]

So, i just want to be sure i got this right... Nick's company developed a new score called the MVX risk score and it's his job to sell it. And if he does s good job, he gets more letters after his name? Does that adequately summarize?

[@StopDropper]

All cause *morality*?

[@Arthurjshurley]

I assume within your lipid energy model you attribute higher LDL's to the higher demand for fuel from fat. When you consumed your Oreos and exogenous ketones, you were consuming two versions of energy. The ketones would cause a reduction in the demand for fat energy. I believe that you could have lowered your LDL simply by adding exogenous ketones.

[@anitamcentofanti3277]

All cause "morality"?

[@edithrowland]

The devil made me do it.

[@HobzyMcRuse]

I'm a fat mass non responder!

[@peterfaber7124]

I replied the below to Bill Cromwell's presentation: This is such a great talk. He sees the world like I do. But I'm wondering about adjusting data for confounders.... The ApoB vs ACM graphs he showed in the end. It shows a pretty much linear relationship between ApoB and ACM,... But I'm wondering,... It's a completely theoretical relationship. In the real world there are almost no people who fit in that adjusted for confounders group. How many people who are completely healthy have sky high ApoB in isolation? Wait,.. they do exist,.. (don't they, Dave? 🙂). These are the LMHRs. And what do we see in these people? They hardly have atherosclerosis and they are metabolically very healthy. So the theoretical relationship between ApoB and ACM doesn't apply to them. (as far as I can tell now, it doesn't) That's where I am now,... I still haven't figured it all out. But the issue I see is that treating people's ApoB based on that theoretical relationship between ApoB and ACM,... may not be as effective as you would hope for. And complimenting people with untreated low ApoB,... may also be a dumb thing to do. Low ApoB seems to be a marker for, as far as I can tell,.. T2D + obesity + mitochondrial dysfunction will drop your ApoB levels like a stone.

[@peterfaber7124]

@@biowm The Massaai people, that eat a high animal food diet, have been found to have atherosclerosis, but strangely, their plaque grows outward, leaving the lumen size the same. So it doesn't cause disease. The factor that seems to cause this difference is their low Linoleic Acid consumption. I don't know what the mechanism is, but there's definitely more to atherosclerosis than just LDL/ApoB.

[@biowm]

My reply was removed, so I'm reposting... The graphs Cromwell used are from a Chinese group who have shown that controlling for comorbidities, and especially malnutrition, removes the association of low LDL-C, non-HDL-C and apoB with increased ACM (PMID: 35146010). Malnutrition is represented by the CONUT score, which is a simple proxy derived from albumin (weighted most), lymphocytes and cholesterol - perhaps not ideal, but a start. Note, while rare in industrial populations, many healthy native people (e.g. Hadza, Tsimane, Tarahumara, etc.) and other mammals have v low LDL. As for high LDL/apoB, I'm v interested in the LMHR study, but I think there are some notable limitations affecting generalisability. They may be healthy, but are presumably in ketosis, which may have its own effects. The study is also only looking at coronary beds over a shortish timeframe. There are many larger studies on healthy low risk people showing LDL-C correlates with subclinical systemic atherosclerosis (e.g. PESA) and CVD events/mortality (e.g. Cooper and MESA). The Horus study even found plaque developed in iliac-aortic beds 10 years prior to coronary/carotids.

[@biowm]

​@@peterfaber7124 Do you have a reference for that? I have read the Masai have low body weight, blood pressure and cholesterol/LDL (PMID:18523037). I hope this post isn't removed again!

[@andreahl1825]

Great discussion Dave but really disappointed about new academia approach, unfollowing Nick;)

[@jimw6659]

What’s happened to Nick? In a very short space of time, he’s become unbearably arrogant.

[@kathya1956]

Did he graduate?

[@MDL.720]

I certainly wouldn’t consider him unbearable but his ego probably has inflated in correlation to his follower count.

[@nicknorwitzPhD]

When you play devil's advocate and try to get into the nuance, you will attract shallow thinking trolls... bring it on Donkey Kong ;)... IMHO the personal attacks devoid of content discussion/dialogue are just reflective of defensive posturing because you don't like the argument(s). But everyone is free to watch and form their own opinion. And for those who feel the Safeway as you (which seems a minority opinion, btw) they are free to find other resources. No sweat.

[@MrSidReal]

It's because his jaw line is at perfect 45° angles

[@nicknorwitzPhD]

@@MrSidReal 🤣

[@witoldoleksiewicz4155]

Nick, sorry, again: "correlation is not causacation". You are mixing correlation with causation in nearly every sentence - it's making me cry about the state of science in 2024...

[@carnigoth]

Can't expect much from Harvard

[@jdogi1]

It is a bit sad to witness another relatively bright mind be taken into the DoD of the establishment. I'm always amazed at the creative lengths to which cancers and bad ideas will go to protect themselves.

[@ghost9-9ghost]

That's becuz nick horowitz isn't a scientist...he's a liar...a fraud ...an actor....a youtuber.

[@Arthurjshurley]

A person on ketogenic diet with high LDL cholesterol takes exogenous ketones and Oreos. Miraculously LDL is lowered. The reduction in LDL cholesterol is attributed to taking the Oreos and the exogenous ketones have nothing to do with it. I hear you guys yammering on about lipid energy model and the LDL cholesterol. From what I gather, the LDL cholesterol is supplying fuel for the body. in your Oreo, you took exogenous ketones to stay in ketosis. The ketones are extra fuel for the body. That means you wouldn't need as many LDL's to supply the energy. You should've just been extra ketones vs statins.

[@user-re6zq8ut2z]

@@ghost9-9ghostwho’s Horowitz? Are you drunk?

[@Kjuken69]

You can study single biomarkers til you drop, you will never find the answer of one marker that the body makes who increase anything related to arterie disease. It's the sum of extremely many factors. And the most important is your own imune systems. Your blood wessels own imune system! The only thing you can do, is to use your own head on what are logic and what's not.