ApoB and Causality in Heart Disease: What Peter Attia Misses

This video is going to be about one word, and only one word: causality. People are obsessed with it. But first let me identify the causal stimulus for this response video: a clip posted in which Peter Attia and Andrew Huberman, two of the biggest names in the health science sphere today, discuss Peter's obsession with causality and how it relates to cardiovascular disease.

To quote Peter Attia: Causality is an obsession of mine. Like most of the day, on some level, I sit around thinking about causality.

Now, to be clear, the purpose of this video is to respectfully debate, respectfully disagree with, respectfully rebut Dr. Peter Attia, because I think he misses a big picture important point. Now, to be clear, before I get to that point, this isn't to do a mic drop on Peter or to put points on some imagined board. This is not to end a discussion. It's not to dunk on anybody. It's to open an important discussion that is desperately needed. And please, this is my challenge to you upfront, consider the arguments I'm making here and how they build off of Peter's claims and try, please try, I'm begging you, to resist drawing possibly false conclusions about my broader positions and beliefs. If you wanna know more about what I believe based on the data, you can see the other content I have. Focus here on the arguments I'm making and try to avoid drawing false conclusions about those I'm not. Anyway, the first 3 minutes of the clip between Andrew and Peter are devoted to talking about lung cancer, actually, where Peter uses the Socratic method on Andrew to examine the causal relationship between smoking and lung cancer.

Would you agree that smoking is causally related to lung cancer?

Yes.

So just to be clear, Andrew, You do not think that it's just an association that smokers get more lung cancer?

No, I do not.

You— in other words, you believe that smoking causes lung cancer then? Yes. Peter ultimately lands on the point: if you believe that smoking is causally related to lung cancer, then smoking cessation reduces the probability of lung cancer. That is a logical equivalency. There can be no debate about that.

That sounds reasonable. So far I'm on board, aren't you? But then Peter pivots, replacing smoking with ApoB and lung cancer with atherosclerosis—cardiovascular disease.

He states: There is no ambiguity that ApoB is causally related to atherosclerosis.

Peter even goes so far as to argue that not treating elevated ApoB and elevated LDL cholesterol, even if a person's overall major adverse cardiovascular event score, risk score, is low, is just as idiotic as the analogy I used around smoking.

If a risk is causal and it is modifiable, it should be modified regardless of the risk tail. In duration.

And here is where I think Peter is wrong, because causality is not the same as importance. Again, here's the point I want you to walk away with: causality is not the logical equivalent of importance, nor does the presence of a causal stimulus necessitate an intervention. So let's broaden, let's illustrate this point. Let's return to Peter's analogy. If you believe X is causally related to Y, then X Cessation reduces the probability of Y. Now let's swap smoking and lung cancer for oxygen and fire. If you believe oxygen is causally related to fire, then oxygen cessation or depletion reduces the probability of a fire. It's technically true, but does that mean I should deplete my environment of oxygen to prevent spontaneous combustion? What Peter knows but underemphasizes is that causality does not imply insufficiency. And often, targeting a causal factor has consequences far beyond reducing the risk of the primary undesired outcome—in this case, heart attacks and atherosclerosis. So yeah, if I remove oxygen from my environment, I'm less likely to burst into flames, but I'll also suffocate, which is not good. So returning to high cholesterol, high LDL, and ApoB, similar logic applies. Yes, ApoB is causal for atherosclerosis. Peter and I actually agree on this point. You might not, but I think you should. But that does not mean ApoB is sufficient to drive atherosclerosis, nor that all elevated ApoB warrants an intervention. There is no ambiguity, to quote Peter, that some people live long, healthy lives with high ApoB or LDL. I actually have a family member in my immediate family in their 60s with lifelong high ApoB and high LDL, as high as 400 mg/dL for LDL, and zero plaque on coronary CT angiography. Interesting. That's their n 1. And "there is no ambiguity" that apple-bee-lowering therapies, they do carry risk. Take statins, the workhorse of the cholesterol-lowering, lipid-lowering world. They can increase blood sugar , cause—and I use that word intentionally—insulin resistance, reduce, deplete GLP-1 hormone levels, and impair mitochondrial function. Even in asymptomatic patients and even at nanomolar concentrations. So no, starting pharmacotherapy for high ApoB is not analogous to encouraging smoking cessation. The risk-benefit calculations of not lighting up a cigarette is entirely different from that of initiating a powerful drug. Now, some may counter with population-level data showing that statins reduce cardiovascular events and mortality. But again, that misses the point. Paraphrasing a rather famous Stanford scientist who actually I interviewed for my channel, that's coming up shortly, and who coincidentally was also a recent guest on the Huberman Lab podcast, I don't care what happens to the average person for one outcome. I care what happens to me for all the outcomes that I care about. Do you agree? Does that make sense to you? And the fact is the unknown risks of some interventions worry me even more than the known ones. So take PCSK9 inhibitors, for example. Suppose a metabolically healthy patient with high LDL and high ApoB is statin intolerant, so their doctor prescribes another medication, a PCSK9 inhibitor, an even stronger LDL-lowering and ApoB-lowering therapy. What are the risks? Now let's turn to Mendelian randomization. Which Peter himself describes in the Huberman clip as among the most important in the argument for a causal role of ApoB in atherosclerosis.

There is no ambiguity that ApoB is causally related to atherosclerosis. You know, how can I tell you that? I can tell you that looking at all of the clinical trial literature, all of the epidemiologic literature, and perhaps even most importantly, the Mendelian randomizations.

One Mendelian randomization— I'm showing the graph now— from this study shows that reduced PCSK9 activity, which lowers LDL and ApoB, is linked with fewer cardiovascular events. It's true. But look at the non-cardiovascular side of the equation. Lowering PCSK9 activity is also associated with a 2.43-fold risk of Alzheimer's disease. Now whether or not Mendelian randomization deserves its elevated status as the gold standard in determining causality is debatable.. But if we take Peter's standard at face value, then these data would imply that ApoB lowering via PCSK9 inhibition actually causes increases in Alzheimer's disease. So, I return to my main point: causality is not equal to importance, nor does causality necessitate treatment. Now, say it with me so you get the point: causality is not equal to importance. Causality is not equal to importance. Causality is not equal to importance. And again, this isn't meant to be the end of a conversation. It is an invitation to a conversation to Peter and to all of you. In fact, many of you have already provided input to this commentary on other platforms, including on my newsletter and on X, formerly Twitter, and I thank you for it. What's clear to me is people want more nuance and less keep it simple stupid, because honestly, You don't need to understand the intricacies of Mendelian randomization or the pathophysiology of atherosclerosis to be able to sense when you're being patronized to. That is not a cut at Peter, but a broad commentary on why dogmatic statements like "lower LDL and ApoB is better" create such an uproar, and a justified one if I do say so myself. And the last thing I'll say is that in the spirit of preventative care, I think it would be wiser to have this discussion sooner rather than later, because just like a nasty atherosclerotic plaque in a person with obesity, double diabetes, and metabolic syndrome, I'm not going anywhere, and I intend to grow quickly, and make some trouble if I need to. Now, I hope you found this reasonable, respectful, if a tad cheeky at the end, and that you're ready to evolve this conversation with me. Stay curious. Thank you for engaging. I'm gonna link a lot more information below for those of you who really want the nuance. Thanks.