Thinking about the recent treatment that Matrix presented for dyslipidemia, do you find yourself retesting lipids if someone is eating a higher fat diet to assess for hyper response to fat intake?

Absolutely. We definitely do a lot of that. A lot of retesting because diet can change dramatically even in response to relatively or seemingly modest changes in saturated fat intake. I’ll just use myself in this example. My LDL-P [low-density lipoprotein particle number] typically hovers around anywhere from the high 900s to, like, 1,200 on my typical diet, which is maybe, like, low to moderate carb Paleo, definitely not restricting saturated fat intake. But when I do my ketogenic diet cycles, which I do for about three to four weeks maybe three or four times a year, my LDL-P goes up to 2,000 during those cycles. That’s not moving from a low-fat diet to a keto diet; that’s moving from an already pretty high-fat diet to keto diet and just the additional saturated fat intake, or an overall fat intake going from low carb to keto can almost double my LDL-P, and I have a lot of patients who are in that category. It’s one reason that people come to see me, because they get on a really low-carb Paleo diet and their cholesterol and LDL-P and other lipids, which were normal before, have skyrocketed, and they’re concerned about that.

This actually takes us into the second question, which is from Amy, asking about podcasts recently where I indicated that people who are hyperresponsive to saturated fat might want to eat fewer fatty meals and less full-fat dairy. This is a pretty complicated topic, but I think the way that I would summarize it is, so right now, our current understanding of atherosclerosis is that it’s a gradient-driven process and primarily mediated by the number of LDL particles that are in the lumen, not the size of the particles; size, as I said in the curriculum, actually loses its statistical significance when particle count when you adjust for particle number. If someone has a very high LDL-P, then the idea is that some of those particles are going to try to diffuse into an area of less concentration, which will cause the particles to penetrate the fragile lining of the endothelium ​which is only one cell thick [3:56]​ that initiates the process of plaque formation, which is the start of the atherosclerotic process, as you know. That’s the current mechanistic understanding of how heart disease develops.

Of course, there are many questions like, does that process happen in the same way for someone who has a high LDL-P and no other risk factors or someone that has a high LDL-P and many other risk factors? I think common sense would say no, but there’s not a lot of research that helps us answer that question. I think I would say, all other things being equal, if you had, like, a doppelganger, if you’re someone who has high LDL-P and you made an exact copy of yourself, and they had normal LDL-P and every other factor was the same, according to our current understanding of heart disease, the copy of you with high LDL-P would be at higher risk.

Now, could that change? Are there things we don’t understand? Absolutely. Do I have concerns or questions about people making significant changes to their diet on the basis of one number on a piece of paper when this uncertainty exists? Yes, because those changes are not happening in a vacuum, and in most cases, people who have gone on a very low-carb diet did so for a reason, and if they’ve stayed on it, they’ve stayed on it for a reason, usually several reasons. They’ve lost weight, their blood sugars have improved, their triglycerides have gone down, all of their metabolic markers have improved, their cognition has improved, they feel better, etc., etc. Asking someone to switch from a diet that made them feel better in almost every way and then also significantly improved 95 percent of their blood chemistry and markers and other markers, and then one marker went up, well, we could still probably expect that that’s a net improvement in net reduction in risk overall.

Now, Tom Dayspring and even people like Peter Attia might say, “Okay. Well, do that. Stay on a low-carb diet, but then just take a statin to reduce your LDL-P,” and then you get the best of both worlds.

My approach is a little more conservative around statin use, but that’s a valid perspective. For someone who is open to taking statins and wants to just maximally reduce their risk according to our current understanding of the process of atherosclerosis and the scientific literature might not be a bad idea, but many of my patients don’t want to take statins. And so, then we’re left with this conversation that we’re having one side of now, where it’s explained to them, “Look, in a perfect world, here’s how we’d answer this question; we’d have two groups of people, we recruit a whole bunch of healthy people because most of the studies that have been done on LDL-P and the association between it and heart disease risk have been done in unhealthy people.” We would recruit a bunch of healthy people and then we would separate them into two groups. We’d feed one of them a high-fat, low-carb or even a ketogenic diet. We’d feed one of them a more standard Paleo-type of diet and we’d follow them for 20 or 30 years and measure what happens, and then we’d know do or we wouldn’t even change the diet. We could just have them all be on the same diet and just measure their LDL-P at the baseline of the study, and then track their LDL-P over time and measure the number of cardiovascular events to see if there is a higher number of cardiovascular events in people with high LDL-P but a healthy lifestyle and no other significant risk factors for disease.

That’s never going to happen. I shouldn’t say never, but no pharmaceutical company is going to fund that study. It would be enormously expensive, tens of millions if not hundreds of millions of dollars to do that, and there’s no incentive for a big pharma to fund that study. Unless a very wealthy patron comes along who wants an answer to this question, we’re just not going to have that research. It’s tricky because basically, it comes down to, at some point, a question of risk tolerance. If you take the hypothetical person I mentioned who improved in so many ways from a low-carb diet willing to tolerate a theoretical slightly higher risk of heart disease in exchange for feeling better and so many other markers improving, most of the time from my patients, the answer has been yes to that question when it comes all the way down to it. However, before we get there, there’s a lot of things that we do. We’ve already talked about some of them in this course and we’ll be talking about more of them. But, for example, we can try people on what I call a Mediterranean Paleo diet or a Mediterranean keto diet where instead of eating a lot of saturated fat, they’re eating more monounsaturated, so more olive oil, olives, avocado, tree nuts, nut oils, etc., and sometimes, that can make a huge difference. They can maintain high fat or even keto but not get the big spike in lipids.

And then, of course, we’re looking for gut issues, SIBO [small intestinal bacterial overgrowth], all the other things that we’ve talked about in the course, including hypothyroidism, which can increase LDL-P, and we can make some gains that way. And then, we can sometimes try the supplements, the tocotrienols and the pantethine, so there are many different things to do. But, ultimately, the diet question really involves all the different factors that I mentioned, so it’s not super easy to answer black and white.