Bonus Episode: Can Your Cholesterol Be TOO Low? Why Starting is Hard, & Your Cardio Time-Hack

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0:32All right. Thanks for your consideration. On to the show.

0:38Welcome back to the Barbell Medicine Plus Ask Us Anything. I'm Dr. Jordan Feigenbaum, and today we've got a jam-packed episode diving into everything from the philosophical debates of lipidology to the psychological friction of getting off the couch. First up, we're asking the question that apparently keeps at least two doctors up at night. Is there such a thing as, quote, too low of a cholesterol level? We'll break down the genetic and clinical trial evidence to help you understand the core debate. Is it about a minimum biological threshold, or is it all just a function of lifetime exposure? Then we'll shift gears to the gym and we'll tackle supersets, trisets, and giant sets.

1:13If you're short on time, is it a good idea to string together three or more non-overlapping exercises? We'll give you the take-home advice on how to be efficient without sacrificing your gains or hogging all of the gym's equipment. On the Mind-Body Connection, we're dissecting a fascinating question. Does acupuncture do anything? We'll talk about the difference between nociception and pain and whether measuring brain activity under anesthesia is a valid way to prove an effect, ultimately clarifying how much of acupuncture's benefit is truly physiological versus a powerful placebo effect. And finally, we're tackling two major life challenges.

1:46One is behavior change. Have you ever noticed that you've had a feeling of dread before starting the task? Is it laziness or is it psychological inertia? And then two, how to do cardio in a time crunch. What to do if you only have two 30-minute sessions a week and you've hit a plateau. We'll explain why intensity is one of the major factors for progressive overload and give you two strategies to facilitate that. Plus, we'll touch on the nuance of monounsaturated fats in your diet, the difference between writing a template and coaching people one-on-one, and a look on ADHD meds and exercise programming.

2:18But without further ado, I do have to introduce the second most handsome doctor in North America, Dr. Austin Baraki. What's going on, man? Hey, I'm doing okay. As we were chatting before getting started, I'm traveling for work at the moment, and So I'm working with a little bit of a different setup in case people, I don't know, detect a difference in the voice or the audio quality or something like that. But yes, I'm away attending on the hospital wards in West Texas at the moment. So not at home in my usual setup, but things are going okay at the moment. Yeah. Austin, nothing's happened to his vocal folds.

2:52Nothing's happened to his oropharynx. He's intact. In fact, it's just, you know, the audio is going through the iPhone 16, which has a decent microphone on it. So we'll see if my audio engineering stuff is up to snuff. And, you know, if we get a bunch of we get a bunch of hate comms on the on this episode, they're like, where's Austin's microphone? And I'm like, look, he ate it, man. I don't know what I don't want to tell you. Yeah, I can deal with the critics. That's OK. But yeah, slide in Austin's DMs if you don't like his sound. He really appreciates that. All right. Well, let's dive in because we do have a lot to get to today.

3:24So first up, is there such a thing as too low of a cholesterol level, specifically LDL and apolipoprotein B? So the question is, hi docs, I have two doctors in my life, my PCP and my cardiologist, who cannot seem to agree on whether there is such a thing as an LDL or APOB level that is too low in the context of primary prevention. I've reviewed what I could of the literature, and honestly, it seems as much of a question of epistemology and risk management as science or medicine. One doctor argues that the evidence from clinical trials and from people born with certain genetic mutations shows that levels at or lower than that of a neonate are at least not harmful.

4:04The other argues that we don't have multi-decade evidence of what happens when we reach those levels in humans through medical interventions rather than genetic mutations. Without making this about my specific case, how do you think about an issue like this? I actually thought this was a very interesting question. It's not new, but it's a different take because we've gotten questions before, I don't think on the AMA, but elsewhere. Hey, look, can cholesterol be too low? Or look at this study. It shows that there's increased mortality when cholesterol levels are too low, and we'll get to why you can see some studies like that.

4:39But it's never been specifically about apolipoprotein B, and it's also never kind of introduced this other wrinkle where it's like, hey, look, what about – do we have multi-decade evidence that lowering this through medications? actually provides the same benefits as some of these genetic mutations. So the premise, as I understand it, is this. I'm going to get you to confirm that we're talking about the same thing. Apolipoprotein B or APOB is a structural protein that's found on potentially atherogenic lipoproteins, making it a critical measure of total particle count. We're talking about the stuff that carries cholesterol around in the body.

5:14So when discussing lipid lowering, achieving ultra-low levels of circulating LDL, also means achieving ultra-low levels of ApoB. So this debate, if it were a debate, centers on whether the human system requires some minimum amount of circulating LDL particles for health, or if you can just go as low as you want, and maybe that's even better. And then we also have to define what is ultra-low in this case. And so we could define that as something below 40 milligrams per deciliter, which approaches the levels that are seen in newborns. They're usually born with like 20 to 40 milligrams per deciliter.

5:50which is during the period of most active brain development and growth. Does that seem like a reasonable kind of like interpretation of what we're talking about here? Yeah, totally. This is analogous to other, you know, contexts where I've gotten this same question. And so I'm, I would say, relatively familiar with this question and the conversation and back and forth and debates around it among the, you know, clinician community and certainly among the Twitter sphere, let's say. Totally. Okay, before we dive into the different lines of evidence and ultimately get to like an answer here. So if there's two doctors, one's a PCP and one's a cardiologist, do you want to pin one of the opinions on one of the physicians?

6:29Like which opinion is attributed to the PCP and which one's attributed to the cardiologist in your best guess? Yeah, my prediction here is that the cardiologist is the one who is more comfortable with the lower ApoB or LDL cholesterol targets. and the primary care physician might be the person who's more concerned that, quote, we don't have multi-decade evidence of what happens when we reach those levels through pharmacologic intervention rather than genetic mutations. That's my guess and my prediction. Yeah, I'd say that I'd be in agreement there. All right, so let's start out with this genetic evidence.

7:01So we're talking about like loss of function type mutations. And I know that you've talked about this a number of times, so I'm going to let you kind of go off on this, King. Like when we talk about genetic evidence, loss of function, Like, what specifically are we talking about? Like, what are we losing function in? And like, what happens? Yeah, I think that without diving into a full exposition of the physiology of circulating LDL and ApoB, it is important to understand, as we've talked about in other contexts, that it matters how you got there. We've talked about that with blood pressure, for example.

7:33It matters how your blood pressure got high or how it got low. And to some extent, there's actually also some similarity here. But understanding the physiology of where do these ApoV particles come from, they're synthesized, produced, and excreted from the liver into the bloodstream. They circulate throughout the body. And then they are also cleared predominantly by the liver as well, but also to some extent in some other tissues. And so the amount that is swimming in our blood at any given time that might be detected when you do a blood draw, that's just a snapshot in time, is going to relate to the difference between how quickly are these particles being produced and excreted from the liver into the bloodstream versus how quickly are they being cleared from the bloodstream.

8:16So there are kind of two angles that you could look at to get a sense of where is this person ultimately settling out, so to speak. And so when we look at, for example, lifestyle things that can impact these blood levels, causing them to rise, a lot of it ends up having to do with impairment in their clearance. They're not as efficient and as effective at getting this stuff out of the blood. So on the other hand, when we see patients with certain genetic mutations and mutations, not like the cool X-Man kind that give you superpowers, but sometimes these mutations can be good or favorable. I only say that because mutation tends to have a negative connotation to it.

8:58But in this situation, when people have what's called that loss of function mutation in a gene called PCSK9, that leads them to be hyper-efficient at clearing LDL particles out of the blood. They can produce it just fine, but it is rapidly cleared so that it doesn't stick around in the bloodstream that long. And when LDL cholesterol and these ApoB particles don't stick around in the bloodstream that long, they don't have that much of an opportunity to get into the walls of our blood vessels and cause problems. And yes, for anybody who is like upset with me right now, I also recognize that there are other contributing accelerants to the process of atherosclerosis, things like smoking and inflammation and insulin resistance and things like that.

9:40But when we look at what is the composition of plaques in arteries, it is not made up of cigarette smoke. There is lipid-laden plaque cholesterol that got there one way or another, and it could have been accelerated by these other risk factors. But we also know that patients who just have isolated severe high blood cholesterol levels, they tend to develop rapidly progressive early or premature atherosclerosis. So people who have these kinds of gene mutations, specifically the example we're talking about is this PCSK9 loss of function, they are super efficient clearers of ApoB particles out of the blood.

10:16What's the effect of this? Is that they live with super low blood levels of LDL cholesterol, super low blood levels of ApoB, almost like they're living on a drug that mimics that effect called a PCSK9 inhibitor. And then what's the downstream effect of that? Is they have a dramatically lower lifetime risk of developing atherosclerotic cardiovascular disease. And the amount of that risk reduction is going to be in proportion to how much lower their blood levels are. Because as we've talked about elsewhere, this is a phenomenon that relates to the cumulative lifelong exposure, how high and for how long.

10:51And so when you're born with low levels and you live most of your life with low levels, you're going to end up being at very low risk. The question or the implication with respect to this question askers scenario, though, is even though these people are born with low blood LDL and ApoB levels and they live with those for a long time, is there some sort of severe off-target harm that they suffer from that would be indicative of their levels being, unquote, too low? For example, do they have a way higher rate of developing early cancers or dying from rapid early onset dementia? Because that's often a concern from people as they're like, oh, too low.

11:29Am I at higher risk of developing dementia or something like that? And that just doesn't really seem to pan out in this patient population. Again, I will recognize that not for two people at a given blood level of LDL cholesterol, they might have gotten there by different ways. And so it's worth examining what happens when we get there by different ways. because are all these scenarios the same ultimately, or are there some variations? And so when we look at other gene mutations, for example, when you're unable to produce ApoB particles or familial hypo-beta lipoproteinemia, or to impress you with my pronunciation there, that's less of an issue related to hyper-efficient clearance of these particles and more of an issue with your ability to produce them.

12:12Those beta lipoprotein particles that would get secreted on those particles, you have a limited ability to do that. Now, when people have two defective genes with that, that leads to a severe impairment in their health because they have limited ability to package all sorts of things on these lipoprotein particles. There's a lot of other things besides just cholesterol on them, and so they end up requiring other treatment approaches relating to their dietary fat intake and fat-soluble vitamins and lots of other things. This is also a super tiny fraction of this population. But more often, these people have heterozygotes, meaning they have one defective gene and one normal gene.

12:54And these people also live with very low blood levels of LDL cholesterol because they're just not as good at producing these circulating particles. but they tend to not have symptoms or complications as a result. Similarly, would you expect to find, for example, that they get very early onset dementia? Because everybody, if you go on the internet and you read about this stuff, you see people say, well, your brain is mostly made of cholesterol. Cholesterol is super important for your brain. If you lower your blood cholesterol, you're going to get dementia without recognizing that there's all sorts of physiology that they don't know in terms of the blood-brain barrier and lipid trafficking in and out of the brain that more so doesn't tend to happen than does and things like that.

13:31And so you would predict, or people who are of that belief might predict that those with very low levels are going to be prone to all these things, which also isn't really what we end up seeing. So that's the approach to this question from the genetic side of things. This person said that their physician was questioning, well, is it safe or reasonable or appropriate to extrapolate what we see in the genetic scenarios to people who don't have those genetic things, but we achieve a similar result through the use of medicines that might be stated, started later in life, which is sort of a valid question, I think.

14:05But the thing is, is that many of these drugs that we have end up in one way or another mimicking the effect of one of these gene mutations. And ultimately people end up getting exposed to it for a smaller fraction of their life compared with if they're born with it. But we can still look at the trial data anyway to approach this question as well. Yeah, yeah. Like just if you look at the genetic data alone, you're like, okay, so apparently there's not some like unknown risk or unknown risks of hearing low LDL level, low apolipoprotein B. Otherwise, it would have shown up in these people who live their entire life, their entire lives with low LDL, low apolipoprotein B.

14:43So from the start, you're like, okay, I'm getting kind of convinced. I'm feeling like pretty okay about this, but maybe it's different if you use a medication to get there or a number of medications there, right? And so fortunately, this has been investigated a number of times. And so just a brief review of some of the longest-term data that we have on this. So first up is the Fourier trial. This is a study on a PCSK9 inhibitor. And effectively, this was done in people with high risk of cardiovascular disease. And it found that reducing their LDL levels produced a persistent cardiovascular benefit.

15:27They also extended this study for 8.6 years was the average follow-up there. And that established a strong dose-dependent relationship between lower LDL levels and a lower risk of heart disease. in a dose-dependent relationship. The more LDL was lowered, the more reduction in adverse cardiovascular outcomes. And this relationship held true down to levels less than 20 milligrams per deciliter, decidedly lower than the neonatal level. And there was no statistically significant increase in serious adverse events with lower LDL levels, including like neurocognitive decline, which was actually tested.

16:07So that's one study. That's the Fourier trial and the Fourier extension on that. The Improve It safety analysis followed patients treated with ezetimibe and simvastatin. Again, these drugs together would lower LDL a bunch. And it showed no increase in adverse events in patients achieving LDL levels less than 30 milligrams per deciliter over more than six years of follow-up. And then finally, the Ebbinghaus study specifically evaluated cognitive performance in patients achieving LDL levels below 25 milligrams per deciliter using PCSK9 inhibitors and reported no change in cognition. Now, full disclosure, if you're looking for multi-decade evidence, 20 years, 30 years, 40 years, fair enough.

16:55We don't have that data. That data does not exist. Perhaps it will. These longitudinal studies going out further into the future will probably be retired by the time that stuff gets published. But we have robust evidence showing that there's a dose-dependent relationship between LDL-lowering and reduced heart disease risk, whether or not you got there via a genetic mutation or through medication. Also, there's no apparent harm that's been identified in these data sets related to just low LDL levels or low apolipoprotein B levels. uh so like i want to point out one very important caveat here not it's not even necessarily a caveat but just something to hammer this home because again having observed and been part of enough of these arguments at this time i already know that there are going to be people who are well maybe not among our listenership so much but if you put this out on the public feed maybe maybe listening who say but i heard about this study or i read this study that showed that people with lower levels of cholesterol had a higher risk of death, right?

18:01This is bandied about all the time. And I'm not intending to be dismissive of that, but rather to help to clarify why that observation is so frequently made and why it does not directly inform our opinion and recommendations here. So when we take patients and do a randomized and prospective study, meaning we take a group of patients at the start and we randomize them, some to lower their blood cholesterol levels, for example, using statins or PCSK9 inhibitors or ezetamib or inclicerine or whatever, you know, benpedoic acid, whichever of the agents you want, and the other group to get placebo or to not have their blood lipids lowered.

18:38And then we follow them forward in time. What do we end up seeing? Reliable, consistent, essentially predictable impact on their heart disease risk over time based on the degree of blood lipid lowering and the amount of time that it is lowered for. What types of studies show us that other finding where people with lower blood cholesterol levels have a higher risk of death? There are a few different study designs that tend to show us this. One is retrospective studies. The other are cross-sectional studies, for example, which are both different forms of observational data where you're not taking people, randomizing them, and following them forward in time.

19:17And some prospective studies, but that are prospective cohorts where you're observing them going forward. You're not taking a group and randomizing them to intervene on their cholesterol levels. Rather, you're taking them from the start and seeing, well, people who have lower versus higher, what happens to them over time. And this is where we have to come back to that same question of it matters how you got there. Because we also know that blood cholesterol levels can be impacted by other things, especially if it's not something that we're intervening on by giving somebody a medicine. But if you have malnutrition, if you have cirrhosis, if you have certain types of chronic inflammatory diseases, if you have advanced cancer, these are all things that can lower your blood levels of cholesterol.

20:00It can incidentally also lower all sorts of other things. It can lower your testosterone. It can lower your thyroid hormone. It can lower your hemoglobin levels. They can lower tons of things, right? And so when we see people, this like U-shaped curve of people who tend to die more when they have low blood cholesterol levels. That is never what we see in prospective randomized trials, where we take people and we randomize them. This group is going to actively lower their blood cholesterol, whether through lifestyle or medicines or anything else, versus not. But in observational data sets, where there is some form of what we call an unmeasured illness phenomenon, where the group that at baseline or at the start is starting out with the lower levels of this, quote unquote, so to speak, those people tend to have more cancer, more illness, more disease, and of course, are going to be at high risk of death from those very things.

20:52If, and this is the final point I'll make here, and then we can move on because it's so important. If, in fact, we saw that those who had the lowest levels of blood cholesterol did have that high risk of death, if that was a robust finding, then what would we see when we actively lower those levels using medicines like statins and PCSK9 inhibitors. People would be dying left and right, way higher rate compared with those who had higher blood lipid levels. What would then our clinical guidelines say? Definitely don't use these drugs. They're contraindicated, as has been the case in many other contexts when we did studies of one drug versus another and the people that got the drug died more.

21:29We stopped using that drug. This has happened many times throughout medical history. And then we would also actively recommend people use strategies to raise their blood cholesterol levels to get up to that sweet spot on the U-shaped curve. We would have to see that that fits in the randomized prospective data. That is not what we see. It's only in these flawed observational studies where there is some other phenomenon that is driving the low level versus the high level, contributing to that risk of death. So that's just a super important phenomenon because it is going to come up for the rest of time.

22:02You're going to go out there, you're going to see these arguments, and you're going to see someone saying, what about this paper? people with low levels died more. Well, they had other reasons to die more. It wasn't because of the cholesterol levels itself. Yeah. Yeah. And this is analogous also to like when you see those, not the same exact studies, like the same papers, but similar observational data where people with a lower BMI on average have a higher all-cause mortality than those with a BMI that's consistent with obesity, that's current definition. And it's like, yeah, if you have cancer, if you have some sort of like severe medical condition that is causing the low BMI in the short, yeah, you're likely to die more than somebody who doesn't have that.

22:41I don't know that we needed a study to tell us that, but apparently we need some nuance in how these studies are communicated so that people don't take that to mean, oh, well, I should just have a BMI of 30, a blood cholesterol, an LDL level of 200, and I'm good to go. It's like, yeah, yeah. Same thing with A1C, hemoglobin A1C measurements for diabetes control, right? You're going to see the lowest, an A1C of like 3%. Yeah, you're probably dying more compared with, you know, and that doesn't mean we recommend people, you know, get their A1Cs up and their weight up and their cholesterol up and their blood pressure up.

23:11I'll tell you, who am I most worried is going to die very soon? The person with the lowest blood pressure in the room, the 60 over 30. I'm about to go do a code blue on them, right? That doesn't mean that we want to actively raise people's blood pressure up to the highest level. Yep, yep, exactly. No, that's a good point. One last little piece of nuance I want to get you to weigh in on this. So a hemorrhagic stroke, so a bleed, there's some signal in meta-analyses of intense LDL lowering trials suggesting a small possible increased risk of hemorrhagic stroke. The evidence for this risk appears most strongly for statins, whereas non-statin therapies like PCSK9 inhibitors have not really shown that clear or consistent safety signal, even though they do achieve ultra-low levels of LDL.

23:58And this is, in my estimation, largely outweighed by the reduction in ischemic stroke, so lack of blood flow to a particular area of the brain. Do you agree with that take? I mean, how do you parse this out? I imagine you don't do much counseling on this specifically, but it's in your brain somewhere. Yeah, I mean, I've been hearing about this for many years. I remember first learning about this going through medical training, and I remain unsure of what to make of it. I will say, you know, this the person who asked this question specifically said without making this about my specific case. But I think that having a specific case in mind is really important when it comes to discussions of how aggressive ought we be when managing these things, because the types of patients in whom I'm even in, you know, entertaining the idea of being this aggressive are people who are at very high risk.

24:45it's not just your run-of-the-mill primary prevention you know because in general i don't necessarily do a ton of the like aggressive optimizing for all comers where it's like if you want to live to be 200 i want to get your lipids to undetectable when you have no family history you're otherwise totally healthy like i think it's generally overly aggressive and overkill for a lot of people unless they specifically for whatever reason are highly motivated to do that but if i have for example somebody who is maybe in their 40s or 30s who already has clinical evidence of atherosclerosis, who has family history of early heart disease, who has elevated lead book protein little a, maybe who has, you know, all sorts of other high risk features.