The Case for Treating Cholesterol Before Plaque Appears | Dr Thomas Dayspring and Dr Dan Soffer

0:03Off the top here, Tom, I think congratulations is in order. I hear you received the Master of National Lipid Association Award or recognition or status. Congratulations. Thank you. I think the NLA was just feeling sorry for an old man. Let's not make this a posthumous award. But I'm so appreciative. I've worked long and hard. To be clear, we also serenaded him with a happy birthday rendition that brought tears to everyone's eyes. The award came down on my 80th birthday. Oh, gosh. Well, happy birthday as well. And I feel grateful to have two MNLA esteemed cardiology experts with me to help us guide through all things primary prevention today.

0:52Dan, you wrote to me recently and you said that the foundation of managing atherosclerosis is the same for everyone because the condition is ubiquitous. So I want to start right there. Remind us what atherosclerosis actually is, when it starts, how prevalent it is. Okay, that's a big topic. The atherosclerosis essentially is ubiquitous. I imagine there are humans that don't have any shred of it, but I don't think we have a really way to know that. We can assume that we all are developing atherosclerosis to some degree, but that the rate that we develop that condition varies tremendously between individuals and based upon a lot of different factors.

1:38We have talked in the past, and I know Tom has given treatise on this as well, about the atherogenesis process, like how atherosclerosis forms. There's a lot of different ways to describe it, but ultimately the present model of how atherosclerosis forms is that there are ApoB containing lipoproteins at a particular range in the circulation. ranging from very low levels to very high levels and everything in between. And that those ApoB containing lipoproteins, most of which are able to penetrate through the interface between the bloodstream and the wall of the artery and get into the wall of the artery.

2:26And then once they're there, they are transformed in a way that makes them trigger a response by the white blood cells that reside in the arterial wall. And when that white blood cell consumes the atherogenic particle, when it consumes the ApoB-containing lipoprotein that's full of cholesterol, that's the initiation of atherosclerosis. And then you repeat that approximately a gazillion times throughout the course of a lifetime, and there are competing processes that slow it down. And so it's not just a straight line, this is the only thing that's happening, but this is the process. And as it repeats, there's an aggregation of these white blood cells.

3:10They're referred to as foam cells after they've consumed an APOB containing lipoprotein. And there's an aggregation and they start acting the way white blood cells do. They start secreting inflammatory cytokines. They start secreting proteases. They actually change the nature of the artery wall. They change the actual structure of the artery wall, and they recruit new white blood cells to the area so that the process propagates. And the atheroma can enlarge. It can enlarge longitudinally, like along the length of the artery, but it can also enlarge centripetally so that it goes outward. And then when it's large enough, it actually will start to indent the area where the blood flows.

3:55So it can actually start to create an effect on the blood flow. So that's atherogenesis. It happens in all of us. The factors that drive it forward are how many of those atherogenic particles are in the circulation and how susceptible your endothelium is to allow those particles to get in. And then there are some changes that occur in the artery wall that are very individual dependent. So two different people on the surface can look like they have exactly the same factors. One person is loaded with plaque, the other person may not have any plaque. And that's the route because there's so many different variables involved.

4:33But ultimately, it's those ApoB-containing lipoproteins that are the substrate that is necessary for atherosclerosis to form. And that susceptibility that results in someone being more or less affected by these ApoB-containing lipoproteins comes down to things like genetics, blood pressure, insulin sensitivity, smoking, all of these other risk factors? Yeah, exactly. The details of that, I think, are something that I can't say that I fully understand, but I can tell you that all those factors you just mentioned affect the endothelial ability to act as a permeable or impervious membrane to the particles in the circulation.

5:15but it goes beyond that. There's also activity in the subendothelium in that it's referred to as a glycoprotein matrix below that top layer where there are changes occurring that can also affect how quickly this process is taking place. Some of these things are really easy to measure. We can measure someone's blood pressure in lots of different ways. We can measure their blood sugar and insulin sensitivity in a lot of different ways. We can measure all different types of lipid and lipid protein parameters that tell us about these things too. And we can ask them about their family history. We can ask them whether they smoke, but there's still many different variables that we are not privy to.

5:56We don't have the technology to interrogate the system to know which aspect is promoting atherosclerosis and which may be protecting us. And we don't even know what all those variables are. We just know where we are now. And so we have measurable and unmeasurable characteristics. How important do you think genetics are? I know it's something that we often kind of list off and we talk about family history. And of course, we've spoken about things like LP little a, which is predominantly driven by genes. But outside of that, how much do we know about someone's overall kind of genetic profile or signature and what role that plays in someone's overall risk of atherosclerosis?

6:41Well, I think it's huge. I don't think it's the only thing. You can have pristine genes and still have an environment that promotes plaque formation and be unlucky in that respect. alternatively you can have normally normal metabolic parameters and have genetic factors that still drives atherosclerosis both extremes are possible there are conditions that are affected by single genes that have big effect mostly that's in the lipid and lipoprotein world that we have the most familiarity with this i think we may have talked about familial hypercholesterolemia before. That's a great example of a classically monogenic disorder.

7:28A single gene is defective and has a big impact on the phenotype. In this case, the LDL cholesterol where the APOB will be very high in people who have monogenic familial hypercholesterolemia. But since there are multiple factors that affect atherosclerosis, you can imagine that if there are multiple genes within each category that could affect each aspect of atherosclerosis, that you have lots of different opportunities for genetic influences in each of these realms. And we see that. With regard to the genetics of atherosclerosis proper that go beyond single gene or multiple genes that affect blood pressure, cholesterol, diabetes, genes that go beyond that there are numerous places throughout the genome that can have an impact on our susceptibility to atherosclerosis and there are very few places i believe it's actually fewer than five places on the genome where a specific variant has a particular impact on atherosclerosis risk and none of them have an impact at the same level as for example the impact of having high blood pressure or the impact of having diabetes or smoking.

8:45One of the ways that that's measured is something called the hazard ratio. You probably know more about that kind of terminology than I do. But hazard ratio is a way of looking at the relative impact of a particular criteria on an outcome. So high blood pressure, smoking, diabetes, each have an independent hazard ratio for the outcome of cardiovascular, a bad outcome, that's on the order of 2 to 4, more than 200 to 400 % increase in cardiovascular risk if you have one of those features. The hazard ratio of the worst single gene variant that is associated with atherosclerosis is less than 1.5, so a less than 50 % increase in cardiovascular risk for any one gene.

9:32but you can inherit multiple genes and they may have small impact. But if you inherit 10 of them or a hundred of them or a thousand of them, you know, it's, we always sort of jokingly refer to that as death by a thousand paper cuts. That's the so-called polygenic risk for atherosclerosis that we now have some tools for measuring. Yeah. That's where my head was kind of going when I was asking that question, the polygenic risk score or profiles that seem to be becoming more and more available. And not only what information are we able to derive from those in terms of risk, but does that actually change management?

10:16If you understand someone's PRS score, is that going to change anything that we're going to discuss today in terms of preventing someone from having an event? It hasn't happened in my clinic yet. It doesn't mean it won't. We do a lot of PRS testing, partly through research, also for clinical reasons. I haven't had a scenario where I got a risk score back and I said, okay, I'm going to treat you differently. But to me, I think the sweet spot for using a PRS would be in an individual for whom imaging is not going to work well for them. Because as I think I tried to stress with our first conversation a year or two ago, how much we put stock in the concept of imaging when we're trying to assess risk for atherosclerosis.

11:08So when an individual for whom imaging is not going to really guide us very well because they're so young, for example, like someone in their 20s, and who doesn't have traditional risk factors that otherwise clearly suggest that they have significant atherosclerosis risk. I imagine there would be some people in that category for whom polygenic risk scoring might influence my decision-making about whether to start them on medicine in their 20s. And I know you've heard me say before that I don't need much justification to offer somebody medical therapy, medication to lower their LDL that I think intrinsically it has benefit for everyone.

11:53And, you know, there are some people I'll avoid giving it to, but in general, anyone who asks me for medicine to lower their LDL, my answer is usually sure. And we'll get into some of the rationale for that, no doubt, as we progress through this conversation. I think you mentioned at the top there that this atherosclerosis is a disease that that most of us will experience. And so what I'm hearing is that if we live long enough, most of us will have some of that plaque build up in the artery. You described the process, but we don't necessarily need to die from it. Is that how you think about this disease, Tom, as well?

12:26Well, yeah. I think if we did 100 % autopsies on everybody when we're croaking, you'd find atherosclerosis in virtually everybody, I think, for sure. But in many of those, It didn't cause any morbidity whatsoever. And that's sort of the trick. How do we know who's going to be buried 80 years down the road with atherosclerosis? And you didn't have to do anything to it. But who at age in their 20s, boy, really probably needs to moderate some of their risk factors and risk markers or something. It's a ubiquitous disease, but we do have a lot of tremendous tools that can help us better ascertain the risk of what we're really trying to do is prevent what we call MACE, major adverse cardiovascular events, heart attack, strokes, bypass, stents, blah, blah, blah, angina.

13:17Otherwise, if it was not going to do anything to you, then who would even worry about the disease? But way too many people, unfortunately, with atherosclerosis do suffer those type of complications. So that is why we really have to, to me, be on the more aggressive side of the equation, ascertaining cardiovascular risk, and then figuring out who we believe in each treatment. And then we have to convince the patient with a good discussion as to why we believe this. And the therapy is, of course, going to be lifestyle in many, or lifestyle plus pharmaceutical agents. over the past three months tawny and i have been in japan korea australia and the united states rarely at the same time which is its own scheduling problem coming home to a calendar with both our schedules on it has been the difference between guessing and actually planning time together the skylight calendar syncs your whole household onto one display google apple outlook daily weekly or monthly views and a color for each person if you've got kids and a sports schedule, that alone earns it.

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15:15Tom, today we're going to focus, zoom in on primary prevention as opposed to secondary prevention. Just so we're clear on our operational definitions here, can you remind people what the difference is between primary and secondary prevention? Yeah, it's evolved over time. People, docs who started out in, when I did, I said in the dark cages, there was primary and secondary prevention. A patient coming into the office had not had a heart attack, a bypass, or a stroke. Had they had any of those, then we'd say, oh my God, we got to prevent the next heart attack, bypass, or stroke. That would be classic secondary prevention.

15:55And anything before, oh, I haven't had a heart attack yet, doc. All right, but I do see some risk factors. We're going to treat you now. That would be primary prevention. But I believe we've evolved way beyond that because of the tools we have now. So I like to call it, number one, primordial prevention. We're all born with fear, unless we're unlucky enough to inherit some really bad genetic condition, pristine arteries throughout your body or so. And that would be, hey, try and lead a good lifestyle, eat well, exercise, mom and dad keep after the kid, don't let him get obese. And then, but at a certain point, and, you know, pediatric societies want basically a standard lipid profile at age nine or so.

16:38The new AHA guidelines said really at around age 20, 21, everybody ought to have at least a standard lipid panel, get their blood pressure measured. So say we did that and I do see APOB, LDL cholesterol up a little bit, the blood pressure is up a little bit, sugar is up a little bit. Well, you are destined. Those are the risk factors, the primary risk factors that drive atherogenesis, as Dan just described. So to me, then, that becomes primary prevention. I've identified biomarkers, maybe even historically a terrible family history. That's primary prevention. I'm going to go after you more aggressively than somebody that I can't find any risk factors in.

17:18And then because of imaging, the CAC scores, which are more commonly done today because they're affordable, but a CTA or even a carotid ultrasound, if I discovered I seen plaque there, to me, then that's secondary prevention. And what I now call heart attacks, bypasses, and strokes, if you've had them, that would be tertiary prevention to prevent the next event. So there's a lot of definitions here, but the classic one is you haven't had an event yet. That's primary prevention. And Dan, is that sort of consistent with how you think about this and the way the guidelines treat this? Yeah, I think I use a little bit different verbiage, but the same basic idea.

18:02Secondary prevention refers to people who have had events, including revascularization with stents or bypass, but major events, heart attack, angina, heart failure due to ischemia, strokes, TIAs, peripheral artery amputations, things like that. That's secondary prevention. That's where that term comes from. And primary prevention is everyone else. The problem is that everyone else includes the 25-year-old vegan marathon runner with four living grandparents and three great-grandparents who has no risk factors for heart disease, but it also includes the 65-year-old diabetic, obese, hypertensive smoker whose calcium score is 3 ,000.

18:43So those people both fall into the same basket, as absurd as that may be, and that's why the terminology primary prevention does not really describe any one thing. It just means I've never had an event before. I think the terminology that we have added to the field is subclinical atherosclerosis. So what Tom was referring to, having an elevated calcium score, an abnormality on a coronary CT angiogram, or some other incidental finding of atherosclerosis from some other CAT scan that you've had done of the brain, of the belly, of the legs. Mammogram abnormalities can show us atherosclerosis and carotid vascular testing.

19:25So lots of different ways that you can identify with imaging the presence of atherosclerosis. and once you've identified that then the condition that we're managing is atherosclerosis not heart disease not even atherosclerotic cardiovascular disease per se it's a condition that is if it's ubiquitous i think we better be clear about whether to call it a disease or a condition you know if you have atherosclerosis and you're going to live to be 120 years old and never suffer from it does it count as a disease maybe i don't know i don't really know what how to define disease. But that person, you know, if I knew that they were going to go 120 years without an event, I may not care.

20:08And the problem is the not knowing. And what are the tools that we have at our disposal to know who is likely to have an event and suffer consequences? And if we have those tools, then we know to ratchet up our treatments to slow down the process, stabilize the process, maybe even reverse the process and keep them from having their events. The call out to the American Heart Association Life's Essential Eight, the trainees who come to clinic with me, you know, by the end of the first day are usually able to recite it because I say it to almost every one of my patients. The foundation of atherosclerosis management is eight things.

20:46It's eat healthy, exercise regularly, maintain a healthy body weight, don't smoke, optimize sleep and stress management, optimize blood pressure control, optimize blood sugar control and insulin sensitivity, and optimize whatever lipid metric Tom, you and I decide is the best metric at the end of this conversation. And we have some other modalities, by the way, besides those eight things, but they are foundational. And before you start talking about, you know, maybe try a little this or some supplement or whatever else you want to do, These are the foundational things that we focus on in people at risk for atherosclerosis.

21:24So is that how the newest guidelines kind of treat that? Let's just say this bucket of people who are primary prevention in that they haven't had an event and they have a lipid abnormality. They're doing the life's essential aid or the lifestyle things. They have a lipid abnormality. Is there a recommendation then to say, hey, let's image that person and let's find out. Are they someone who hasn't had an event but does have plaque or hasn't had an event and doesn't have plaque and therefore that information helps with your sort of recommendation around lipid lowering therapy? You know, the guidelines operate by, you know, different approaches than sometimes, you know, than many clinicians and also on, you know, when we're having conversations like this.

22:09But I think it's worth reviewing the main criteria in the guidelines that qualify people for the addition of pharmacologic management with LDL lowering therapy, primarily with statins as the foundation. So the guidelines list have categories of risk where they say, if you have these things, it's a class one should do recommendation to add pharmacologic lowering to achieve LDL cholesterol to a lower level and to specific levels and non-HDL cholesterol as well as APOB in certain circumstances. And there's five groups. One is everyone with secondary prevention, and arguably there's a subgroup of very high versus high risk.

22:56Then the other four groups are adults who have severe hypercholesterolemia, typically familial hypercholesterolemia, but not exclusively. Adults with diabetes, adults with HIV, adults with chronic kidney disease stages three or four, and everyone else who might qualify based upon risk analysis. And that's a big group. And it's complicated to figure out who those people are. If you think about cardiovascular disease mortality and morbidity in general in the United States, what's that look like over the last, let's say, 50 years? What progress has been made? And if you look at the residual disease burden that's left over today, is most of that from under-treating people who have had an event, so secondary prevention, or is most of that from this group of people that we're talking about who have not had an event and we're not assessing their risk early enough and intervening early enough?

24:00I'd love to go through the statistics and the data with you. But before I do that, can I ask Tom to tell us what a typical weekend on call was like for him at age 35? How many people he admitted to the ICU with a myocardial infarction? Yeah, and this is where I don't think the youngsters like the medical student who's listening to us today is ever going to see in his career again. I sure hope not. But remember, I graduated med school 72, finished my residency 75, and then went into to private practice. And just like now, atherosclerosis is the leading line one on most people's death certificate, but it was happening in a lot more younger people and a lot more suddenly than it does today.

24:43For good reason. We had zero treatments of atherosclerosis other than blood pressure was in its primitive years on lowering blood pressure, but lipids were not understood. We weren't measuring anything other than total cholesterol. And the levels that we were told were fearsome were astronomical using today's criteria. But nonetheless, there was nothing we could do for them. So what that meant is, boy, if you were a young house officer then or even in early private practice, you got a lot of experience signing death certificates. When I was a resident and, you know, you're working in my days every other night, you were on call.

25:22And if you were covering the CCU that night, you would at least have three or four acute coronary syndrome admissions. A couple of them were in flagrant pulmonary edema, which I'm not so sure people even see anymore, where they're foaming at the mouth because they're in gross heart failure because so much of their myocardium was destroyed by an ischemic event. And we had ways of getting him out of that, but CPR, and you were always doing a couple of CPRs on a given night. So that was terrible. Now, when you went into private practice, I joke, you know, it was kind I shouldn't say this, but it was kind of fun.

25:59It was a great experience when you're a young resident, getting all that experience, seeing people, trying to bring them back from the dead. It wasn't fun to go out and tell the family that, sorry, the Mr. or Mrs. has passed away. But once you go into private practice, and I've probably joked about this before on other podcasts, you're not living in the hospital anymore. It's not just a rundown for the CCU in two minutes or the ER and see these people. You're at home. You get a call. Hey, Dr. Dayspring, your patient XYZ is in the emergency room now and he's had a heart attack. You'd have to get in your car, drive to the hospital, and spend all night at the bedside with that patient.

26:36It wasn't just a 10-minute visit, take a history and go home because you just had to wait for the next arrhythmia to occur or they're going to go into heart failure. So I always joke that's the real reason I got into lipids about 10 years later because I wanted to sleep more at night. But yeah, what Dan said is right. That is why I am so super aggressive. People call me too aggressive when I see risk factors because it was no fun signing death certificates to people who shouldn't be dying. These weren't 80-year-old cancer patients or 90-year-olds who it's time to say goodbye to you. These were young people in the prime of life.

27:13And nothing worse than a young 30-, 40-year-old man and you got to go out and meet the young widow or so. God forbid the kids were in the emergency room or the hospital with them. So I fear this disease I always have and that's never going to change. That incidence is no longer there. But that doesn't mean it's any less of a serious disease when people do show up with acute coronary syndromes. It's just that our therapeutic armamentarium is so much better nowadays. They really pull out so many people back from the dead that we had no prayer of doing back then. By the time I finished residency, Tom was just recovering from his well-deserved post-traumatic stress disorder from having taken care of those patients.

27:54It truly is vicarious trauma and an experience when you see people in front of you dying from things that could have been prevented. But by the time I finished residency, my senior colleagues who were training me were telling me the same war stories, but I never really experienced that kind of thing. I never had a weekend on call covering for my medical group where we had three or four myocardial infarctions. In fact, I could go six months while on call covering a weekend call before a third myocardial infarction occurred. So a huge change in that generation and a half from the 1970s even to the early 2000s.

28:36Now, there was sort of an uptick in cardiovascular mortality at around 2010 that a lot of people think is attributed to the diabetes pandemic and that that was sort of pushing back against all the technological advancements that were made. But the mortality improvements overall may not have done as well as we'd like them to do, but they have improved tremendously. And when you look at age-adjusted mortality, that's actually something I like to talk to my patients about because my understanding when I look at this literature is that I feel more confident telling my patients that when they're receiving care, they really should not be dying from this condition.

29:18the age-adjusted mortality improvement from 1970 to the present has fallen by as much as 80 plus percent and that is like fall off your chair did you just say 80 plus percent the answer is yes i mean it is that's that's sort of like the ability to treat strep throat you know i mean the difference between having penicillin and not having penicillin and it's incredible what our emergency medical technicians can do and our ER doctors and our CCU staff and then all of the medical therapies we have in terms of changing mortality that's related to atherosclerosis. Our patients still die. They still die from heart disease.

29:58And some of the non-atherosclerosis heart disease might actually be downstream from atherosclerosis. Some of the heart failure might actually be secondary heart failure from atherosclerosis or their strokes were related to atrial fibrillation, but the reason they were having atrial fibrillation in the first place was because of atherosclerotic and heart muscle changes from prior atherosclerosis. So sometimes it's a little hard to collect that data and get the true outcome, but there's no doubt that we have gotten much, much better at keeping our patients from dying from atherosclerosis. Is the kind of opportunity, so to speak, in terms of reducing any residual risk, is that intervening earlier?

30:41Is that why the latest 2026 guidelines, I presume, have kind of introduced much earlier and I'd say aggressive screening, particularly people that had first or second degree relatives with premature cardiovascular disease. I think they were recommending screening as early as two years old. That would be for people with familial hypercholesterolemia, even the homozygous at age two. I think age nine is where the PED society in general thinks. Even at age nine, even if you have heterozygous FH, that's still young enough where you can help that person for the rest of their life. And the current guidelines as previous, around age 20, 21, that's when people should get their first lipid panel if they've not had it.

31:25The timing of when to test, there's some nuance to understanding it. The recommendation for universal screening for lipid testing in pediatric population is primarily to identify a common inherited condition, familial hypercholesterolemia. It occurs roughly 1 in 300 in the general population as a monogenic disorder, a single gene causing high levels of LDL cholesterol. And you can wait until they're adults and hope that they don't have a lot of disease and hope that they don't die before you check them, or you can check it at a young age and identify who has this condition and make a difference in their outcome by treating them early.

32:07And so we screen the entire population, or we try to, between ages 9 and 11. That's a recommendation since 2011 by the American Academy of Pediatrics and American Heart Association that was reiterated in the 2026 dyslipidemia guideline. The time to screen as early as two years old is if you know that one of the parents has familial hypercholesterolemia. We rarely do that, even when we know that the parent has familial hypercholesterolemia, because it's hard to check blood on a two-year-old. It's challenging. But I just recommended it this week on a patient of mine who actually does not have monogenic familial hypercholesterolemia, but has severe hypercholesterolemia, presumably from polygenic cause, and so does her husband.

32:51And they have a they have a five-month-old. And I told them, I said, I don't know how your genetics are going to come together for your child, but please check your five-month-old, six-month-old, two-year-old. I don't want to wait on testing this child. And I may test them multiple times in their childhood because if they have the severest of the severe lipid disorder, something called homozygous familial hypercholesterolemia, in its most severe form, that disease can cause heart attacks and death before age 15. So that's a rare condition, not an uncommon condition, but a rare condition that you would rarely be screening for.

33:34But there are times where we're going to screen kids as young as two years old to identify that. And that is treatable nowadays at that very young ages if you've diagnosed it. Treat them as soon as you identify it, yeah. And for everyone else, so if you're a teenager or a young adult, just to underscore this idea of screening, was it doing lipid testing every five years from the age of around 19 or 20, Dan? Yeah. So you check them at 9 to 11. If they don't have an inherited lipid disorder, check them again when you're 17 to 21, somewhere in that ballpark. And if they still look good, check in every five years or so and make sure everything is good.

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36:29Check your health the way that I do. Function provides more than 160 lab tests for$1 a day and member pricing on advanced imaging. Join at functionhealth.com forward slash Simon Hill and use the code Simon25 for a$25 credit. Tom, before we get into how we actually assess someone's risk. Dan mentioned there's a risk analysis that is sort of done in the clinic when an individual comes to see him. How confident should we be that this relationship between ApoB or LDL cholesterol and atherosclerosis is causal? That ApoB is actually causing, driving atherosclerosis. It's not just an association that we've kind of grown attached to.

37:17I know we've been through this, but for someone that is maybe confused by this, has heard that some of the healthiest long-lived people have higher LDL cholesterol, what's the evidence that gets you there to say that lower is better for longer, ApoB is causing driving atherosclerosis? Yes. Well, because we've way beyond 1970 when I started, we have a multitude of clinical trials that provide the evidence showing us what are the etiologic agents of atherosclerosis. And we have a ton of observational trials, suggestive data. We have a bunch of randomized controlled data, which is level one evidence.

38:04And now we have the genetic data, the Mendelian randomization trials. And if you put that all together and the major medical societies have done that, the first was the European Atherosclerosis Society back in – they did papers, I believe it was 2017 and part two, 2020, where they declared LDL cholesterol. And, of course, APO-B is causal of disease based on those type of trials. And they have a wonderful graphic. Brian Ferentz was the lead author on that, where they, a little dot of every one of those clinical trials, what was the baseline LDL-C and what was the on-treatment LDL-C and all of the curves are going down.

38:46And even when you took an LDL-C from 70 down to 15, there was still further event reduction. So it's the multitude of those trials that provide the causality rationale behind this. This is not back in my day where, hey, one trial suggested cholesterol, we didn't even know what ApoB was, is going to be an influence. The data is overwhelming. And Dan, you alluded to this earlier, but what do you say to the person who pushes back and says, my parent or my friend is 60 or 70 and has had high LDL cholesterol their entire life had a CT angiogram and they had no plaque at all. If this causes atherosclerosis, they should have plaque.

39:30Everyone should. I'm never really comfortable with the term that, you know, describing LDL or ApoB containing lipoproteins as the cause of atherosclerosis. They are the necessary substrate for atherosclerosis. Absolutely. No ApoB, no LDL, there's no athero but that's not the same as the cause like a lot of things have to happen for athero to occur and that paper that tom that actually that series of papers that tom was referring to by the way is landmark brilliant work on this and and i love everything about it except using the term cause but i think it's more like a slogan than an actual description i don't think tom or Brian Ferentz or anyone at the EAS thinks of it differently than I do.

40:19I just think the verbiage is a little different. And so when someone comes in and says, you know, how can you have this thing that causes the disease and not have that thing? I'll remind them that it's a complicated physiology that's taking place. And as we started off this conversation explaining that there's a lot of moving parts. And you can definitely live to be 120 years old with an LDL cholesterol of 300 milligrams per deciliter and never having treated it and never have a cardiovascular event. But it's such a powerful indicator of risk when it's at the extremes, when it's super high, and also when it's super low.

41:01But most of us don't live at the high or the low, we're in between. We're in between the severe and the low. And as an indicator of risk, there are multiple other things that actually indicate risk together with the LDL cholesterol or the ApoB that give us a broader picture of someone's risk. So that's risk assessment, trying to ascertain who has the disease and using that information to make a decision about the disease. The other piece of this is, all right, I've established that you have the disease or atherosclerosis. What do you do with LDL or ApoB then? In everybody who has significant atherosclerosis, everyone targets LDL, cholesterol, and ApoB.

41:48So because it's instrumental in developing plaque, you have to drive that number to lower levels to reduce their risk. So 100 % of people who have atherosclerosis, it's a target of therapy. But as a tool to assess who has disease and who's at risk, its greatest value is at the extremes, at the highest and the lowest. Let me refine what Dan just says. It's a multifactorial disease, atherosclerosis, but the initial event is the invasion of an ApoB particle carrying cholesterol into the artery wall. That is why it is causal. That doesn't mean if an ApoB particle goes into the artery wall and dumps cholesterol that everybody's going to have a heart attack down the road.

42:27That would depend on a whole bunch of other factors going on. But it is causal. No ApoB, no cholesterol in the artery wall, no atherosclerosis. But yet in some people, it could be elevated, but with a certain local environment or genetic makeup or whatever, despite having elevated numbers of those ApoB containing lipoproteins, they're not getting plaque buildup. But in that case, they went into the artery wall and they were released right back to the plasma, but the initial event, anybody who has atherosclerosis had to have an ApoB particle, as Dan said earlier, a gazillion of them over time, crashing the artery wall, depositing cholesterol.

43:10It's the only sine qua non for atherosclerosis. No cholesterol in the artery wall, no atherosclerosis. I don't care if you have 42 other risk factors, your smoke, hypertension, diabetes, no cholesterol in the artery wall, no atherosclerosis. So again, this is semantics, But it is causal when you look at it in that vein. Not that everybody's going to, with high ApoB or LDL cholesterol in the plasma, is going to have atherosclerotic disease. Let me add that something that Tom has expounded upon on social media is this concept of normal cholesterol or normal LDL cholesterol or normal ApoB. So when you choose the term norm or normal, we're referring to population ranges within two standard deviations of the mean.

43:55Within that range, there's a huge range of what your LDL cholesterol or ApoB may be. And even at the lower end of that, that looks like low LDL cholesterol or low ApoB, that's still a lot of ApoB in the circulation. That's just, but in the population that you're at the lower end for the population. Remember, the condition is ubiquitous. We all get this. So even people who are born with low levels are prone to atherosclerosis. until you get to a certain point that's super low levels. Now you're outside the two standard deviations of the mean and you have an inherited genetic variant that affects how your body puts together or deals with these particles.

44:40And you actually have very low levels of ApoB containing lipoproteins. Those people, as far as we can tell, don't seem to be developing atherosclerosis, But I can't say we have any autopsy studies to see if they have any athero. Can you contextualize that for us? What are those numbers where we are typically seeing regression or no plaque development versus the quote-unquote normal kind of numbers that people may see on their lab reports where a lot of people are laying down plaque? Well, a physiologic cholesterol or hypobeta-lipototinemia was a condition DM was referring to, a very low ApoB, is really defined as under 50, maybe 40 milligrams per deciliter.

45:25And look, that's what we have when we're born, for the most part, other than you're not one of these kids who had FH patients or parents. So that would be a physiologic level. And of course, they don't get atherosclerosis until their levels go much higher in decades down the road. So I like to call it physiologic hypodeta. Look, everything is caused by genes. So if you're going you have an LDL cholesterol at 20 or 30 and it persists, you have some genes that are causing machinations that prevent higher levels or so. Just on that term physiologic, because I've had some pushback on that, Tom, online when I've shared that from some people that have said, is that really physiological cholesterol levels, say below 50 milligrams per deciliter, if very few people in adulthood can get there without medication.

46:16We don't know if they couldn't because the lifestyles they lead are what's jumping it up in so many people or so. But yes, the proof is you don't need an LDL cholesterol of 120 to make your adrenal glands, your gonads work or anything else, your brain to work. Children at very young ages, when their brain is forming like crazy and their adrenal glands are working. They're not producing gonadal hormones, but they're fine with such very low ApoB or LDL cholesterol levels. And so are the people who Dan described as having hypobeta lipoproteinemia, which is a lifelong, very low ApoB and LDL cholesterol level.

46:57They don't suffer from cholesterol deficiency diseases. Prior to 1900, prior to the industrial revolution, You know, atherosclerotic cardiovascular disease still existed, but it was a rare condition to manifest. And it was really the advent of the industrialization that led to this being a topic of interest for so many of us. And actually, it was, you know, a major public political event that really brought it to attention. We went from being a people where atherosclerotic cardiovascular disease was largely unheard of to, hey, are we in the middle of a pandemic here? Because, you know, we just lost, you know, we just lost one president, you know, when FDR had a major stroke.

47:44And then we lost Dwight Eisenhower to another heart attack, you know, event 10 years later. So by the time we got to the mid-century, people sort of looked up and said, what the heck is going on here? there is something different going on with atherosclerosis. And that's when this whole field began. So when we start talking about like, what's physiologic and what do wild, you know, unindustrialized humans have, it's interesting. I think it's fun to talk about, but it's largely a moot point. Like we live in the world we live in. There's clearly something different going on since 1900. And, you know, if you can somehow live a life that you might have lived in the 1800s, yeah, you're probably not going to die from atherosclerotic cardiovascular disease.

48:32You might die from malaria or measles or, you know, abscessed tooth, you know, something like that. But this is the world we live in. And we have some, we do have some hunter-gatherer data that would suggest levels like what you're talking about is physiologic. I don't know those numbers off the top of my head, but my understanding when talking to, I want to say the name, I think it was Greg Thomas from UC Irvine who was part of that. First, he was part of the Horace group that looked at Egyptian mummies and the presence of atherosclerosis in CAT scanned Egyptian mummies, but he also was part of a group that looked at the Chimani people in the Bolivian rainforest and did all kinds of cardiometabolic testing and even some imaging, they didn't have atherosclerosis and they didn't have super low LDL cholesterols either.

49:19They didn't have levels like 20 to 50. They were, I think, more like 50 to 100, somewhere in that ballpark in terms of LDL cholesterol. And by the way, they were not healthy, right? They were sick as can be, infected with all kinds of parasites and everything. And they had inflammatory markers out the wazoo, but they didn't get atherosclerosis. They were interesting to look at those kinds of people. I think they're We can learn some things, but that's not who we take care of on a day-to-day basis. But they didn't have the lifestyle of the modern person today. They were active, running around all the time, not living long enough to have these other chronic diseases.

49:56But I think that might be the point that some are making online who, let's say they take a position that, you know, Tom, your position is too aggressive. recommending that too many people go on lipid-lowering therapy to get below 50 milligrams per deciliter. And really, if people just adopted a healthy lifestyle and weren't eating the ultra processed foods and managed their body weight and did exercise and weren't smoking and drinking alcohol, all these sorts of things, that the aggressive approach to lipid-lowering therapy wouldn't be needed. Is that a fair position for someone to take? Yeah, but I don't need to believe If everybody has seven APOB under 50, I would do an evaluation when they came in.

50:38And if they're young and I don't find a bunch of other risk factors, no LP middle A, a terrible family history, I don't know that I'm going to put them on anything to make their APOB 50. I'd be happy with a 70 or 80 in such a person. So everything is applied to the individual patient. You can see, hey, Tom said you got to get your APOB 30 on his latest tweet. but they don't know who I was referring to or who I might think needs them. Most of these are, comes out of Ferrier or Odyssey where acute coronary syndrome patients where, yeah, that's who I really want to blow away their APOB. You know, there were two concepts addressed in the guideline.

51:16One is in general, lower for longer is better. Just in general, just as a generality. And two, the intensity of LDL lowering treatment should match the severity of the disease, process that you're treating. Someone with loads of disease, throw the kitchen sink at them. Someone who, at the other end of the spectrum, you're talking about primordial prevention, a little bit of management can go a very long way. Tom referred to some of the evidence tangentially as, you know, from the Mendelian randomization data that supports that kind of long-term approach. That's not interventional data, that's observational data, but it's very powerful information that I think we can take to how we manage care for patients over decades.

52:03We have a new tool that's emerging and it's called LDL-C years. You can even extrapolate APO-B years. So you come in, you tell me your age, I see what your LDL cholesterol is, I multiply one by the other and I get a product there. And it looks like that multiplication goes to around 5 ,000, and I'm talking milligrams per deciliter, not molar concentrations. then you are at that. That's a plaque burden that you're at definitely a risk for something happening or so. If that product comes under 5 ,000, maybe you can have a less aggressive treatment to proceed down the road or so. So that's a very interesting tool that can be used, I think.

52:44And just think about the kids who have an LDL cholesterol of 230, but they're only 12 years old. You do that. Oh my God. At that age, they've already hit the 5 ,000 mark. So they need, So that's an interesting new concept that can be worked into evaluation of patients. I have an avatar that I want to put to you guys, kind of hypothetical case study, which is a presentation I'd say that I would receive a few messages a week at least from this type of person. And Dan, on email, you told me you see this person quite regularly in clinic. Before we get there, because you've mentioned the new guidelines a couple of times.

53:24So I understand that you were on the committee for the 2026 dyslipidemia guideline at a high level. How does this new set of guidelines differ from older ones in terms of the primary prevention, this conversation we're having specifically related to kind of acting earlier? What's different about these guidelines? Well, several things. I have to say about this set of guidelines, and I can't take any credit for this aspect, but it's the set of guidelines that most closely aligned with the way I manage care already. And in years past, I would read the guidelines, appreciate what they were saying, totally get why they were written the way they were written, and still go back to clinic and say, I think I need to do better than what they're recommending.

54:07It's a good minimum standard. This is the first time where I feel like if I follow the guidelines here, for the most part, with some exceptions, I'm really going to be taking very good care of my patients. So to me, that's a big thing. And kudos to Roger Blumenthal and Pam Morris for directing us through this incredible process. It's daunting, I have to tell you, being part of that guideline. The piece of the guidelines, though, that really addresses this primordial approach, for one thing, we have a risk calculator. Remember I said there are five groups for whom we should be talking about the introduction of pharmacotherapy?

54:45The last group is after you calculate someone's risk and you think it's high enough to justify using medicine. So that last group, the risk calculator that's recommended now is called the Prevent ASCVD risk calculator. And one of the things that's different about this besides using a database that's much larger than any database that we've ever used before, which we think will improve its discriminatory variability is that it expands the range that we can actually assess risk. So instead of ages 40 to 75, now we think we can use this risk calculators going down to about age 30 to 79. So it's lower at both ends, but incorporating that in the adults in the 30 to 40 range is really the big change.

55:34So now we have a risk calculator that can be applied to that population. Now, almost everybody from 30 to age 40 is going to have a low calculated risk and not qualify for therapy based upon their 10-year risk. But this risk calculator also provides a 30-year risk calculator, which I think is interesting for the 30-year-old to know what happens when you get to be 60 years old. What is the likelihood? And there's some guidance that's based upon 30-year risk that's built into the risk process, risk assessment process. The other thing about this is that besides incorporating all of the major atherosclerotic cardiovascular risk factors, there's some newer introductions that are different from what we've used before.

56:22We have the inclusion of a kidney function assay that's part of it. And maybe the most novel part of it is they included zip code. Now, zip code is not a be-all end-all for socioeconomic deprivation, but it turns out to be a very useful tool to incorporate the impact of social and economic challenges. And when you add that to the risk calculator, it's thought to improve our ability to discriminate who's developing atherosclerosis because that's one of those risk factors. And one of the things that we know if you can address that can have an impact. That's why life's essential aid includes, you know, stress management on the list.

57:03Now that's probably the hardest thing to do. It's very easy to lower someone's LDL. It's very difficult to ease their social and economic stress. Like that's, that's the virtually impossible thing to change, but we now have that. And then we also have this concept of risk enhancing factors. So you may think that somebody, you know, you may calculate their risk and say, hmm, they look like they're pretty low, but I'm kind of worried about these other things. So there's a whole list of what are called risk enhancing factors that are known to increase cardiovascular risk and in some people can be a major contributor even if there's no measurable atherosclerotic cardiovascular risk factor.

57:46So genetic factors, like for example, if you have a strong family history of early heart disease, if someone says my mother had a heart attack at 35 years old and she was a two-pack-a-day smoker and used cocaine and I don't do any of those things, I'm not that worried about the cardiovascular risk of my young patient. But if that same person says my 35-year-old mother had a heart attack and didn't do those things and has no other risk factors to explain her heart attack, I have to think that there's a very important potential genetic implication there. And so it's not enough to just say family history of early heart disease.

58:25It's family history of early heart disease with an explanation, but there are other family characteristics. We mentioned the polygenic risk scoring. That's something that might influence your decision-making. There are some other medical and metabolic phenomena like reproductive abnormalities. If you have polyendocrine, polymetabolic ovarian syndrome, you know, I do some research on this and I'm still having trouble remembering in the name of the... Polyendocrine metabolic ovarian syndrome, premature menopause, early menopause, history of preeclampsia or history of gestational diabetes. Those kinds of things can be a marker of enhanced risk.

59:03Chronic autoimmune inflammatory diseases, especially things like systemic vasculitis, scleroderma, psoriasis, lupus. These are major proponents. These are things that drive atherosclerosis and increase risk. There are some ethnicities that, for reasons that I think are very complicated, and it's not just genetic, and it's not just environmental, but probably a combination, but certain ethnicities are particularly prone to developing accelerated atherosclerosis. And then there's some very easy measured things that are not part of the risk calculation. High triglycerides, high levels of HSCRP, high levels of ApoB, high levels of, did I say LPA?

59:45High levels of LPA. Those are things that are not part of the risk calculator necessarily, but are clearly affecting atherosclerotic risk. And they're told in the guideline, hey, incorporate that into your decision-making. So those risk enhances are important because they might prompt considering treatment in someone who has a low 10-year risk who's 30 but has a heightened low low 30-year risk or even a low 30-year risk right yeah

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1:01:45We all have the draw. Half a bottle of magnesium that never did anything, a probiotic from two summers ago, a greens powder used twice. And the question I get more than any other, are any of these supplements doing anything? Often no, and it's not just the ingredients. The dose is too low, the form is the cheap one, or worse yet, what's inside the container doesn't match the label. I sit on Iron Maid's scientific advisory board, so I've seen firsthand how Daily Essentials is built. 19 ingredients in one sachet in the right dose and form. NSF certified for sport, every batch screened by an outside lab against more than 200 banned substances.

1:02:27Not just the first batch, every single batch. So you know what's on the label is actually in each serve and nothing else. Importantly, it tastes great. I'd bet that the powders that are going hard in your drawer are the ones that taste a little bit like pond water. One drink that you take consistently every day beats 16 you keep meaning to. Give it a month and judge for yourself. 90-day money-back guarantee on the quarterly plan. Go to im8health.com and use the code Simon at checkout for 10 % off your first order plus a free welcome kit. That's code Simon at im8health.com. Okay, so let me throw this kind of hypothetical avatar or case study to you.

1:03:12And I think it's quite similar to one, Dan, that you shared off-air when we were chatting earlier. So a young male, let's say early 30s, does have that strong family history of cardiovascular disease. now let's let's let's assume that that strong history is in first or second degree relatives that didn't have those risky kind of behaviors that you just spoke to so they were doing generally well this this person doesn't have symptoms they haven't had an event they haven't they haven't had imaging so you don't know whether they have any plaque or not and let's just say normal lp little a and metabolic health they're a non-smoker etc and and this person comes to you and says look i do have a strong family history of cardiovascular disease i think a lot of people have that family history of cardiovascular disease i'm sure that's quite common with the people you see and his his apobe is elevated between like 90 and 120 he's heard tom speak about apobe and he's sitting there as a 30-year-old wondering what he should do.

1:04:23How would you kind of go about assessing his risk and what recommendations might you have for someone like that? Maybe I see that five times a day. So we see patients like that are very common. You know, when there's no measured and demonstrable risk and their calculated risk appears low, but they're going out of their way to come to a lipid specialist and go to preventive cardiology and ask me, is there anything I should do to reduce my risk over the course of the next 50 years? I sort of go into my routine. I'm like, sure, yes, it's life's essential eight. And of the things that are on that number eight list, really only one of them is a pharmacologic agent.

1:05:10Everything else is, you know, we have thresholds of when to treat the blood pressure, thresholds of when to treat blood sugar. By the way, we don't have any thresholds for when to treat insulin resistance. So that's a whole other thing. But we do have thresholds of when to treat the atherogenic lipoproteins. And I already told you what my threshold was for that, which is someone walks past me and says, hey, I think I want to start a drug for reducing cardiovascular risk? My answer is, of course. So that person you just described in their mid-30s who has two relatives who were young, who developed heart disease, especially first-degree or second-degree relatives, I'm very comfortable telling them, no matter what your tests show, I think there may be value in you walking around the rest of your life with a much lower level of LDL cholesterol and ApoB.

1:06:01And here's how you can do it. And these are the safe, effective, well-tolerated, inexpensive, easy to use therapies to achieve that. If along the way, you don't feel good with the thing that I'm giving you, let's try something different. And we'll keep making modifications until I make sure that you feel normal while you're on your therapy. And we have a sort of a routine. We go through, we're going to do this one first, then this one second, this one third. And I'll work with them as long as, until they say, hey, I don't want to do this anymore. But I think they would benefit from having fewer LDL particles in their bloodstream, less APOB, and regardless of what their LPA level is in this case here.

1:06:44Yeah, look, in your avatar with that strong family history in APOB at 90, I thought you said, he's going on lipid-lowering therapy in my clinic. And by the way, I do have a low threshold for the mid-30s for using imaging too. Even though imaging is complicated and I'm not an imager, but that 30-year-old who says, oh, my mom died from a heart attack at 35, boy, do I really want to know how much plaque they have in their arteries. And so evaluating that person with imaging whenever I can, I have a low threshold for ordering that kind of exam. And I'm assuming at that age, you're thinking a CT angiogram or a CIMT?

1:07:27Yeah, my partner orders a lot of CIMT. I order less. I order a lot more coronary CT angiogram whenever possible. Is the biggest barrier to the CT angiogram the cost? And I guess there is a little bit of radiation, but it seems to be coming down a lot with the newer machines. Is it mostly a cost barrier? At my medical center, they go through these machines so rapidly. They're always getting the next greatest and fanciest machine. Each generation has less and less radiation. are. It's well below what the American College of Radiology recommends to even have a conversation about how much radiation exposure there is.

1:08:01Why do you like the CT angiogram more than the CIMT? Well, they're both complicated reports. So I always like things simple. There's two aspects to a CIMT. One is the quick look is their plaque. And that turns out to be actually the most important aspect of the CIMT. They do a quick look, they do a scan along the length of the carotid artery. By the way, some institutions also do femoral, but our institution, we just do carotid. But, you know, is there plaque present? And off the top of my head, I want to say, I believe the typical threshold for intimal medial thickness for the presence of plaque is referred to is at the 1.5 millimeter thickness.

1:08:46Anything 1.5 millimeter or greater is considered plaque. and then the other aspect is where they actually do dedicated measurements at pre-specified parts of the carotid artery there's four different parts they do direct measurements you can have plaque in one part of your carotid artery that did not get included in those measurements so their carotid imt can look completely normal but they have plaque elsewhere and so our at our institution, when we order it, they'll tell us those two things. And, you know, it's confusing for the patients to say, wait, one part of this says I have normal IMT and the other one says I have plaque.

1:09:24Which is it? And the answer is both. So it can be a complicated result. Also, the reason CIMT has fallen out of favor around the world for clinical reasons and also for research reasons is for two different reasons. One is I think the reproducibility is poor. So if you go get carotid IMT five days in a row at five different sites, I think you can get a pretty wide variety of results. And it's so that's disconcerting. And I don't, I just don't think it's reproducible enough in the clinic. And it's fallen out of favor for research reasons because we have clinical trials with proven therapies that are beneficial where there was no benefit or there were no changes that were considered favorable seen on CIMT.

1:10:08And in some cases, there were some that we're favorable where we think the therapy is not beneficial. So it doesn't match the clinical outcomes that we really want to follow. So CIMT has mostly fallen out of favor for the most part. I think this is not a plug at all, but from what I've seen, I think there are some companies that are trying to improve the reliability, whether you have the same clinician doing it, because it's very clinician dependent, like who's doing the ultrasound, how are they trained, are they doing it the same way each time so with this avatar if we continue on let's say that when he comes to see for the first time he actually has had some imaging and so his the apob same level 90 to 120 that same history but this time he's had a ct angiogram and at mid 30s he has no no signs of subclinical atherosclerosis how does that change your your recommendations decision-making, if at all.

1:11:06This guy's 35. Let's say mid-30s. Listen, that's an abnormal ApoB with that family history. Even if I don't see plaque, that's great news. But I would do more of a workup looking for some of these other extenuating risk factors too, of course, not just ApoB. And my inclination would be still to treat him. I mean, I'm not throwing a PCSK9 inhibitor at him, but the low-dose statin, azetimi, I would probably be measuring biomarkers of synthesis absorption and see where I can go. Incredibly safe drugs that have almost no downside. And if I can make that APOB go from 90 to 70 with basically free and with no side effects, why not?

1:11:47I don't want to come off as being just like a guideline, you know, pounding my chest about the guideline. But there are some things about the guidelines that I think are really beneficial. One of which is just the framework that they use for recommendations. You know, they call these things, class of recommendations, you've heard that terminology before, class one, class 2A, class 2B. Each of these classes of recommendations is based upon an expert panel that weighs the data and then makes their recommendation based upon the evidence that's available. And there's verbiage associated with each class of recommendation.

1:12:25So something that's a class one recommendation, The verbiage that you should be using with a patient who has a class one recommendation for something is, hey, patient, you should do this thing. A class 2A recommendation, you should say, it is reasonable to do this thing. A class 2B recommendation is, it may be reasonable to do this thing. And a class 3 recommendation is, you should not do this thing, or maybe it's harmful, please don't do this thing. so that's what those classes mean and so this patient you just described is not going to have a heart attack stroke or death in the next five years and they're not going to hopefully fall off the face of the planet they're going to follow up and you can manage their care and if they say no thank you dr dayspring i don't want that statin and i don't want that ezetimide because of something i heard on the internet i'm totally fine with that and i will say to them you're okay you do not have a class one arm twisting recommendation here.

1:13:27I'm happy to prescribe medicine for you. Please come back. Let's come back every year. Let's reevaluate you. And then we'll figure out some way to take a look at your arteries again in three to seven years. And we'll track it over time. If we start to see some change, I'm going to lean heavier on you to take that medicine. At that point, there's already some visible plaque, but it doesn't mean it's irretrievable doesn't mean we can't stop it from progressing at that point. It also doesn't mean we can't induce plaque regression at that point. Does the verbiage change if this person, it's the exact same presentation, they've had imaging, they don't have plaque today, but on top of that elevated A per B, they have elevated LP little a?

1:14:11That puts them in a little bit of a risk enhancer, if you will, that's what you want to call it, but it does elevate them to a little bit higher risk category or so. And again, especially with the family history there, it would be pretty tough for me not to recommend treatment for that. And the treatment right now is APLB lowering down the road, but I don't even think down the road we're going to have a primary prevention therapy for LP little A that is going to be FDA recognized anyway. I totally agree, Tom. It's that family history is what sticks in the crawl there, right? You hear that and then you're like, huh, you have a high LPA also?

1:14:48What are you waiting for? Why aren't we doing all the things possible? Not all of our patients have the same goals in mind. It seems crazy to think that why wouldn't everybody want to have the best health outcome possible? But not everybody thinks about this stuff night and day the way Tom and I do. Sometimes they just want to live their lives and not have to take these things. And if that patient was completely open to drug recommendations, what would the APOB target be? Would it be getting that person from 110 down to 50? Are you happy with them at 70? Is it going to be a monotherapy discussion?

1:15:26How do you kind of begin to have that sort of recommendation with them? Well, if you start with the statinazetamide, I think we started off with a 90 here. You could pretty much get that down to 60 or probably 50 with it or so, which I'd be fine with. I would go ahead and do imaging if I subsequently did find there was high LP little a. And if the image was positive, then I get even more aggressive with the ApoB lowering there. But if imaging was negative, 60 for me. Again, we don't have trials yet to give us the answer to this. So as a guy who signed too many death certificates, I'm very biased.

1:16:04Blowing away ApoB. You know, the lower for longer concept. I don't think I'm going to overshoot. I think I'm going to tell them about the different pharmacologic options available as adjuncts to heart healthy lifestyle, including dietary change. The national guideline recommends a specific LDL cholesterol, non-HDL cholesterol, and ApoB for people at intermediate risk. They recommend it for people at high risk, and they recommend it for people at very high risk. And you can use those as a estimate that's based upon clinical trial outcomes, but there is no cardiovascular outcome trial that matches the scenario that you just described.

1:16:40So we have to extrapolate evidence from everything we know around us and include our bias. I already diagnosed Tom's post-traumatic stress disorder from having practiced in the 1970s and 80s. And so he's going to be heavily biased towards, boy, I really don't want this nice young person to go through the same thing that I saw over and over and over again 50 years ago. Talk to me about the choice of starting with statins. So this person's a little bit outside of the box. Is the first line therapy recommendation still to always start with a statin? Well, the guidelines would tell you that. As I mentioned before, and we've talked about this on previous podcasts, Simon, I would be evaluating synthesis and absorption and making a decision based on that.

1:17:24Also, if the ApoB was really high and I knew what I wanted it to be, sometimes, hey, let's just go with both initially. It's a very aggressive way to lower ApoB or LDL cholesterol if you're still looking at that. And when do you have a discussion around a PCSK9 inhibitor, Dan? Because it seems like it's more of a statin plus Zedia conversation, at least initially, are the PCSK9 inhibitors, I guess, less prescribed because of cost, evidence? I'm not as sophisticated a lipid specialist as Tom. I tend to make decisions on more simplistic approaches. And ultimately, and most of the guidelines have actually stressed this point, which is make sure that the clinician and patient are on the same page because if they're not, doesn't even matter what you prescribe, it's not being taken.

1:18:14So that's the final point. So whatever you decide, you have to be on the same page. From my perspective, the thing that drives my decision-making about my first recommendation is the multitude of clinical trials that have been done with statin class. We now have over 30 major cardiovascular outcome trials showing that statins reduce some combination of heart attacks, strokes, cardiovascular events, and even mortality across a wide range of patient types. And when you have that much data, you actually start looking at meta-analyses. You combine the literature and you show that there's a linear relationship between LDL cholesterol reduction with statins and cardiovascular event rates.

1:19:01And so there's so much evidence supporting that approach. it's where i start the conversation the other sort of silos that i think about when i'm having the conversation is potency i just told you that ldl cholesterol lowering potency predicts the outcome so i i want the most potent therapy that i can use for that person and i want tolerability not safety none of these drugs have any safety concerns but there are some tolerability concerns as anybody who owns the internet knows, right? The statins in particular, which have the most evidence, also have the most complaints. I don't know if that's because they're the most toxic, or it's just the most number of people who take them.

1:19:43But regardless, they have the reputation of being difficult to tolerate, and they are truly difficult to tolerate. And they occupy a lot of our time spent in a lipid clinic. So I'd like to start with the conversation talking about statins, but that's not the end of the conversation. And if I have a patient who says to me, I'm not taking a statin, okay, maybe we'll revisit it some down the road if we need a little bit, but let's see what else we can do. And that's where we start talking about other therapies. So it's cardiovascular outcome trials, the evidence, the potency, the tolerability, and finally the ease and the access and the cost all sort of lumped into one.

1:20:25If somebody says, I'm going to take one of those fancy new PCSK9 inhibitors and they don't have the resources to access them, well, that's a moot point. But if somebody says, I'm going to take a PCSK9 inhibitor and their insurance company won't authorize it because they don't qualify based upon the financial characteristics and they have the ability to pay out of pocket for it, it's fine with me. I think the benefit is the LDL lowering. I don't think there's a magical property of statins versus azadamide versus PCSK9 inhibitors versus bempedoic acid on the arterial wall that distinguishes them from each other.

1:21:04I really think it's the evidence and the ease and the patient preference that's going to drive the decision. And does the insurance coverage, does that come down to the clinical evidence and the lack of long-term studies on, say, PCSK9 inhibitors in this population that we're talking about? So there's a cycle that goes on. You have a gap in the evidence. We take care of patients. It's 2010. We have the meta-analysis of all these clinical trials showing that statins reduce cardiovascular event rates. We have exactly zero trials in 2010 with ezetimibe, PCSK9 inhibitors, pempidoic acid. In fact, pempidoic acid hasn't even...

1:21:45Some of these drugs haven't even been invented yet. So in 2010, it's a statin-only world. That's what the evidence taught us. So the guideline writers write a guideline that says that. Then the insurance says, okay, we're going to do what the guideline authors told us what the evidence says. So the insurers only authorize things that the guideline authors write. Lo and behold, new evidence comes to light. New drugs get FDA approved. The guidelines haven't been written yet. So there's a gap between the time the last guideline and the next guideline. In the interim, insurers say, we're not paying for any of the new stuff.

1:22:20We don't have enough data. The guidelines haven't told us to do that yet. Eventually, the guidelines get rewritten. They say, hey, there's new evidence. Here's what the evidence shows us. And very straight on with the evidence, not extrapolations like this is the evidence, hardline evidence. Then the insurance companies tend to follow and they write those new guidelines and people start to have wider access based upon this new information. In the meantime, new evidence keeps coming out. New clinical trials are being done. We broaden the scope of who we can treat with these things. And now we have the 2026 guideline that's the most recent, and it includes three cardiovascular outcome trials with PCSK9 inhibitors.

1:23:02It includes evidence from ezetimide cardiovascular outcome trial, benpedoic acid cardiovascular outcome trial, in addition to the statins. And we have a broader use access for these drugs. You mentioned tolerability. Based on the evidence and your clinical experience prescribing these with patients and getting feedback of statins, bemphedoic acid, ezetimibe, and PCSK9 inhibitors, is there a class of those lipid-lowering drugs that you would say is best tolerated generally? Yeah, PCSK9 inhibitors and ezetimibe. Is that similar to what you see, Tom? With the statins, although there have been a lot of nice articles written that really the FDA or to take away about 90 % of the side effects that have been reported in clinical trials that are not real.

1:23:47But you do have the potential glycemic aggravation and you certainly have myopathic symptoms in some, which you don't see with PCSK9 or ezetamide. Is that because of how targeted the drug is? Are PCSK9 inhibitors and ezetamide a little bit more targeted than benbedoic acid and statins? Well, they're all ApoB-lowering drugs, but they have different mechanisms of action. the ezetimibe is pretty much working in the gut and statins get into every cell in your body to inhibit cholesterol synthesis and pcsk9 is pretty much working on ldo receptors in the liver that's what i was getting at their effect on cells in the in the liver versus cells throughout the body and whether there's a difference between the statins ezetimibe pcsk9 and bambidoic acid Well, even azetamide is depleting the liver of its pool of cholesterol, that's why the liver expresses LDL receptors to get more cholesterol.

1:24:44The PCSK9 is a protein that modulates how long LDL receptors recycle, so it's acting on that. And benpedoic acid is inhibiting synthesis only in the liver and no other cell, where statins get into every cell in the body. But still, they're overwhelmingly considering that they've been around going on 40 years, multi-millions of patients taking them. I mean, that's a pretty safe drug. It's probably safer than almost all drugs that are prescribed by doctors. But there are some side effects with the statins not seen with those other drugs. But point being, with this person in front of you, Dan, you'd have that discussion and then work with them and they could choose whichever lipid-lowering therapy they desired.

1:25:28You mentioned that you think the benefits are driven by the amount that you get LDL cholesterol down or APOB down. And I'm assuming that you're starting off with one medication and then reassessing and checking. And what does that process look like? Talk to me about when you may add another medication on top. Well, I mentioned that we've come a long way from 2013 when we were not just advocating statins first and statins only, but also high intensity statin versus moderate intensity statin. And one of the things that Tom has taught all of us is that you can achieve really good response and really good tolerability with a high potency statin taken at a lower dose and even sometimes even a less frequent dosing scheme.

1:26:18And if you need additional LDL lowering to add to that, that's where adding a second non-statin can be really beneficial. If you go in the way back machine, back into the 1990s and the 2000s and even into the early 2010s, you know, we really spent a lot of time focused on statin-associated muscle problems. problems. And probably the person who's published most and taught the community the most about that is someone named Paul Thompson, who I just happened to run into this weekend. And Paul doesn't come and speak to our meetings anymore because we have a lot of other approaches that we can follow.

1:26:56But we learned a lot from Paul regarding exercise physiology and the impact of statins in exercise, the impact of statins, like the mechanism of how statins might affect muscle function. You know, if you just watch TV, you think that everybody who takes a statin is going to benefit from CoQ10. That's the thing that's going to solve it all. And Paul narrowed it down that the last time I saw him speak, I think the list was like 14 different things mechanistically how statins could potentially affect muscle function and muscle tolerability. One of them was coenzyme Q10 depletion, but that doesn't account for the other 13 things that were on his list.

1:27:37I may have that number wrong. It might've been 12 or 18 or something, but there's a lot of potential reasons why statins might affect the muscles. And I don't know whether it's going to affect my patient's muscles until I put them on the drug. I don't have a test for whether or not it's affecting their muscles other than to ask them, how do you feel? When they say, I feel fine, then their muscles are fine. If they have good exercise capacity, they're fine. If they don't feel fine, the test for finding out whether it's the drug is I tell them, okay, stop that drug for two to four weeks, then go back on it, then tell me whether you think there's an association.

1:28:13Now I've just done a very low-tech but incredibly sensitive and specific test to determine whether the statin is affecting their muscles adversely. And that's the tool that I use in clinic. I know know, maybe Tom knows about some other fancier tool to answer that question. No, that's worked forever for me too. It's really the only way in the real world. There are no tests you can really do to say, aha, this is definitely a stat. I mean, other than your CK going through the roof, no, there's no test. So talk to the patient and tell a patient who's having muscle aches, you got to stay on the statin because you're not going to.

1:28:48Can those muscle aches occur with benpidoic acid? Not any more than in the placebo group. So, benpedoic acid only works in the liver. It doesn't inhibit cholesterol synthesis in any other organ in the body. There's a specific enzyme in the liver that changes a prodrug benpedoic acid to its active form. So, no other cell can be affected by benpedoic acid. Dan, how often would you be shifting a patient from a statin to benpedoic acid? I have to admit, Simon, I don't prescribe a ton of benpedoic acid. It has a lot to do with the timing and what's available. I don't really favor drugs that lower LDL cholesterol and ApoB around 20 % if they cost more than$10 for 90 days.

1:29:32I'm willing to use them, but if I'm going to spend money on a drug to lower LDL cholesterol, I'd rather take a drug that lowers LDL cholesterol and ApoB by 40, 50, 60%. I think if you're going to spend the money, knock it down. So I tend to go to PCSK9 inhibitors before benpedeic acid, but if someone can't access a PCSK9 inhibitor in that context, then I prescribe benpedeic acid for sure. But it's fourth on my list after statins, ezetimi, PCSK9 inhibitors. It's a very expensive drug, and it's also tough to get approved by third-party carriers also without really documenting the statin intolerance.

1:30:11Now, I take it, but I've been able to prove my statin intolerance. And for the most part, if you're in a primary prevention setting, Bemento-Gaz, you're going to have to combine it with ezetimibe to actually make a combination tablet. Rare would you go with BA alone. They're a hindrance. I've been using WHOOP for over six years, and I can confidently say it keeps me on track when it comes to my sleep and exercise routines. The next generation of WHOOP isn't just tracking your workouts. It's monitoring your sleep quality, your recovery state, and even giving you insights into your biological age.

1:30:49No screen, no distractions, just continuous data on what your body actually needs. And here's what matters. Daily WHOOP wear is linked to increased physical activity, to better sleep, and improved heart rate variability. I have no doubt that my WHOOP is helping me train smarter, recover faster, and make decisions that support my long-term health. Head to join.whoop.com forward slash Simon. That's join.whoop.com forward slash Simon to get one month off your first subscription. Dan, were you pleased to see the oral PCSK9 inhibitor get approved recently? Sure. It looks clean. It looks fantastic. It looks like the impact is similar in terms of LDL, cholesterol, and ApoB reduction to the monoclonal antibodies and to the adnectin albumin conjugate.

1:31:50It looks really good. And I think I definitely have patients who say, gee, I'd rather take a pill than give myself shots. And so I think that what we're going to find is whether or not there's a difference between cost and accessibility. But the tolerability looks similar to all the other four PCSQ-9 inhibitors. That's not available yet, or it is? Another month or so should be. I've prescribed it now three times this week, so we'll see what happens. Yeah, but is the pharmacy filling them or not? There is a technical rule when you administer it, you're not supposed to eat for half an hour afterwards, which might be annoying to some people and not so to others.

1:32:31I've actually had surprisingly few patients tell me that they wanted to switch from their shots to the pills. I would think as new starts, people would say, yeah, let me try the pill and I'll abide by those administration rules. Myself, who's been on an injectable Evolocumab for 10 years, every two weeks in a little auto pen, I'm not switching. Well, that's the same for me too, Tom. I actually prefer the injection. I find I can do it and I don't have to think about it every single day. So I guess it's going to come down to the individual there. But I'm sure there are a lot of people that do not like injecting themselves.

1:33:04Simon, what if I give you a shot every six months? What if I did that? I actually like that even better. I like that even better if there was cardiovascular outcome data. What if I gave you one shot, but forever? Well, I'm keeping an eye on Verve and we'll see what the trial results show, Dan. Maybe I could put my hand up and be one of the first people that do that. You're not going to qualify for the clinical trial. You don't meet the criteria, but when you sort of go through, what would be the easiest thing for you? Is it a daily pill? Is it a shot every two weeks? Is it a shot once a month?

1:33:35Is it a shot every six months? It depends how low you want to go. What if you got a shot once a year with something that typically lowers LDL cholesterol by 50%, but after six months, it starts to rise again. And so over a time average reduction, you get a net 30, 35 % reduction, but you only have to do the shot once a year when you go in for your annual physical that sounds pretty good in that case though i think i'd probably i'd prefer twice a year and to try and keep the average down a little bit lower but for the moment every two weeks i think is good given that repatha has the the hard outcome evidence over like inclicerine but i think that outcome evidence is coming out soon right yeah the orion 4 trial is due to be by the end of calendar year i can't remember the exact date that they claimed.

1:34:23I don't think it's going to be reported at American Heart in November. I think it's later than that. Just quickly before we kind of wrap this up, conscious that half our audience at least are women. Does this discussion at all change if you have a woman in her 30s and she is potentially interested in having children, let's say, over the next handful of years? How, if at all, does this discussion around medications and optimization of ApoB change at all? Well, listen, I think if the woman had risk factors that warrant treatment, you're going to treat her. And if she's going to conceive, once she does conceive, you would likely withhold therapy unless she's a total nightmare.

1:35:04And then after the baby is born, maybe after lactation is done, you'd resume the treatments. That's the current approach. Only a minority would need to be treated during their pregnancy with lipid-modulating drugs. Interesting, Dan. I forget where I saw it that, you know, for years, oh, you take a bile acid sequestering if you're a woman during pregnancy, but they're now relating that that can interfere with the absorption of fat-soluble vitamins, which would not be a desirable thing to do in a woman. So without, again, how come data? Who knows? More importantly, Tom, when that patient comes back and tells you about the bloating and constipation that you gave them during pregnancy and they punch you in the nose, they're not going to be very happy.

1:35:43Yeah. And can aggravate triglycerides, which always rise significantly in pregnancy too. So not the easiest drug. I can't say I've prescribed much in the way of bioacids sequestrants during pregnancy. I feel like a 20 % LDL cholesterol lowering, it's just not worth the discomfort of taking them. One interesting thing I wanted to bring up, and now that you mention women, I know there's the Vesalius trial out there, which was sort of a primary prevention setting where Evolocumab, the PCSK9 inhibitor, significantly lowered events and it dropped the LDL-C to, I believe, around 45, which is just, hey, there's a primary prevention setting where you could be using a PCSK9.

1:36:26But more recently, there was a nice article published. They measured PCSK9 serum levels in the patients in that trial. And it's been known for a while that high PCSK9 in the blood is a risk factor for heart disease. But in Vesalius, it was much more of a risk factor in women than it was in men. And with the PCSK9 inhibitors may actually work better in women than they do in men. So it's all food for thought, hypothesis generating. But I thought that was a fascinating new finding into this alias trial. Tom, you're a troublemaker. You just generated so many phone calls to my office on that one. Back to our avatar, if this person did have elevated LP little a, I know right now Horizon hasn't been published or any of these other studies looking at LP little a lowering drugs.

1:37:16And as Tom mentioned, those are not in primary prevention cohorts anyway. Is there a case to say to this person, maybe try the PCSK9 inhibitor because it will lower that ApoB and you'll also get a small reduction in your LP little a at the same time that may be meaningful or not? Well, that case is there right now, but the worst case scenario, say Pellicarsin shows lowering LP little a doesn't matter, then I doubt if lowering a PCSK9 inhibitor matters also. I think more, a lot of people are doing just that. we know that no matter who you are, no matter what your risk is, you can make your risk lower by lowering LDL cholesterol and ApoB.

1:37:56So if the choice is between ezetimibe and a PCSQ9 inhibitor in somebody who is at high risk and has a high LPA, what Tom was saying is the benefit may not be from LPA lowering. It might just be from having lower LDL cholesterol and lower ApoB. So you're going to achieve a much better LDL cholesterol lowering and ApoB in that person. And if they have a high LPA, their risk for heart disease and atherosclerosis is higher than it would be if they had a normal LPA to start with. So it's reasonable to use that approach. And we also have observational evidence that in subsets of the Fourier trial, that in people who have high LPA seem to have a better outcome than if they didn't have a high LPA.

1:38:43So I think it's reasonable to reach for the PCSK9 inhibitor if all things are equal. But if it's a matter of, I can't afford that, but I can afford this other one, take the one that they can afford. Lower the LDL, lower the ApoB. I wanted to talk about Zeus trial that recently came out looking at an inflammatory inhibitor, but I think we'll dedicate another episode. We'll get you back in a few months to some of these other trials like Horizon and the Orion trial that we mentioned, and we can kind of do an episode dedicated to some of the latest clinical trials on different drugs targeting other risk factors or potential risk factors and what the results were, whether they were null or positive, et cetera.

1:39:27Just before we kind of land this, I'm conscious of giving people a practical takeaway. We've covered a lot of kind of nuance and guideline information here. If we come back to this idea of primary prevention, let's say someone listening right now hasn't done a blood test lately. Yes, they have a family history of cardiovascular disease, but they couldn't tell you much else. Where do they start? Well, they start by getting their risk factors checked, their blood pressure checked, their waist size. If they can't tell by looking in a mirror that they might have a problem there, and then they're going to go into their physician.

1:40:02They're going to probably get a standard lipid profile. All of the guidelines now say once in your life, you have to have LP little A checks. So that's got to be on your to-do list. And if you're on Tom Dayspring's to-do list while you're getting a lipid profile, get an APOB also. Anything you'd add to that, Dan? Yeah, assess the risk, personalize it, re-evaluate. And everybody who comes to ask that question should be reminded that life's essential eight is the foundation of care for slowing atherosclerosis progression and optimizing your outcome. And then we're going to choose pharmacologic therapy according to the needs of that particular individual.

1:40:42And we have lots to choose from, but in general, when we're targeting LBL cholesterol and ApoB, you know, lower for longer is better and customize the intensity of the therapy based upon the degree of risk and plaque that that individual has. Aim for very low levels and very high risk people. You can be more hands-off and more observational in people at lower risk. And the good news, Simon, for your followers of all those eight factors that Dan talked about, you have a podcast on each and every one of them. There's a big archive there for people to go through, including a bunch of episodes with both of you.

1:41:18So thank you so much for hanging out with me again. Extremely grateful to have access to each of you. And you both provide such incredible information that really can help people navigate cardiovascular disease and just feel more confident. So thanks for being with us again. I look forward to having you both on, hopefully in the coming months. And Robert, our medical student, are you still here with us, mate? Robert, well done for making it through that. Do you have any questions you want to ask the guys before we close this out? Something that I thought about during this conversation was in patients who have no evidence on imaging of any plaque, is there any evidence to show that those people do have, I guess not subclinical, but sub-imaging level of evidence of atherosclerosis that then would put them at higher risk relative to somebody else with the same imaging findings?

1:42:11Arterial wall biopsy. Well, it depends on the imaging, right? If you're talking about calcium scoring, we do think that we're only, you know, so with calcium scouring, we're only detecting calcified plaque. And so they may have significant atherosclerosis that's not calcified yet. But with coronary CT angiography, I think we've improved our sensitivity to detect atherosclerosis at least at the gross level, like the visible level within the radiographic precision that we have. But could you have a completely pristine coronary CT angiogram and still be developing atherosclerosis? The answer is yes.

1:42:53That's why it's not a lifetime guarantee of the outcome. And if we think that they may have features that are promoting plaque, even though we don't see it, then we need to continue to monitor that person and maybe even intervene even with the imaging when the imaging is negative. There's another subset, by the way, is we talk about plaque as occurring in the coronary arteries because chronologically, that tends to be the body part that gets affected before other arterial systems from plaque. But some individuals will develop intracranial atherosclerosis but have complete coronary sparing. So their coronary CTA looks pristine, but they have lots of plaque in their intracranial vessels or elsewhere.

1:43:40So having a pristine CCTA doesn't mean that person doesn't have plaque. It just means they don't have coronary plaque. As a predictor of their event rate from all atherosclerotic cardiovascular disease, it's an excellent predictor, but it's not a foolproof predictor. Great. Awesome. Thanks, Robert. Thank you, gents. This has been awesome. Appreciate it. There you have it, friends. I hope you enjoyed this episode. If you did, and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify. Finally, thank you for showing up and the effort that you're making to take control of your health.

1:44:20I look forward to hanging out with you again in the next episode.