D (2:09)

I'm doing fantastic. I'm just happy to talk about one of my favorite topics tonight, so it'll be a great show.

B (2:15)

Before we get into that, why don't you tell us a little bit more about who we talk to and maybe even sort of the broad strokes about what we talked about.

D (2:22)

Yeah. Today we're joined by Dr. Greg Katz. Greg is a cardiologist and Assistant professor of Medicine at the NYU Grossman School of Medicine where he serves as an Associate Program Director for the Internal Medicine Residency Program. He is board certified in both cardiovascular disease and internal medicine and he trained entirely at nyu, including his Fellowship in Cardiology. Greg's clinical work focuses on cardiovascular disease prevention, managing complex lipid disorders, and long term risk reduction for patients. He's active in the American College of Cardiology at both the state and national level and he co hosts the Core IM Podcast, specifically their Beyond Journal Club series in coordination with the NEJM Group Group. Greg also writes a widely read newsletter on cardiovascular topics. You can find him on substack at Greg KatzMD highly recommend or you'll encounter articles that cut through the noise on cardiovascular risk, exercise, nutrition and other clinical controversies. Be sure to check it out. So without further ado, let's get to it.

A (3:20)

A reminder that this and most episodes will be available for CME credit for all health professionals through VCU health@curbsiders.vcuhealth.org. Greg, we've been talking for a while. Thank you so much for coming on the show. We have a lot to get to. Very ambitious script as we talked about, but first audience wants to know what's a hobby or interest that you have outside of medicine?

C (3:46)

So I have little kids and that occupies almost all of my existential energy. But the hobby for myself is I love lifting weights and I love the feeling of being in the gym and really pushing myself to a very uncomfortable place. And then the way I feel positive about the world in ways that I didn't feel before the workout is it's the best therapy that I've ever found.

A (4:10)

Okay, and what sort of weightlifting is this like a group class? Is it like CrossFit? Are you doing, are you just lifting by yourself?

C (4:18)

I've done all of the above, but right now I lift by myself and I do a full body workout twice a week. My favorite current exercise is the pendulum squat, which if you've never done it, it's worth googling to see an image of it because it's basically like all of the pain of a squat, but it doesn't have axial load and so your spine is very happy with you. And you know, like we get older, our joints don't feel as good as they did when we were younger and so I could not recommend that exercise highly enough.

A (4:48)

I actually don't know that one. Is it a single leg movement or

C (4:50)

is it you can do it single leg, but it's a double leg movement. It's a specialized piece of equipment. The weight is kind of like behind you, and it's sort of. It's a pendulum, and your back is against a map. And you just need. Once you Google it, it makes total sense what it is. But until you've seen a picture, it's like the picture is a thousand. It tells a thousand words.

A (5:12)

I actually think I've seen that on The Jeff Nippard YouTube channel probably. I think that's one of the pieces of. It's a piece of equipment that not every fitness center has. I think that's why I think so anyway, 100%.

C (5:24)

Literally, the gym I joined, I joined because they had a pendulum squash.

A (5:28)

Okay. All right, this makes sense now. All right, Paul Williams, now that you're. Let's bring you back into the conversation here. I know this is not your favorite topic.

B (5:36)

No, I dissociated for a second there. But no, I guess I hate weights and resistance training and all, but I just find it deeply more. And I'm not saying you're talking about it is fascinating. That is not what I'm implying. I said me doing the activity itself, I cannot find any joy in it. So it's so nice when I see people that do. I feel like I would look very strange also if I was muscular. So that's another consideration. I think I'm just better off scrawny. But let me ask this. Could you tell us about. Could you share with us some advice or feedback that you've received during your training or that you like to give to trainees that you find especially useful or helpful for folks?

C (6:11)

So I'll tell you a piece of advice that I heard myself that impacted basically every interaction that I have in the hospital and that I tell to almost every resident or fellow that I work with, which is your job is to not just know the medicine and take care of patients. It's to elevate the experience for everybody around you. And that means that you want to bring a positive attitude that makes your team more joyful about medicine. It means you want to help cheer the patient up. It means you want to make the experience more academic and look something up that's going to elevate the way that we all think about the case. And it also means that you are kind to all of the people behind you in the pecking order who can't make your job better and can't open doors for you. So the PCTs, the medical assistants, the staff that Cleans the hospital. The way that you treat them and how you make their experience is reflective of how your reputation is gonna look to everybody else. And so your job as a doctor is not just to know the medicine and not just take care of patients. It's to elevate the experience for those around you.

A (7:13)

Really fantastic advice. Listen, I think everybody that's starting in the hospital could definitely and actually anybody at any level could maybe. I needed to hear that. Paul Williams. That's a good.

B (7:26)

No, I mean, I love it because they're these sort of agonizing think pieces in the primary care space like how can we attract more trainees to primary care? And I truly think the trick is to actually have them catch you enjoying it and sort of being joyful. And I think like that is the, that is the thing more than anything else. And I think people who work with me might find that hilarious thing as someone who tends to spend a fair amount of time stomping around and being unhappy. But I do think when you're actually caught having fun and being excited about medicine and sort and as you say, elevating the experience, I think like that's the ticket to get people interested in the thing that you do. So I just, I like that advice very much. Cool.

A (7:56)

And I think we're about to get a lot of people interested in what Greg does because we're going to give him a case from Cash Slack and we're going to talk about some very interesting topics here. So Wirtz, do you want to do the honors?

D (8:07)

Absolutely. We have Arthur. He's our patient. He goes by Art. Esclerosis. He is our 46 year old man presenting for a routine visit. He wants to talk about heart attack prevention and longevity. His motivation for this is that his father needed a bypass surgery at age 68. Art remembers how much of an ordeal that whole process was for his family. He himself has no known ascvd and he has never smoked. His blood pressure in Clinic is 13284 without any medications. His BMI is 29 with an elevated waist circumference. He exercises by walking around the block a couple times a week when life allows. He sleeps about six hours per night and uses his CPAP routinely for diagnosed osa. And he eats a standard American diet. Annual labs show an LDL C of 123, an HDL C of 41, triglycerides of 190, a non HDLC of 159 and an A1C of 5.7. The rest of his Labs are unremarkable. So, you know, a lot of our guidelines are built around secondary prevention. But this patient is a very common primary care scenario. You know, you have someone with clear risk factors. They're motivated, but they themselves have never had an MI or a stroke. So when a patient like this shows up to your clinic, what jumps out to you? How do you think about primary versus primordial prevention in real life? And how do you actually help patients understand and act on that risk before something bad happens?

C (9:31)

So a patient like this, 46 years old, very clear evidence of metabolic syndrome, central obesity, sleep apnea, dyslipidemia, elevated A1C. He may be a primary prevention case, but he is a secondary prevention case waiting to happen. And the only difference between him being primary prevention and him being secondary prevention is the time when he's coming to medical attention. And so I look at a patient like this, and I tell folks like this all the time, you are coming to medical attention at the perfect time. Because we see a whole bunch of red flags in your history, a whole bunch of red flags in your family history, and a whole bunch of red flags in all of your objective data. And if we do a good job of taking action, some of that action is going to be things that we give to you in terms of medications. Some of those are going to be things that you do at home for lifestyle adjustments. Some of those things are going to be ways that we better understand your risk. But we can help you prevent a heart attack if we understand where you're at right now and we pull the right levers to help sort of optimize the risk factors that are in our control. I always tell patients, there's some things that are in our control and some things that aren't in our control, like we can't change who your parents are, but there's a whole bunch of stuff for this patient that we have real opportunity to make his life better.

B (10:50)

Yeah.

A (10:51)

I think, Paul Williams, you think people become desensitized to some labs like this where it's just so common to see this sort of presentation?

B (10:59)

Yeah. To Greg's point, this is someone who's on the cusp of stuff, but because they've crossed that threshold, it's kind of easy to not look at it in aggregate and think, oh, this is a potential problem. So I think that's. Individually, none of these things are terribly alarming. It's when you sort of add them up that it becomes a little bit more something to wrap your hands around.

A (11:16)

Yeah. And I think you don't want to be. I think some patients might be turned off. You got to kind of gauge where they're at with things. I think recently in my practice, because of the type of practice I have, people are coming to me wanting to know if they are metabolically healthy, because I think they're getting this type of information that, hey, we need to check to see if you have metabolic dysfunction. But a lot of. For most of my career, it's been people coming to me and like, oh, my numbers aren't that bad. Right. So I don't need to do anything about it yet. Right. And that was kind of. That was kind of where things are. But I think now it feels to me, at least, that, like, things are swinging and people are more interested in, like, how can I avo bad things happening and what should I do about this?

C (12:01)

So there's different perspectives that people have about how to approach stuff like this. And one of the questions that I ask people when they come in, like, this is, how medicalized do you want to be? And what that means is there's a whole bunch of treatments that we can give you prescriptions that you can leave the visit with. There's testing that we can do to better kind of triangulate your individual risk. There's a lot that we have the ability to do. But understanding how far down the road of being a person who is part of the medical system is a really important piece of information. Like, some people want every data point, and some people just want to know, doctor, am I going to be okay? And just like some people are willing to take any prescription that you give them or any supplement that you could possibly think of. You know, like, the better living through chemistry kind of folks.

A (12:47)

Yeah.

C (12:47)

And then other people will not touch a prescription, but they'll only touch a supplement. Some people will not touch a supplement, but they'll only touch a prescription. So people don't want anything. And so to understand what are we going to do for a patient like this, we need to understand, like, you need to take his temperature, you need to understand where he is mentally coming from, and you need to meet that person where they are, because otherwise it's just going to be a frustrating interaction for both parties.

B (13:10)

Yeah, I do. What? Just since we're spending some time on the fluffy stuff, and this is my bread and butter. I do. I'm looking at this patient. This is someone who is adherent with their cpap. They're walking. They're actually coming to their doctor's visit. They've had labs done, like, this is somebody who is doing something. So I think it's the other. To your point, Matt, I do feel like we sometimes pathologize risk in a way that seems almost sort of accusatory or like, as we're trying to use it as a scare tactic rather than sort of celebrating the victories and recognize them as ways that we can still improve and actually prevent suffering. So anyway, sorry, I'm not sure if that point was helpful at all.

C (13:42)

The soft stuff, like, that's all that patients care about. Patients care that you care about them. And in order to practice the art of medicine, you need to understand the science of medicine. But medicine is an art. And if you don't pay attention to who the humans are, like, chatgpt will be 100% a better doctor than you. And so I just think that it's really, really important to not just focus on like his BMI and the fact that he has sleep apnea. But I will tell you, just going to the medicine, I look at this scenario, he's 46 years old and he already has sleep apnea, he already has prediabetes, he has a triglyceride to HDL ratio that's almost 4 to 1, little bit over 4 to 1. He's somebody who is not just metabolically unhealthy, he's somebody who already has consequences of that. And he's somebody who, if you're asking me sort of like, how do I approach this from, do we do lifestyle, do we do medications, do we do additional testing? I'm an all of the above person. Like, all these things are tools, and tools are only as good as how you use them. And so for somebody like this, you can, like, this guy can leave the appointment with four prescriptions and with a blood pressure monitor and with statin and with a GLP1 and with the plan to get a calcium score or coronary cta. But it's, I think that the order of operations can end up being really challenging for somebody like this. And so understanding who the human is just matters a ton.

B (15:19)

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A (18:18)

So let's talk about you mentioned triglyceride to HDL ratio and we gave you some Lipid numbers here, when, when I was trained, that was not even something that was on my radar. In fact, in probably, probably before the past year or two, that's not something that I had thought about. Triglyceride to HDL ratio. And so tell us how you look at a lipid, like the standard lipid panel and then we can go into the APOB LP and some of the other ones that people may be less familiar with.

C (18:46)

So I actually, I hear that from doctors a lot that they don't think about the triglyceride to HDL ratio. But I think that you do because you learned about metabolic syndrome and you know about the criteria for that and you know, you like triglycerides and HDL are part of what goes into the definition of metabolic syndrome. So I think that all doctors kind of like intuitively know about it. And you know, it's having a metabolic health is having a moment in the longevity space. But it's been part of like classic medical teaching for decades. And you know, because doctors kind of suck at translating things into normal human language. I don't think that the fact that this metabolic syndrome is part of the medical literature and is like syndrome X was like Gerald Raven in the 1980s. Like we've known about this for how many years at this point. And so it's, it's, it's a failure of the way that doctors market and we focus on rent seeking, that this is not sort of more widely known, that this is something that, that we should appreciate. But the way I look at a lipid panel is there's two major pathophysiological pieces of information that you're getting from it. One is related to the LDL or the non hdl, which is your atherogenic particles. It is cholesterol floating through the bloodstream in the form of lipoproteins, because cholesterol is not water soluble and blood is mainly water and it's floating through the bloodstream. It can get stuck in the subendothelial space that causes inflammation. And that's what leads to the process of atherosclerosis. And so the LDL or the non HDL is telling us about that specific direction, that specific pathogenic process. And then the triglyceride to HDL ratio is helpful for understanding metabolic syndrome, metabolic health, insulin resistance. And so I always describe to patients that metabolic health is the spectrum of sort of how your body is processing energy that goes all the way from your health is perfect to you have full blown diabetes and it's not, not. You're healthy, and then all of a sudden you have out of control blood sugar. It's a spectrum. And it's a very, very continuous variable. It's not a categorical variable. Even though in medicine we like to sort of like lump things in together if you have good metabolic health or you don't have good metabolic health. But understanding it as a spectrum, I think is really, really important. So I look at the lipid panel as telling me two different physiologic stories about why somebody might be at risk for cardiovascular disease.

A (21:04)

Yeah, I think that's a really good, very smart reframing of the, you know, the metabolic syndrome risk factors. Which I think what's nice about metabolic syndrome and thinking about it is just, it's data points that we have on almost all our patients. Right. And I guess maybe we don't measure waist circumference on all patients. That's something that I've started to incorporate in my practice recently, though, doing a waist to hip ratio.

C (21:27)

Waist to height ratio is actually a little bit better than waist to height ratio.

A (21:30)

Waist to height is even better. Oh, okay. I didn't know that. Yeah, yeah. So that is something that. But we're getting that on most patients, and we know it's associated with a lot of the stuff you mentioned. Diabetes, sleep apnea, fatty liver is one of the ones. Osteoarthritis, ckd. So the list goes on and on with what metabolic syndrome is associated with. So, Wirtz, do we have more labs on this guy?

D (21:53)

Yes. So you decide to send an APOB and LP so we can talk about maybe why we sent those labs and kind of their role in this lipid discussion. But we get back an APOB of 127 milligrams per deciliter and an LP of 80 nanomoles per liter. So going off of these numbers, how do we make sense of this? How do we place this into the broader discussion of what we already have?

C (22:19)

Yeah. So the decision about what to order, like, we should understand what we're looking for when we order it. And so I look at APOB as helping me understand whether the LDL tells me the story about atherogenic particles. And so, you know, the main particle that can get. The main cholesterol containing particle that can get stuck in the walls of the endothelium is LDL. LDL accounts for 90% of those atherogenic particles for most people. But the LDL cholesterol number that you get on a lipid panel doesn't tell you much about the number of particles that are circulating through the bloodstream. And so I think about cholesterol, and I think about cardiovascular disease and that relationship as it's almost like a traffic problem. And so if I want to know what the traffic is like on the street, what LDL is telling me, LDL is telling me the number of people who are traveling up the road. But what APOB tells me is it tells me the number of vehicles that are going up the road. And so even though directionally, knowing the number of people can be informative for understanding what the traffic is like, if I really want to know what the traffic is like, I need to check apob. And the reason for that is it most commonly comes into play in patients like this one who have elevated triglycerides, because the triglycerides crowd out the cholesterol on the lipid particles, and you need more particles to ferry the same amount of cholesterol around your body. And, you know, there have been a ton of different discordance analyses. Discordance analyses are basically when you look at two variables that usually travel together, but in some cases are a little bit different. And so LDL circle compared to apob when those two things are discordant, meaning the LDL is either higher or lower than you would expect based on the apob. APOB better predicts risk. And this has been shown in population after population, in study after study. It's pretty well replicated to the point that all of the major professional guidelines talk about the appropriate clinical use of APOB and how it can be helpful for better triangulating atherogenic risk for a subset of patients. And the folks who tend to have discordant are people like this patient with high triglycerides, big waist circumference, insulin resistance. And when I look at it's really, really tough sometimes to go from like we were all trained think in LDL, LDL under 70 for secondary prevention, now maybe under 55 for secondary prevention. And then I introduced this brand new test that you have to remember to order because it doesn't come with the standard lipid panel. And then we're not fluent in APOB until we've practiced with it for a while. And so a good rule of thumb is that the APOB should be about 15 to 20% lower than the LDL. And red flags to me are when the APOB is actually higher than the LDL. And when that's the case, APOB is definitely the better metric to track, because in study after study it really clear that APOB better predicts risk of heart disease, risk of MI than LDL does when they're discordant. And so, so I'll measure them in everybody and if the APOB is exactly what I expect it to be, somewhere in the 15 or so percent less than the LDL, then we don't necessarily need to follow APOB. But in this patient, his APOB is 127 milligrams per deciliter and his LDL is 123 milligrams per deciliter. To me, if you look at his LDL, you're going to be falsely reassured about his overall cardiovascular risk.

A (25:43)

Yeah. Wow. Paul Williams, any comments, questions, concerns? I know you've been somewhat of a skeptic about ordering APOB or just not sure if you needed to order it. And it sounds like you don't for every patient, but just curious.

B (26:00)

Yeah, I guess functionally, how often does that change? Actual management? I guess would be sort of my follow up question. I think if we again looking at this patient we've decided has, has pretty high cardiometabolic risk, we'll be having a conversation about the statin, if they're open to that, I guess. How much more does it add, especially if you have a significant LDL lowering and how does that change management of the APOB doesn't drop as much, I guess. I'm just not quite sure the impact on management specifically.

C (26:28)

So if you plot out on the x axis the LDL and on the Y axis the apob, what you see is that, that across the population it really tracks pretty well. But there's a fair number of people where there's discordance high or discordance low and it ends up being about a third of the population where there's a significant discrepancy between what you would think the APOB would be and you know, in practice it probably has more of a role for secondary prevention than for primary prevention. But APOB is inexpensive, it's readily available and, and if you're going to use a biomarker, shouldn't you use the best biomarker? And so for me, if I'm like, I don't treat populations, I treat individual human beings. And when I'm deciding about should we increase the statin dose, should we add ezetimibe, should we think about a PCSK9 inhibitor? I want to understand to the best of my ability, if we're going to track a biomarker, why not track the best biomarker? I Fully get. It's a little bit onerous. It's not part of the standard lipid panel. It doesn't change practice for everybody. And so. And there's certain patients where it's totally unnecessary and lots of people will have a drop that goes down, like their LDL goes down and their APOB goes down by a similar order of magnitude. But I look at it very simply of, like, if it's not an expensive test and it's easily accessible and I can get it with a standard blood, like, why not check the best biomarker?

A (27:57)

Greg, the most labs that I've ordered from have APOB cut off, like less than 80 or less than 90, set off as, like, sort of the. Not ideal, but the normal value or a lower risk. Do you have a target that you, if you are treating somebody for secondary prevention, do you have, like, a target? Is it less than 60 or down in the 30s or so?

C (28:20)

This. I think that this kind of gets to a little bit of where my clinical practice is slightly different than the guidelines. And so you know the guidelines. And like, to a certain extent, the way that I take care of patients, I use the Alara perspective when it comes to lipids, like, as low, as reasonably achievable, just like radiation. Sure. And so. But I think that the way I try to frame a patient whose secondary prevention, prior heart attack, prior stroke, is I try to think about what's driving their risk. Was it that they had poorly controlled blood pressure for years and years and years, and it's actually hypertension and I need to control that? Was it that they've been. They had an elevated LDL or an elevated APOB for a really long time, and that's actually where the problem is. So they have a chronic inflammatory disease like loop lupus. Is that where the problem, or is it just their family history? And, you know, if somebody starts at an LDL of 170mg per deciliter and APOB of 150, and I get them, I get that APOB down to 60, I'm pretty happy with that. But if it's somebody who is really young or who's had recurrent events, then, you know, a lot of the data from some of the RCTs would suggest that your benefit in risk reduction goes down even as you get down to, like, 40 with the APOB. And so. But in real life, what are your limitations? Well, your limitations are how many medications does somebody want to take? How sort of consistent can somebody be with the lifestyle modifications, more fiber in the diet, maintaining a healthy weight, staying physically active, et cetera. And what gets covered by insurance. And do people want to do injections? And so in actual clinical practice, the number of people who get too low is a tiny fraction of the number of people who. I'm just struggling to get them to a level that I consider even reasonably acceptable for secondary prevention.

A (30:02)

Yeah, okay. I think that's great. So that's another thing people can target. And I've been ordering APOB for the past year or two and I find it just becomes like, it's just like looking at the lipid panel. It's another number to look at, another data point that you can get, especially for people that are more on the. We had someone. You described it a little differently. We had a past guest describe. Some patients are maximalist, some patients are minimalist when it comes to testing. So I've had a lot more people come in specifically asking for an APOB to be checked. But I think it can be helpful in some cases just to tie bow

B (30:44)

on this, but do we have like, are there treatment targets specifically in the guidelines yet, or is that something that we expect to actually be happening at some point?

C (30:50)

At some point, I'm sure it will be. All the guidelines, as far as I'm familiar with, all have LDL targets. They don't have APOB targets. But you can reasonably. I don't think it's an insane extrapolation to say that, but, you know, if your LDL target is 55, your APOB target should be about 45 to 48 or something along those lines like that. That's a pretty reasonable extrapolation to me. But importantly, there's never been really any good data that suggests that there's too low of a level. And there's plenty of data that suggests we under treat a fair number of secondary prevention patients.

B (31:23)

Yeah, I just remember when the, the paradigm shifted. The, the lipid guideline was it was 2015 or they came out where they just recommended sort of the binary of statin or non statin. And the patients would be like, what should my target be? And you're like, there isn't one.

A (31:34)

2013.

B (31:35)

Yeah, it just should be better. So like, I just, that's, that's the conversation I would sort of hope to avoid by sort of just. Yeah. So that I, I think the lipid

C (31:42)

guidelines really do a disservice to practicing clinicians and they're overly convoluted. They give these arbitrary thresholds. And very, very importantly, I think the guidelines undertreat young people who are at high risk and they over treat old people who are at lower risk. And, and so yeah know, I very, very much believe that you need to individualize this stuff and that this like turning doctors into algorithms is something that I think is a real disservice to the patient doctor relationship and just like the way that you take care of patients. And so, you know, the people who work on the guidelines are really smart. They review a ton of data. I don't mean to like, I'm not trying to insult them. I have a legitimate disagreement and I think that reasonable people can look at the same information and can disagree with how the guidelines end up coming out. And so to me the guidelines are more confusing than they are illuminating for a lot of patients.

A (32:34)

So Paul Wertz, why don't we talk a little bit. I think you had a question about the prevent calculator and that kind of leads into a little bit what we're getting at here with this. How good are the risk calculators for especially if it's a young person with a high cholesterol. So Wert.

D (32:51)

Yeah, so let's say this patient, they want to lower their risk to the maximal extent possible. And you as the primary care provider, what you know how to do is to use this prevent calculator. It used to be the pooled Colholt equation that used to be the thing to use and now this is the thing to use in place of that. So when you plug those numbers in, let's say you get a 10 year risk of about 2 to 3% and a 30 year risk of 17%. What do those numbers actually mean and why is there a separate calculator for CVD and ascvd? How should clinicians make sense of prevents compared to the prior risk tools that we used to use? And then how do these estimates influence decisions? Like, like let's say you don't know where to go next. How might they influence decisions on getting a CAC score or trying lifestyle or starting the patient on a medication? So at the end of the day, how do you put all that together and decide what to do next?

C (33:44)

The glib answer is I don't use those calculators because I think they misinform as much as they do inform. But the sort of more thoughtful, really considered answer is that risk estimates are and every kind of risk calculator is based on a retrospective analysis that's usually prospectively validated to estimate risk across a population. And it's really, really good across a population. But it's not so good for individuals. And I think the people who are really missed in the guidelines are people who have really strong family histories, young people with metabolic syndrome who are at increased risk. And because age is such a big factor in what somebody's 10 year risk is or what somebody's 30 year risk is, young people are really, young people with significant risk risk are really under treated by the guidelines. And again, because age is so important, old people are often over medicalized who don't necessarily need to be medicalized. And so I think that this is great for a population. And if you take a hundred people who have this exact risk profile, then over the next 10 years, two to three of them are going to have a heart attack or a stroke. But that to me, and I also think when we give people granular numbers in risk, it sometimes misleads us to think that like all risk is created equal. And what I mean by that is if there's some, I don't know if you're all familiar with the concept of asymmetric risk, but it's a lot of how I think about cardiovascular disease. It's a lot about how I think about anticoagulation and afib, which is that if I over treat you and I put you on medications that you don't tolerate, you know what happens is like if you go on a statin and you have muscle aches, then, then I stop the statin and your muscle aches go away. If I put you on ezetimibe and you have a GI consequence, or I put you on a PCSK9 inhibitor and you have an injection site reaction, you know what, we stop the medicine and the side effects go away. But cardiovascular disease is the number one killer. And if I under treat you because I'm worried about side effects or because I think that this 2 to 3% number is not, not a high enough number for you to merit treatment for very clearly uncontrolled cardiovascular disease risk factors. And you have a heart attack like that could ruin your life forever. You know, you have a plaque rupture in the wrong location and you're a little bit farther away from getting medical attention, or you don't know exactly what it is, and then you have an ischemic cardiomyopathy and your life is forever different, or you have a piece of plaque in a carotid artery break off and go to your brain, you have a stroke and your life is forever changed. And so I don't think that the numbers that we get from A risk calculator capture the fact that risk is asymmetric because drugs are often going to have side effects. Like somewhere in the 5 to 10% of people who you put on medications will have a side effect of some kind, but the side effects go away. And I think that we do patients a disservice when we use this risk. It's not written on a stone tablet, it's based on a large data analysis and it works across a population. And so especially for a 46 year old individual who has a ton of non optimized risk factors, I think the risk calculator is going to be more, it's going to be more problematic for him than it's going to be helpful in my eyes.

A (37:03)

Right. So we did it for this guy. The 10 year risk would come out to be 2 to 3% and the 30 year risk would come out to be around 17%. So that 10 year risk is what a lot of the treatment decisions are based on. So he wouldn't, wouldn't necessarily be treated. I do want to swing back to his lp. We actually forgot to talk about that. And then this guy, let's say he heard from a friend that he should get a calcium score. And how would you talk to him about the data points? We have already he had the high APOB and he had a LP of 80 and he wants to know if he needs a calcium score.

C (37:41)

Can I say one more thing about the risk calculators before I go into that? So the other thing that to me does not make sense about the risk calculators is that they're used to decide should you lower lipids. But like nobody, if his blood pressure was 160 over 90, there'd be no debate. Oh, his 10 year risk is 2 to 3%, so who cares if we lower his blood pressure? And so there's something very odd to me about treating a very clear causative risk factor like dyslipidemia, a completely different way than we treat a very clear causative risk factor like hypertension. And so, you know, you want to talk about his, his lp. So LP is a fascinating test and it's something where you're starting to hear more and more about it. A handful of years ago, one of the personal trainers on the Biggest Loser, Bob Harper, while he was working out, he had a cardiac arrest in the gym. By all sort of external metrics, he's the picture of health. But it turns out strong family history of cardiovascular disease and he had a LP that was through the roof. And so even for somebody who does quote, unquote, quote everything, right, LP can still be a real problem. And so lipoprotein A. And the nomenclature is tough because it's lipoprotein lowercase a, not to be confused with apolipoprotein capital A hyphen 1, which is the apolipoprotein on HDL, and it's pronounced Lp, little A, literally little A. And so it's A the nomenclature, like they needed a more person. Yeah, it's a mess. But LP is basically an LDL particle, particle that is covalently bound to apolipoprotein lowercase a. And it's problematic for three reasons. One is that it's pro atherogenic, the second that it is pro oxidative, pro inflammatory. And the third is that that apolipoprotein lowercase A has these little things on it called kringle repeats, which are structurally homologous to plasmin. And so it's prothrombotic as a result. So some people hypothesize that having high LP levels actually was protective teleologically because it protected us from bleeding out. And so the pro thrombotic nature in the modern world, like so many other things, ended up being disadvantageous. And it's not selected out for because reproduction happens for most people before we develop cardiovascular disease. So that's sort of an aside. The way that I use that test, that LP test is, is it's a tiebreaker for a million other decisions that I make. And, you know, when we have drugs that are available to treat that condition or to treat elevated LP levels, which we should have RCT outcomes data later this year, later 2026 or 2027. And so when we have outcomes data, that will hopefully give us a direct target for treatment. But the way I use it in the real world is I use it in combination with somebody's family history. And so lp, most people have normal to mildly elevated levels. And there's two different tests. There's a nanomoles per liter test and there's a milligrams per deciliter test. And you should be familiar with that specific assay that you have and what the percentiles are like for that assay. But in general, a value of 150 or maybe 100 or over is something where I start to think of that as a real red flag. And especially when it's in the context of somebody in your family, especially a first degree relative with a heart attack or stroke before age 60, that LP being elevated is to me, a tiebreaker for all of those 50, 50 decisions. Should I treat your blood pressure of 134 over 82 with more medication? Should I add ezetimibe to your 20 milligrams of rosuvastatin? How much do I need to push the diet and lifestyle component of this? We didn't talk about at all what this person should be doing from what should this person be eating, how should this person be exercising? But it. That's a real. Those are really important things. And I talk about sleep and stress management and what someone's diet. I talk about that all day with my patients in clinic. But high LP is going to be a tiebreaker for me of do I put this person on a GLP1 agonist. And so I use it very much in the context of it's a risk enhancer and the amount that it increases risk is going to be proportional to just how elevated it is. And so it's not something we have direct targets to treat. And a lot of really smart doctors who I respect say, well, well, if we're not going to be able to do anything with that test result, why the hell are we ordering it? And that's a reasonable perspective. But to me, when I'm thinking about cardiovascular risk, I want to get the information that I can about things that raise that risk, because it's going to. Understanding the totality and the holistic perspective about how risky somebody is from a cardiovascular perspective influences how I manage. Manage all of those other things. And it influences the tone of my voice with my recommendations. Like, maybe that's all nonsense. I'm not sure I'm, like, open to being persuaded that I'm wrong, but it's definitely how I use that test.

A (42:41)

All right, I like it. I mean, I think that's on par with what the guidelines say now, too, is to use it as a. It's like one of the things we just factor in when we're sizing someone up and calculating their risk. And it's another data point that might push us towards a decision. So that's why I find it's useful to get for people.

B (43:06)

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A (46:01)

Paul Wirtz let's say we proceed to the calcium score. Do we have results of that? And then we can talk about it?

D (46:06)

Yeah. So we have a calcium score of 68 in this patient. So if we could maybe talk about why we ordered a calcium score in this patient. Like, we have this elevated apob, we have the elevated lp, we have all these other risk enhancing factors what may have driven us to order a calcium score. And then now that we have this score of 68 in this 46 year old, how do you interpret that? What counts as normal, borderline or high in that age? And then when you're putting that all together, how do you actually sequence treatment? So this patient, remember, is they're maximally motivated, they want to lower the risk as much as possible. How might you actually talk through a sequence of treatment for them?

C (46:45)

Yeah, so a coronary artery calcium score or a CAC score is a very, it's a very controversial area in medicine. And I think a lot of cardiologists have been very eager to sort of like jump on the bandwagon of get a lot of imaging. And there have been a lot of smart people who look at that as the cardiologists are insane because the RCT data just is not there to support that as an intervention. And I understand that perspective, but I kind of disagree with that perspective. And so a CAC score, there's two different types of imaging of the coronary arteries that we can do with CT scan. The first and most basic is a coronary calcium score or a CAC score that is a low radiation, zero contrast chest CT that basically looks to see is there any calcium buildup in the arteries around the heart. And I always tell patients, you've probably heard the term hardening of the arteries before. Well, a calcium score is looking to see if you have any signs of hardening of the arteries. And that tells you nothing about the degree of stenosis. It tells you nothing about the presence or absence of soft plaque. It tells you nothing about symptoms that somebody is having. And so a CAC score is a useless test for somebody who's having chest pain or shortness of breath or discomfort of any kind. The other test that can be done as a CT scan is a coronary cta. Coronary CTA is different than a calcium score because it uses contrast, because it has thinner slices, and because it can see Soft plaque in addition to calcified plaque. And so when you get a coronary cta, you are also getting a coronary calcium score, but you're also getting a whole bunch of different information. And I don't think it's worth, for the purposes of this case, talking about the sort of more advanced levels of what the coronary, coronary CTA can tell you. You can have these add ons from companies like Heartflow or clearly where you do either AI or fluid dynamic interpretation of the images to figure out is this a hemodynamically significant stenosis and how high risk are the features of the plaque. But the way that I think that those are sort of solutions in need of problems to solve right now. But the way that I use any kind of coronary imaging is it is telling me about the presence or absence of cardiovascular disease. And so for this 46 year old patient to see a calcium score of over zero to me is a gigantic red flag. I probably wouldn't have ordered a calcium score for a 46 year old because I would have expected it to be zero. And I would have expected that to be falsely reassuring for somebody who's at increased risk. And so if I see a patient who's under 50 or under like 55 if they're a woman, I think a calcium score has very little clinical utility unless it is unexpectedly positive. And so this test, seeing a calcium score that's elevated for this guy, like what a blessing that this is elevated. He hasn't had a heart attack because it's just adding to this litany of things that we know about this patient that says that he's at much higher risk than he would like to be from a cardiovascular perspective. And importantly, doctors misuse coronary imaging quite frequently. And it's really, really common. Where I see somebody who gets a calcium score done, calcium score is over a thousand, that leads to a stress echo. And there's something funny on the stress test. Or they get a nuke and the nuke has a mild inferior reversible perfusion defect. And then all of a sudden this patient is in the cath lab getting a stent that's not going to make them live longer or feel better. And so being aware of what the diagnostic cascade is and how getting this cardiovascular imaging sometimes tempts us into doing unnecessary procedures on patients is just a really, really important understanding for us to have of what are we doing with this test and what I'm doing with these tests. Any kind of coronary imaging is, it's Helping me understand how aggressively I need to medically treat somebody or whether I need to medically treat somebody. And so for this patient, when I see a calcium score of over zero, I'm like, holy crap, what a gigantic red flag. This guy is at really elevated risk. A 46 year old should have a calcium score of zero. If you're not sure what to make of the numbers, there's a couple of different ways that you can handle it. One option is the MESA database has a very good percentile calculator that you can literally type into Google MESA calcium calculator and the first link will come up. It's all built on the MESA study database, which is the multi ethnic study of atherosclerosis. And you can put in a patient's age, their ethnicity, their calcium score, and it will tell you and their gender, and it will give you their calcium percentile based on age and those other demographic characteristics. But to me, when I see a young person with any calcium, it is a gigantic red flag. For older people over the age of 60 or over the age of 55, I'm using the calcium score much more as helping me figure out is this person at higher risk than I would expect based on their age or they are lower risk than I would expect based on their age.

A (51:46)

That's a great overview. And the calcium score in my area is usually $300 or less. It's usually out of pocket test. My understanding is it's lower radiation and the coronary. The CCTA is a more expensive test, $1,000 or more and a higher dose of radiation. But I do have a lot of people getting calcium scores now, even before they come to me. Some patients are just getting them on their own.

C (52:12)

Yeah, the calcium score in a young person can be really falsely reassuring. And so I think it has almost no usefulness in somebody this age. In this case case, it clearly did have usefulness, but that's a surprising result. And so I often counsel patients who are young, like when I have a 42 year old, like I'm not sure the calcium score is going to be all that helpful. And If a coronary CTA was covered by insurance and it didn't cost them 1,000, or if they're at an academic center, it's probably like $2,500 out of pocket. It would be a test that I would use for my young folks who I want to better understand their cardiovascular disease. But in practice, a coronary CTA is covered to evaluate symptoms of chest discomfor or persistent symptoms after A stress test has been unrevealing. It's not done as a preventive test. I'm not sure that that's where we'll be in 10 years, but that's where we are now.

B (53:04)

It's kind of lightly alarming to hear that framework because I would suspect that the CAC score is being ordered for younger patients. Right. Because as you mentioned before, if you're using risk calculators, we believe there is utility that's going to be driven by age. So the person who is older just by the calculator, they're more likely to actually have a risk score that would actually put them on statin therapy in the first place. So the typewriter breaker seems to me to be used more frequently in sort of younger patients. And if this is underestimating risk, that's a. Seems like a concern, I guess, is all, is all I'm saying here.

C (53:32)

The Steelman argument for using a CAC in young patients is that so much about what we do in medicine is trying to figure out the tiny fraction of people who are really vulnerable at elevated risk from like the huge swath of everyone else who's going to do fine, even if the doctors don't do a great job of taking care of them. And seeing a calcium score of over zero in a young person is a truly alarming finding. And so maybe it's actually that's the Steel man case is that it's helpful for identifying the highest risk cohort. But to me, I would want to be treated very differently medically if I had plaque in my arteries versus if I didn't have plaque in my arteries. And whether the plaque is calcified or not calcified is part of what I would want as the sort of comprehensive understanding of disease. But it's not the only definition data point.

A (54:20)

So, yeah, so I, I want to try to summarize for the audience just to see with the CAC score specifically. So, because I'm seeing sometimes people in their. I don't, I don't think people in their 30s need to get them unless maybe they have tremendous risk factors or something and you're expecting it to be positive. But I'm seeing a lot of patients in their 40s just proactively getting it now because of the social media environment, the podcast environment, these sort of like Rogan Sphere podcasts and things like that, some of those people are just telling everyone they need to get a CAC score. So people in their 40s, if the CAC score is positive, that's alarming. We should aggressively manage risk factors, medications, whatever. If it's someone we're worried about and it's a zero calcium score, then maybe the plaque is there, but it's just not calcified. So we might even consider a CCTA day for those people. If they're in their mid-50s or above. A calcium score is a good starting point. And then if someone's in, like, their late 60s or 70s, in my opinion, if they, like, I'm expecting those people to have calcium. Right. So does it become like, is there like a certain sweet spot age range where you think, is it like 55 to 70? It makes sense. And then once they're 75 or older, I haven't really thought to get calcium scores in those folks.

C (55:42)

So I'll give you a clinical anecdote of how I've used a calcium score in an older patient. And so I take care of this woman in her 70s. She has had really, really high lipids for decades of her life. Her LDL fluctuates between, I think, around 160 and around 190 without treatment. And she has failed every medication that we have. She has had side effects from, from four different statins, from ezetimibe, from bempedoic acid, from PCSK9, from two PCSK9 inhibitors. I don't use inclisiran because there's no outcomes data for it. And it's like, truly, until there's outcomes data for a drug that doesn't treat an orphan disease, I'm just not ready to prescribe that medication. But this patient failed all of these therapies, and her LDL is still really quite elevated. And so, so what I used the calcium score for her was, I wanted to know, like, is her cal. I think she was around 74 when we got the calcium score. If her calcium score was 1000, I would have tried to figure out an alternate day statin dosing regimen or something that was really sort of like trying to be creative to get the lipids down. Maybe I would put her on crazy doses of psyllium fiber supplements to try to bring those numbers really quite a bit lower.

A (56:58)

Nattokinase.

C (56:59)

Yeah, nattokinase is really interesting, and I don't think we have time to talk about it, but truly fascinating to me.

A (57:06)

That'll be a part two.

C (57:07)

Yeah. So how I use the calcium score for her. So her calcium score was like 2, and she's in her 70s. And so to me, what that does is that lowers the temperature on how we need to worry about her lipids. And so I used it as, again I use it like a little bit as a tiebreaker of do I need to really do something for this patient or can I just leave her alone and tell her like, like ignore the lipids, like don't take medicines that make your life totally miserable. And so I used it in the latter case, but you know, if it had been really high, I would have been stuck in a not wonderful position. But that's how I use it for an older person is a de escalation rather than an escalation.

A (57:43)

Yeah. Okay, so the middle, in middle age, that's probably the sweet spot for using it. Yeah. Okay, Greg, so you mentioned a bunch of meds there in the context of talking about your, your older patient or you tried kind of all, all the meds on for someone like Art, who we presented initially here. This is our 46 year old guy. Metabolic Syndrome. LDL was 123, his APOB was 127. LPA, LP was 80 nanomoles per liter. So how might you talk to him and what's your framework for talking to patients about cholesterol lowering medications, cardiac risk medications?

C (58:23)

So honestly for this patient, you could make an argument that he should go on a GLP1 drug before he goes on a lipid drug. That's, you know, we don't have data to really understand that, but you could, you could certainly make a pretty compelling argument that if you're going to pharmacologically treat patient who has metabolic syndrome, sleep apnea, abdominal obesity, that you're better off actually treating something that is going to probably lower his lipids also. And so it's a reasonable strategy. But, but in the purpose of talking about the lipid conversation, statins have the most data. They're really well tolerated medications. What you hear on the Internet about statins is so different than how every doctor who takes care of patients and who makes decisions about their own medical health would think about statins. And so I look at statins as it is my first line, 8 to 10% of people have some type of muscle ache. I'm not one of those nocebo guys who thinks it's all nonsense. I take patients at their word when they have side effects from medications. And these are artificial substances that people are putting into their body. People are allowed to have whatever side effect they damn please. And so I never question a patient about whether a side effect is real. And if they have side effects, I just take them off of a drug. And if somebody has side effects on one statin, I usually use rosuvastatin. I usually start at 5 milligrams to begin with. I'll switch to atorvastatin. If somebody has side effect, I'll start at 10 milligrams of atorvastatin and sort of like go up as needed. But if somebody has side effects to that, I will either start them on azetamine or I will think about using Pitavastatin. Brand name is Livalo for that. And what's nice about Pitavastatin is it comes in a 1mg pill. And so for patients who are medication averse, 1mg for whatever reason feels like it's a lot less significant than 5mg or 10mg. And my biases go in weird directions too. So I don't necessarily disagree with that. But pitavastatin is the statin that has the lowest incidence of statin induced myalgias. And so it's a very reasonable option for a lot of of folks. Ezetimibe, 10 milligrams once a day is a very useful adjunctive treatment. My clinical experience is that the response to that drug is so heterogeneous that I've had some patients who their LDL drops by 50%. I've had other patients where the LDL drops by basically nothing when you put them on ezetimibe and probably has to do with the polymorphisms that relate to cholesterol absorption in the intestines. And so with all of these medications, the responses that people have are heterogeneous. And so I put people on medicines, I monitor how they feel on those medications, and then I monitor what their lipids are to decide is this working, should we augment it? Somebody not feeling good on it? Bempedoic acid is actually my last line drug. It's sometimes nice because it's a pill and it doesn't work in the muscle, it only works in the liver to inhibit cholesterol synthesis through a different enzyme than than HMG, CoA reductase. The issues with bempedoic acid, one is it's not that potent. Two is that it can raise uric acid levels and it can raise transaminase levels. So you should monitor those things. And it's also just a real challenge in the real world to get coverage for it. And So I use PCSK9 inhibitors quite a bit more frequently than I use bempedoic acid. The limitations for PCSK9 inhibitors are two real ones. One is it's an injection, and some patients don't like needles. Two is that insurance coverage can sometimes be problematic, although that has really changed over the last, like, three or four years. And it's much easier in practice to get PCSK9 inhibitors approved than it used to be. For me, there's two PCSK9 inhibitors that you can use. There's Evolocumab and there's Alarocumab. Evolocumab has done such a better. The folks who make that medication have done such a better job of getting it on formularies that it's almost always the preferred medication. You know, it's interesting if you look at the initial data. Sorry, am I talking too much about this?

A (62:09)

No, this is fantastic.

B (62:10)

Yeah, keep going.

A (62:11)

Paul Williams looks like he's really. He's thrilled.

C (62:14)

Yeah, it's really. It's kind of fascinating, actually, to look at. The first RCT is looking at the PCSK9 inhibitors, because there was Fourier, which studied Evolocumab, and then there's Odyssey Outcomes, which studied Alarocumab. So Fourier had this signal for increased mortality in the Evolocumab group. Like, there were more people dead in the evolocumab group than the placebo group at the end of that trial, which was odd because it certainly lowered major adverse cardiovascular events. And so there was cons. I had some real concern after that first generation of studies came out about whether Evolocumab was actually a worse drug than Alarocumab. And so Alarocumab had a mortality benefit in Odyssey Outcomes. And so it seemed to me like. Like when we have a choice between those two, that's the one that we should use. And then Vesalius came out not that long ago, I think late last year, which was an interesting study looking at patients who were primary prevention but had clear evidence of dyslipidemia, metabolic syndrome, and were already treated with statins. Not very many of them were on Ezetimibe, but a fair number of them had elevated coronary calcium scores. And the Vesalia study really sort of laid to rest my concerns about the signal for potential increased mortality with Evolocumab. And so that ends up just being what I use more of the time, mainly because coverage is a lot easier. And in the real world, those practical things really matter. PCSKNI inhibitors are super well tolerated. I've had one patient with an anaphylactic reaction and a handful who had. Who had sort of injection site reactions. But those side effects are very, very rare. And as an aside, if you have somebody who has an anaphylactic reaction to one. Every allergist and pharmacist that I've talked to recommend not putting them on the other PCSKN inhibitor.

A (64:02)

And I still get some people worried about the LDL getting too low with that. And we need some cholesterol. And we covered on one of our hotcakes episodes, we covered the studies kind of looking at like the, you know, cognition and does this seem to cause any problems? And it doesn't seem to cause any problems as of yet.

C (64:23)

So. But vascular dementia is a very real cause of demonstration dementia. And the vascular hypothesis of Alzheimer's is a competing hypothesis to the amyloid hypothesis of Alzheimer's. And so when patients tell me they're worried about the cognitive side effects, especially patients who I already see evidence of plaque in their blood vessels, I tell them, I'm so much more worried about you developing vascular dementia than I am about you developing statin induced dementia or lipid, like low LDL related dementia. And so the real risk in the real world world is very much, to me much more related to vascular events than it is to this theoretical possible hypothesized conjecture that has never really sort of been replicated in real world studies.

B (65:05)

Can I ask one more question, madam? I am seeing locally a lot of consideration for patients who are pre diabetic in terms of statin selection. And I'm wondering if that impacts your choice of statin for someone who's for some Mr. Sclerosis from her his a1c is 5.77. You mentioned you tend to lead with the high potency statins, which I think are more likely to kind of advance A1C. Is that a consideration or how do you think about that when you're prescribing?

C (65:28)

Just one of the folks who trained me, he would say if you get diabetes from a statin, you are a Snickers bar away from getting diabetes anyway. And so statins will raise your A1C by 0.1, maybe 0.2. I look at that side effect as the same way that I look at the side effect of muscle aches, which, which is if you get it and it seems to be problematic, then we just switch the medication. And I think that we put too much emphasis on making the decision, a very high stakes decision. And so patients have all kinds of different perspectives about statins, especially the most informed folks will often come in with the strongest perspectives. And my goal of that first conversation, I just want to lower the temperature of how big a deal this is. And how important or life changing of a decision and going on a statin is. And so like, yes, your A1C may go up, but like overall your risk is gonna go down. You don't get extra points at the pearly gates for having an A1C at 0.1 percentage points lower.

B (66:26)

Oh, don't say that. That's why I tell my patients to get them below their A1Cs.

A (66:30)

Wirtz, let's go to our next case because I think we have a contrasting patient here.

D (66:37)

Yeah, so this patient from the doorway looks very healthy on paper. So we've got Ms. Lola Lipa. She is a 38 year old runner. She does about 30 a week. Her BMI is 22. She has normal blood pressure. Her A1C is 5.2. Her LDL is 77. Triglycerides are 70. On paper she looks incredibly low risk. But you find out that her father died of heart disease when she was young. She had a brother who had an MI at age 41. So her informed primary care clinician digs a little bit deeper, finds out that her LP comes back at 220 millimoles per liter and an APOB of 95. So she's saying, my LDL is great, fitter than almost everyone I know. Why am I high risk? How do you use a case like this to explain the limits of lifestyle for LP specifically? And even with these excellent habits, can biology still drive the risk? And how do you think about lowering her risk if she's already doing everything right, so to speak?

C (67:40)

This patient, a young person who takes really good care of themselves, is interested in, in all of the sort of like lifestyle interventions that lead to really good quality of life for a lot of patients. But her family history is insanely alarming. Her father died when she was young, her brother had a heart attack when he was 41. This is the exact patient where a risk calculator does them a total disservice. And so, you know, an LP of 220 nanomoles per liter is a really, really high LP Little A. And you add in that LP Little A LA along with her family history, and this is a patient who is coming to medical. She's really lucky that she's coming to medical attention because this is a very, very scary family history and lab data that we have. And so for somebody like this, it's really tricky because we don't have a ton of levers that we can pull to lower risk. Like we can't change her genetics. She doesn't have Metabolic syndrome. Her blood pressure is well controlled, her LDL is not even that high, and her APOB of 95 is really driven by that LP level little A. And so this is a patient who I do two things. For one thing is I really sort of have a focused conversation about this is what your genetics are. And I think that those genetics are real and they're concerning because of what has happened to these two relatives of yours. And to me, the right time to act is this second. It's not something where I would even try to wait for imaging. Sometimes you'll use imaging in a patient like, like this to try to persuade them about treatment. But to me, this is somebody who we should be treating pretty quickly. And when I have somebody who has a pretty well controlled LDL or pretty well controlled apob, but has elevated risk related to something that I can't modify, how I approach it is I tell that patient, look, we don't have a ton that we can do, but I know for sure that your risk will be lower if we get your LDL down to 50 and your APOB down to 65. And I don't think I'm going to get the help the APOB down to 40, 40 because it's just driven by the LP. But I'm gonna try to lower those numbers to much lower than I would want them for any comparable person because of what this person's family history is like. And this is also the type of patient who I would think about for primary prevention. Aspirin, high lp. Remember, LP is pro thrombotic and she has had multiple first degree relatives who have had premature mis. And so there's probably something that is pro thrombotic about the phenotype of their lp. We don't have assays to figure out the Kringle repeats and how actually thrombotic robotic they are. But to me, this is somebody who I really think about aspirin for primary prevention. And your limitations for that are going to be how much does she bleed during her menstrual cycle? Does she have baseline anemia? But this is somebody who I would truly consider as being an important patient to think about aspirin for primary prevention. The other thing that you need for a patient like this, a young woman who has a cardiovascular disease history, is you need an obstetric history because that's an important part of your risk assessment. You need to know infertility, you need to know pregnancy complications, preeclampsia, gestational diabetes, gestational hypertension, that she have pcos and even young thin people can have all of those conditions. And those are important because those are risk enhancing pieces of information. And when you're trying to understand somebody's risk, you should understand their risk as holistically as possible.

A (71:03)

So if she said no, I'm not going to take any medication unless I have more evidence. I'm not just going to go off one piece of data. Data. Is she someone you would get a calcium score.

C (71:14)

I would order her for a coronary CTA and I would push her really hard to tell me about some. Everyone's had chest discomfort at one time or another. And so I would ask her to tell me about a time when she had chest discomfort and I would write that she had chest discomfort in her chart and I would order the coronary cta.

A (71:30)

Yeah. Okay.

C (71:32)

I want to know if she has soft plaque. And like I, I fully. That is not a guideline. Recommended perspective and, and reasonable smart doctors are going to hear me say that and are gonna think I'm like absolutely nuts. But for me, if that's something, if looking at imaging of her arteries is gonna be something that would persuade her to go on medical therapy, to me, I'm doing her a disservice if I don't get all the data that I can to convince her that medical therapy is right.

A (72:01)

Yeah. Okay. Paul, did you think he was gonna say aspirin, statin and C for this case? Paul Williams.

B (72:13)

Oh, no, I did not.

C (72:15)

I wouldn't order the CCTA unless she was telling me that she would only go on treatments if there was stuff in her artery. I don't come at patients and say you need a ccta. I come at patients and I try to understand holistically what their risk is. And the most important teaching point from this case is a risk calculator. Absolutely. Misses the boat for.

A (72:36)

Yeah, no, I'm picking up what you're putting down. I mean, I'm following. I think it sounds reasonable to me and I think it's like aggressive primary prevention. You're trying to make sure that this person doesn't have a life changing cardiac event which happened to her brother just a couple years older than her. So I get it. Let's go on for interest of time. We have another case here.

B (73:01)

Here.

A (73:02)

Paul Wertz, do you want to get into our final case and we can use the rest of our time going through that for a few minutes?

D (73:10)

Yeah. So let's talk about Gary. We got a 42 year old veteran. He comes in for his routine Visit. His BMI is around.

B (73:16)

Let me pause for one second here. I'm sorry, Paul. We have Paul, we have art, esclerosis, and then we have Lola, like. And now we're doing Gary for this case. Where did Gary.

D (73:31)

Gary is like the macho.

B (73:32)

What happened? You're writing this? Just ran out of steam towards the end, huh, buddy? Sorry. Go ahead. All right.

A (73:42)

I thought you were going to say that your cat was going crazy. We needed to pause that because Ollie really. Ollie's really been vocal. If people are watching the YouTube video, Ali's been all over the place and has been meowing pretty aggressively for the past 15 minutes.

D (73:57)

So probably also pretty passionate about primary prevention. Sure.

B (74:01)

Sorry to interrupt. So sorry. Carry on.

D (74:03)

All right, so gary, he's our 42 year old veteran. He comes in for a routine visit. His bmi is around 25. He looks fairly muscular. He says he goes to the gym regularly, but he's under a lot of stress and usually sleeps about six and a half hours per night. His blood pressure has been running in the 140s without meds. When you look at his labs, you see an A1C of 5.5. But his triglycerides are 210. His HDL is low at 38 and his LDL is high at 187. Gary is very interested in maximum health and longevity. He wears a continuous glucose monitor from time to time and he uses a health ring to to track his sleep, his heart rate variability and recovery, among many other variables. Variables he noticed that oatmeal or fruit will push his glucose up to around 160 postprandially. So he then cut carbs aggressively. Now he eats mostly bacon and steak for breakfast because he likes that his CGM stays flat. So what Gary is really asking here are whether markers of insulin resistance like a homa IR matter more for long term health than his lipid profile and how much weight he should be giving this CGM data compared with his lipid profile panel. So let's say his APOB is 190. His LP is 37. So low on the LP, he points to his A1C of 5.5 and his improved CGM patterns after the aforementioned dietary changes as reassurance that he is very metabolically healthy. But you see that his triglycerides are over 200. His HDL is low. So considering that there may be some underlying insulin resistance present even with his, quote, normal A1C for a motivated patient like Gary, is there any value to checking like a fasting Insulin or a homa IR or can you just use the triglyceride to HDL ratio to spot the danger?

C (75:56)

This is such. There's so much to unpack in a case like this. There's just so many layers of it. So when somebody gets a lipid panel and the triglycerides are high, the first thing that you need to do is ask the patient whether or not they were fasting, because fasting versus non fasting is going to impact triglycerides more than any other parameter in the lipid panel. But presuming that that is a fasting lipid panel and the triglycerides are high, the HDL is low, A1C is kind of like creeping up. It's not in the pre diabetes range, but it's certainly at the higher end of the normal range. Whether the metabolic syndrome question. Question is an interesting question in a patient like this, because to me, it's not clear from the data we have how worried we should be about metabolic syndrome. I think that I probably am, but I'm not sure how accurate that is. And so, you know, is a fasting insulin an important piece of information? It's not a vital piece of information, but it's a data point because people will get elevated fasting insulin before they develop overt hyperglycemic homa ir. It sounds like a really fancy test, but it's basically just an equation where you plug in fasting insulin and fasting glucose. And so whoever came up with that is pretty good at marketing because it sounds like it's such a big deal more than it actually is. The triglyceride to HDL ratio is a great tool, and it's notable that it's over. It's like five to one in this patient. But that's not going to be perfect for everybody. In particular, folks who identify as African American American often have a higher HDL than you would expect and do not manifest with the elevated triglycerides as often as you would expect it to. And so in a patient who identifies as African American, I often don't treat that ratio as being as important as some other patients. But, you know, like, there's a ton of inter ethnicity and interracial variation. And so you can't necessarily say that one person fits into the entirety of the cohort. And remember, metabolic syndrome is a spectrum. And so you're trying to figure out where on that spectrum as somebody. And so I think a fasting insulin is a totally reasonable thing to check for a patient like this as part of your understanding of does this patient have metabolic syndrome? You also didn't give us the transaminase levels. And so if his alt was 48, to me, maybe he has metabolic associated fatty liver disease. And we actually do have evidence of elevated, like sort of manifestations of elevated visceral fat. And we didn't sort of talk about the visceral fat versus subcutaneous fat. Discussion. But a lot of insulin resistance and a lot of metabolic syndrome really comes down to do your genetics mean that you have a higher depot of subcutaneous fat versus are you more likely to store your excess calories as visceral fat? But what's interesting about this guy's diet and the way that it's interacting with his CGM is a little bit of a Rorschach test about what do you think about saturated fat? And so I think officially, RFK just ended the war on saturated fat. So we're not at war with saturated fat anymore, which is is, I think, good news for everybody. But the saturated fat question is really, really interesting because saturated fat in our diet is going to impact fluidity of our cell membranes, and that's going to impact what happens with the residence time of our atherogenic lipoproteins. And so part of the reason that saturated fat got a reputation for being linked to increased cardiovascular risk is because people who have a diet that's higher in saturated fat, saturated fat on average will have a higher total cholesterol and a higher LDL cholesterol. And that's probably linked to the way that the LDL receptor sits on the surface of hepatocytes differently depending on membrane fluidity, which is influenced by fatty acid composition in our diet. That said, whether you think saturated fat is uniquely problematic because of its lipid effect, or whether you think that it is more concerning because of the way that saturated fat is more likely than polyunsaturated fat to lead to hepatic steatosis. And whether there's untold biological mechanisms that we don't fully understand of why that might be more problematic, I think is still something that needs to be elucidated. Whenever anybody tells you I understand the mechanism of this, and so we should do this thing because mechanistically it makes sense and you start falling in love with the biology that is a recipe over and over in medicine for just make making a total error in judgment, because mechanisms are always more complicated than we think that they are. And so I tell my residents all the time, like, don't fall in love with the mechanism. Do not fall in love with the biology. Pay attention to what the outcomes data look like. And this question of, is saturated fat worse for you than polyunsaturated fat sort of like bleeds into the seed oil question. And like, there's a lot of things that are going to be part of this patient's social media diet that are going to influence a lot of your conversation. And so you probably are not confronting every single one of these questions with this individual the first time that you meet them. And I think that it's for somebody like, like this, he's very plugged in. He's asking these questions that suggest that he's pretty well informed and he's paying attention to this. For a patient like this, I kind of just order whatever they want me to order. And I trust my ability to interpret what those lab tests are going to. To tell us about this person's health. And, you know, whether the keto diet, which leads to a really high LDL cholesterol, is atherogenic is a question that I think we have pretty good data to understand. I don't know if you're all familiar with the keto CTA study.

A (81:24)

Yeah, I was fascinated with it. I think you wrote about on your substack, right?

C (81:27)

Yeah. So that study was. It's basically they took patients who were. The term that they use is lean mass, hyper responders, which is a marketing term that basically means somebody who eats a low carb diet, does not have diabetes, loses weight, probably feels pretty good, but their LDL goes up really high. And the question that they asked was, if we do a coronary CTA on these patients at times zero, and then we repeat the coronary CTA a year later, what do we see in terms of progression of subclinical cardiovascular disease? And what they found is that the rate of progression of cardiovascular disease in this cohort of patients was basically as fast as any cohort of patients that's ever been studied in terms of progression of subclinical atherosclerosis. And so maybe that is mediated by the fact that these diets tend to be high in saturated fat and that tends to raise the ldl. But I don't know that we understand that mechanism with the precision that we need to say definitively that is why. So I look at it as that is an atherogenic diet. And if that is your phenotype, low carb, high fat, and you have a really high LDL response as a consequence of that, that's probably putting you at elevated risk for cardiovascular disease. And the question of whether you can just treat somebody's lipids and keep them on the diet that makes them feel good, I think is a question that we don't really know the answer to. But in general, general patients are going to eat what they want to eat. And you know, the amount of, the amount of influence that a doctor has over this decision that somebody makes two to three times a day, every day of their life. I'm under no illusion that the things that I say are going to drastically cause changes. And I also feel like a lot of patients who are marinating in this, this ecosystem of wellness and longevity are distrustful of doctors. And my experience with it is that a lot of the time they think I just want to like, throw them on a statin and I want to ruin their metabolic health. And so I come at all of my decisions of like, the patient needs to understand that I have the same goal that they have, which is I don't want them to have a heart attack, I don't want them to have a stroke. And I read everything. I'm constantly learning about this stuff. And I communicate to patients our goal is the, the same. I get paid the exact same amount of money whether I put you on a statin or I don't put you on a statin or I put you on a GLP or I don't put you on a glp. And my salary is not influenced at all by any of the prescriptions that I give to you. And I'm going to give you my gen. My, my true medical perspective based on my read of the data. I'm not going to synthesize something that chat GBT told me. I'm not going to copy something from social media. I'm going to look at your data and I'm going to read the literature and I'm going to come to a conclusion solution about what I think is the recommendation that I have for you. And so, and I think if you. And again, like, coming back to like that soft side of medicine, if you don't talk to patients like they're adults and that you are on the same team and you try to pretend that you know better and they're missing like that to me is just like one. I'm wrong about things all the time. And I don't presume that I have all the answers, but I do think that patients respond well to the idea, like, we are on the same side, we both want the same thing, which is for you to feel good and for Nothing bad to happen. And so for somebody like this, I think that you can interrogate whether he has metabolic syndrome. You can check his transaminases, you can get a fasting insulin level. You can look for a hepatic ultrasound or a fiber scan to see if there's any evidence of a fatty liver. But high triglyceride to HDL ratio, low hdl, you know, he has high blood pressure. He probably has metabolic syndrome to some extent. How much is that dictated by the fact that he's under a ton of stress, he doesn't sleep very well. How much of that is that? He probably lifts a lot of weights and doesn't do much cardio. And would he benefit from more aerobic activity? Like, there's a lot that you can do from a lifestyle perspective that doesn't involve any medication. And, like, are we sure his BMI is 25? Are we sure he doesn't have sleep apnea? Does he wake up feeling rested? Like, does he need a sleep study? Study, like, people who work out a lot sometimes have thick necks, sometimes have sleep apnea. That's undiagnosed. And so I think you can do a lot of different things for this patient. If you're asking me, like, what would I do for somebody like this who was basically like, doctor, I will do whatever you want, what I'd probably do is I'd put him on a lipid lowering medication. I would treat his high blood pressure.

A (85:46)

Yeah, we're gonna need to start wrapping up here. But for, for the audience, there's this group of people that are eating the carnivore diet. If you're not familiar with it, where they're. They're mostly just eating meat. So it's a very high saturated fat diet. And there's a number of these people, and I've come across some of them in practice. That's when I first learned about the carnivore diet. Is somebody who had a normal total cholesterol. His total cholesterol went up to 500, and his LDL went from 130 up to 300 on this ketogenic kind of high fat, high meat diet. And this was a guy in his 30s, and he was saying, oh, it doesn't matter. I have a zero calcium score. But as you told us already, we expect a zero calcium score for someone in the their 30s. And if the longer that you're exposed to the higher cholesterol, the more we think that you would be at risk for atherosclerosis. So that's why that study was done. Right. So they're saying, okay, for these people that do have that response, does it matter? And right now the only study we have seems to suggest yes, there is some increase atherosclerosis, increased pace of it, even if it's subclinical. Is that a fair summary of.

C (86:57)

Yeah, that was a totally alarming study. It suggests, suggests that this is a very atherogenic phenotype. And so, yeah, I was really surprised by what that data looked like.

A (87:05)

Yeah. So we can link to your sub stack on that one. And I understand why a lot of people like that diet or like those very restrictive diets because maybe there is something that they were eating, maybe they have some food allergy or intolerance. And when they go on that very restrictive diet, they're no longer exposed to whatever was bothering them, so they feel better. And of course, if they're wearing a cgm, they're going to get beautiful readings on there because they're not really causing glucose to spike. So anyway, I think that's an interesting thing that we could do a full episode on just that topic alone. But Paul Williams, before we go for take home points, do you guys have any other questions about this specific case?

D (87:54)

No, I think we covered everything. I think in a very interesting point is that with that CTA study they measured one year, which I feel like is not very much time. Right. Like this is potentially decades.

C (88:06)

Crazy short. Crazy short time.

D (88:07)

Crazy short time. So I feel like that just further emphasizes that point.

A (88:12)

Yeah, we did a lifestyle medicine episode where we talked to a doctor at Duke who treats people with ketogenic diet and we talked about the lean mass hyper responder and how we at this time we don't really know. But I believe the conclusion from that, or at least my conclusion from that and how I practice is if someone's on a ketogenic diet and their lipids look okay, you know, it's not as concerning, but if their lipids spike up like that, I'm looking for it and we're going to change course. So as far as we have the evidence right now, I think that's where it's at. Concur, Greg, we talked about so much here and we'll have to have another conversation because I know the well of knowledge for you in this area is really deep and we could keep, we'll keep monitoring the substack for more interesting things to talk to you about. But what do you want people to remember from this conversation? Like two or three take home points?

C (89:10)

Cardiovascular disease is largely prevented preventable risk calculators miss young patients who are at elevated risk and you need to meet patients where they are and understand who the human is, not just what the risk calculator tells you.

A (89:25)

Anything you want to plug, we'll give you a chance to plug. Maybe a podcast that you appear on. That's very good. I would say great.

C (89:32)

Oh thanks. I do the Beyond Journal Club podcast with Core I am and the NEJM Group and and subscribe to my substack all right.

A (89:41)

Greg KatzMD yeah, strong recommend.

B (89:49)

This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole

A (89:57)

holes.

B (90:00)

I was praying that words would jump in with a yummy but nope. I had to settle for for why I was saying holes. Still hungry for more generated.

D (90:07)

Sorry, can we do that? I said it.

A (90:11)

Keep this all in.

B (90:13)

Keep all of this. All right. Still hungry for more. Join our Patreon and get all of our episodes ad free plus twice monthly bonus episodes at patreon.com curbsiders. You can find our show notes at the curbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice, changing articles, guidelines and news in internal medicine.

A (90:31)

And we're committed to high value practice changing knowledge and we want your feedback. So please email us@askcurbsidersmail.com a reminder that this and most episodes are available for CME credit for all health professionals through VCU healthcurbsiders.vcuhealth.org Special thanks to our writer and producer for this episode, Dr. Paul Wertz, and to our whole Curbsiders team. Our technical production is done by the team at Podpaste. Elizabeth Croto does our show social Media. Jen Watto runs our Patreon. Krista Chu Manchu moderates our Discord. Stuart Brigham composed our theme music and with all that, until next time, I've been Dr. Matthew Frank Waddo.

D (91:06)

I've been Dr. Paul Wertz and as

B (91:08)

always, I'm Dr. Paul Nelson Williams. Thank you and goodbye.

C (91:29)

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Are you one of those people who sometimes uses words? Do you communicate or acquire information with, you know, language? Hey, us too. So join us on Lexicon Valley to true over the history, culture and many mysteries of English, plus some rice cracks. Find us on one of those apps where people listen to podcasts.