Now,

cholesterol-lowering medications, particularly statins being the most commonly prescribed type of medication in this area play a pivotal role in reducing LDL cholesterol concentrations and then also therefore ApoB concentrations as well. And when we look at LDL cholesterol or LDL particles or ApoB, these are causal markers in atherosclerosis development. Now the efficacy of these medications is well documented with numerous clinical trials demonstrating substantial benefits in reducing cardiovascular events and improving overall mortality rates. But despite the robust evidence supporting some of these benefits for cholesterol-lowering medications, there are still a variety of misconceptions and misunderstandings about their use. And back in episode 525 of the podcast, I discussed this topic with preventative cardiologist Dr. Patty Barrett, where we looked at the different types of lipid-lowering medications, the mechanism of action of each of those, the potential side effects that may occur, and then the misconceptions about some of these drugs that are unfortunately somewhat widespread. In this particular clip he talks about his framework of risk factor disease event as a way to help patients understand this relationship as well as offering what he sees as some ideal lipid targets depending on someone's intended risk reduction and their tolerance for how much they want to really push that risk down? The

model that I try and emphasize to my patients, or I always think of in my head, is we need to think of three separate categories. When you think of risk factors, we need to think of the disease, which is coronary artery disease or atherosclerosis, and then the event, so a plaque rupture, which is a heart attack. Now, ultimately, the goal is to reduce events. But if our goal is to reduce events, we need to minimize the plaque burden, because we know that the more plaque you have, correctionally, the higher your risk of an event. And we also know that you can't die from a condition that you don't have. So therefore, if you also look at the healthy centenarian population, they die from the same thing as everybody else. Basically, cardiovascular disease, cancer, and dementia. The key difference between them and Oz is they get those conditions 20 to 25 years later than everybody else. So it's not that they actually die from different things or they don't get common traditional diseases. They just have a phase shift in the timing of the onset. Now, a significant reason for that is obviously a genetic component. But if you think of that as your model, then you have to say, listen, I have to really overemphasize my management of my risk factors because everyone given a long enough time horizon will eventually develop coronary atherosclerosis. So if you manage your risk factors very aggressively, early, and for long enough, you can then create a similar phase shift in terms of the timing of onset of coronary atherosclerosis and the accumulation of that burden of atherosclerosis, which ultimately then drives your risk of an event, which is a heart attack. Because heart disease basically happens to everyone, but heart disease happens slowly, but heart attacks happen suddenly. But the thing is that you're always trying to minimize the burden of atherosclerosis to minimize the thing that is likely to kill you, which is the heart attack. So the goal is, I say this to my patients and it's for myself, is to live a long and healthy life and die old with coronary artery disease rather than from it. And so that's the model. It's the three things. It's risk factors, disease, event. And we're always trying to think of the categorization of each of those things. So

if we are looking at that, in this case, if we're talking about APOB, and we want to have a reduced burden of APOB over time is going to reduce that risk. And this gets into this interesting area of thinking about those targets on two levels. And we don't need to necessarily get too deep onto this because these could be full podcasts in a mob themselves. But one would be relating what those that maybe you might ideally like to see in your patients for something like ApoB versus either, not even what reference ranges might be, because a lot of the times, probably a lot of people listening are more familiar of thinking about their LDL cholesterol number as well. And so in relation to those two things, where should we be aiming? In other words, if we're trying to reduce this risk over time, if we're looking at either LDL cholesterol or maybe someone is able to get an ApoB test and can look at that and any of these distinctions in between that you might think are useful for people to know. Yeah.

So again, the way I always frame this with my patients is I always ask them what their goal is. And so if your goal is to maximally reduce your risk of coronary artery disease and by ultimate extension, a risk of an event, and how aggressively you want to approach that, then we need to have much more aggressive targets in terms of our earlier approach to this. But if your goal is to do as little as possible, and you're not that willing to escalate up from, say, a lifestyle intervention to the addition of a medication, then we have to be honest about our expectations. So for me, it's always calibrated against what is your goal? And where is your level of risk tolerance on this? Because you have to make your bet at the start, and then you have to ask yourself whether you're all in not. And so my view on this is it's like Charles Bukowski. If you're going to do it, go all the way. And so with that in mind, you then have to say, listen, if I am looking to reduce my risk as much as possible, do I have any evidence to support that if I can achieve an ApoB level or an LDL level or non-HDL level, and I can maintain that level for the majority of my life, that it is related to a minimal accumulation of plaque. And typically that is in the order of less than the fifth percentile in the population. So you're talking at least an ApoB of less than 0.6, you're down at LDL levels of less than 1.4, and at least a non-HDL of less than two. And so all directionally, you're at very low percentiles in the population. But the reality is that is the case for a very small number of people in the population, as illustrated by the fact that it's the fifth percentile in the population. And so for many people, if they want to achieve that cumulative total lipid burden that is minimized over time, they will have to be very aggressive with either their, say, dietary strategies that they use, depending on the range that they would need to get down to those targets, or if they're willing to, in addition to that, use a lipid lowering therapy like a medication as an adjuvant to that approach to get there. And so it really then comes down to what is your risk tolerance, what is your desire, and what is your objective. And then the last thing that is the most critical to consider is over what time horizon? Because if you run an ApoB concentration at above the 99th percentile for 50, 60, 70 years of your life, and then you say, listen, well, now I'm going to minimize my plaque burden and I'm going to go to the less than the fifth percentile. Yes, will have achieved your lipid parameters at less than the fifth percentile, but your total lifetime cumulative burden will still have been exceptionally high. And so it will potentially advantage you, but not as much if you've actually minimized that lifetime burden. And we know, again, from various different interventions, we know that from randomized control trials, running these very low lipid targets results in a 20 to 30% reduction in events on a relative basis. But that is really looking at time horizons over three to five years. Observational data looks at a 40 to 50% relative risk reduction. But again, you're looking at 10 to 12 years. And then when you look at Mendelian randomization data, you're looking at 70 to 80% reduction, but you're looking at time horizons of 50 years with that. And so we have to obviously understand the limitations as we move from a randomized trials up to Mendelian randomization and observational data. But all of it in line supports that very low cumulative lipid levels, generally below the fifth percentile, are associated with the lowest risk.