**EP365: Talking All Things Risk - Primary, Secondary, Continuum and Residual** **Dr. Warwick Bishop:** Hi, my name is Dr. Warwick Bishop and welcome to my podcast and videocast station. As always, I'm really grateful if you've taken the time to tune in. I know how valuable every minute is in our day, so I hope I'm able to give you something interesting, informative, and useful for you in your best health journey. Today, I'm pretty keen to talk about risk. And I'm pretty keen to talk about risk in the context of why we make such a big deal about lowering cholesterol. It's a space where there's often a bit of confusion, where some of the cholesterol and statin non-believers may push back. I want to talk about it in a really quite pragmatic and common-sense way, so you understand where someone who works in that space, who's done so for nearly a couple of decades and who has kept up with the literature to try and apply that appropriately to their own patient cohort, puts emphasis and tries to understand the bigger picture. So, for those listening, I'm going to do my very best to share what's going to be a slideshow so that you can listen to it. I’ll try and describe what the people on video will be seeing. I'm going to be talking about how we approach risk, how we think about primary and secondary risk. I also want to throw in there how we think of risk, or I believe we should think of risk as a continuum. Because if we think about treating individuals, secondary prevention is treating people who have had an event—a heart attack, a stent, a stroke, a bypass—people who have clearly defined themselves at high risk. There is no doubt in the literature that lowering cholesterol for those people can improve their outcome. I'm going to talk about that a little bit more later on, where a lot of confusion seems to come from and where the statin and cholesterol naysayers, for want of a better term, or those people who are skeptical of the virtues of lowering cholesterol, often share where they believe there's holes in the discussion is in the context of primary prevention. And I agree. Primary prevention is very difficult to address because in primary prevention, we're dealing with a group of people who are a mixed bag. They're heterogeneous. Some of those people will have high-risk plaques; some of those people won't. And of course, we're then in the position where we might be treating the all to benefit the few. That's why I think imaging is so important. I've talked about imaging, particularly imaging the coronary arteries, but you can also image the carotid arteries in individuals to get an appreciation of their propensity to put plaque in arteries. Once you take the concept of imaging into the equation, then we can recognize atherosclerotic cardiovascular disease as a continuum. The opportunity to identify plaque buildup as the very beginning of that atherosclerotic process allows us to recognize that over time that will likely progress. We can also recognize that there are a number of drivers that can increase the likelihood of plaque progression. So, quick recap: secondary prevention—no question these individuals will benefit from reduction of their cholesterol compared to if they're not reducing their cholesterol. Primary prevention is much harder to identify those at high risk within the pack because there will be many who are low risk. And so you're treating the all to try and benefit what potentially could be the few. If we shift that around and then recognize that coronary artery disease is a poor term, we should think of it as the development of atherosclerotic plaque, either pre-clinical or post-clinical—in other words, without any symptoms or identification, so silent—or once it's made its presence felt with some sort of symptom. We should consider it as a continuum of risk. This is able to be done these days by our beautiful imaging techniques. So this is what we're going to talk about a little bit, and I think there's real value in thinking about that continuum. When we think about the cholesterol-lowering trials across the board, we know if we take people who are high risk in the secondary prevention setting, and even in the primary prevention setting, we're able to reduce their risk of future events. We know that about one millimole of cholesterol lowering equates to a 20% relative risk reduction of future events for those individuals compared to those not treated. Finding those high-risk individuals and lowering their cholesterol is really important. I want to talk about risk today, and I'm going to talk about risk as primary, secondary, and along that continuum. But I'm also going to talk about the risk that remains once we lower cholesterol. Because we know that when we lower cholesterol, there's still a risk that individuals carry. We don't negate completely the risk of heart attack by lowering the cholesterol substantially. We reduce it, but we don't make it zero. The fact that we don't reduce risk to zero means that there is still some risk left. The word we use for that is residual risk. So when we're managing people, we will lower their cholesterol as a primary focus. We'll lower it as low as possible, but we know we'll still end up with some residual risk for that individual. We know that because we've driven cholesterol levels down to very low levels. When we look at the combination of the statin agents plus ezetimibe in the IMPROVE-IT trial, these were low levels of cholesterol that were obtained, but coronary artery disease events still occurred at a lower rate in the lower cholesterol cohorts compared to placebo, but they still occurred. So we didn't get those numbers down to zero. Even using the powerful PCSK9 inhibitors in trial data, we know that we reduce that cholesterol level dramatically, but we don't negate the residual risk and don't pull that down to zero. So what does all that mean? Well, it means that there are other factors at play feeding into risk, and things like hypertension, smoking, obesity, poor diet, poor exercise, depression, and adherence are all common-sense things that we might imagine we want to address when we're dealing with an individual who we believe is at high risk, either through secondary prevention or through that continuum by using imaging. When I talk about that continuum, we know that when we find someone with a calcium score of 300 or more, that individual carries the same risk as someone who's in a secondary prevention category. So that's how we think about that continuum, and I really want you to get that. Remember, that continuum runs over time. Back to the residual risk, though. We're thinking, what is driving that residual risk? Well, really importantly, as I've already alluded to, there are common-sense things that we would try and stop: hypertension, smoking, obesity, diet, exercise, depression, adherence. These things are straightforward. We obviously lower the cholesterol as well. But then there are other things as well—things like inflammation. This feeds in and it is important. Things like the risk of clot formation. We often use blood thinners to really try and offset that in terms of what we can do therapeutically to diminish that residual risk. We know diabetes carries a residual risk. We know that we can use triglycerides—raised triglyceride levels as a marker of processes that point to increased residual risk. We also know that addressing those individuals with raised triglycerides who are at high risk by giving them the purified fish oil products that are now available, we can really tap into improvements and start to eat away at that residual risk that those people would otherwise be suffering. One of the other significant residual risk contributors that's in study right at the moment is lipoprotein(a). Watch this space because there is on the very near horizon—I'm talking 2024—some really exciting and interesting information which will inform us if lowering lipoprotein(a) over and above our LDL cholesterol lowering offers us an improvement. Well, you're probably sitting there and saying, "Why do we make such a big deal about cholesterol if there are so many other factors?" Well, often the example I'll share with my own patients is, you'd be blind Freddy to think cholesterol is the only mechanism driving coronary artery disease. Of course, it doesn't make sense that that's the case. It is an incredibly complicated biological process. But what I say to my patients is, let's use an analogy. Let's consider the economy. The economy is an incredibly complex organism. It happens to be man-made, but nonetheless, the influences and impacts within a political, economic, and medical context—COVID, the impact of COVID, the impact of geological forces on the economy, earthquakes, tsunamis. The economy is outrageously complex. We don't fully understand it. But every major central bank in the world pretty well has one lever that it can pull. And that lever is interest rates. Does it release interest rates? Does it make money more available? Or does it pull hard on interest rates, raising interest rates and making money less available? Well, even though the economy is an outrageously complex machine or mechanism, that one intervention—releasing interest rates or pulling back on interest rates—can dramatically impact the entire economy. It won't be the whole effect, but a little bit like LDL cholesterol, the so-called bad cholesterol. We've got one lever that we can pull really hard. The really nice thing is that we're starting to understand more and more levers. But the LDL cholesterol, the so-called bad cholesterol, with that ApoB companion, which seems to get it into mischief, we know that if we look at modifiable risks for individuals having a heart attack, that the cholesterol levels represent 50% of the modifiable risk that could be adjusted to reduce the risk of heart attack for that individual. So is cholesterol the whole story? Of course not. Is it important in the story? Outrageously so. So we really do need to put in place the fundamentals to get all the other stuff in place. How do we put it all together, though? Well, one of the things I try and really do in my own mind on a regular basis is understand traditional risk. Traditional risk includes things like age, blood pressure, cholesterol levels, smoking, diabetes—all those sorts of things. I try and marry that up in the primary prevention setting or in that continuum setting with what I see on imaging. Now, I can preface this by saying all secondary prevention people need therapy, full stop. We need to get their cholesterol down and deal with those residual risks as best as possible. But in the primary prevention setting, this is the space where there's lots of conversation out in social media about not taking statins early on. Not everyone needs them, so forth and so on. And I agree with that. But this is how I approach it to get around that uncertainty. I try and marry traditional risk factors with what we see on a scan. Whenever we deal with risk, risk management is really the process of understanding the links in a chain and then looking for the weakest link and then making a plan to deal with that weakest link. So if we're thinking about traditional risks, if your cholesterol is low and then we marry that up with a score, which is a low score, then everything seems congruent—not much to really worry about immediately. We'd obviously think about long term, and I think that that concept of continuum means that we drop that concept of low risk over a five-year period and think about people's 20, 30, 40, 50-year lifetime risk. But that means that when we then look at traditional risks and find someone who's got high blood pressure or high cholesterol, we really need to be treating that even if they don't have scan features or evidence of early plaque in the arteries, because we know that that wear and tear will have an impact in the longer term. So for those looking at this on video, you can see the matrix I've got here where low traditional risk and low scanning risk gives us a green square, but very high traditional risk and very high scanning risk gives us a hot pink square. For those listening, imagine this continuum where you're marrying up the risks for the individual who's involved. This is incredibly important so that we're making the best decisions—not just for now and the next five years, but for the rest of this person's life. Well, that's risk. I hope you found it interesting. I've covered a lot of really important components there. We've talked about primary prevention, secondary prevention. We've turned that into a continuum. We've talked about why LDL cholesterol is so important to get down because it is one of the fundamental risks we can alter, like the interest rates for central banks. We've also talked about residual risk and the factors we would address, recognizing that it all impacts together in an individual patient. We've also touched on how important it is, particularly in that primary prevention setting, to marry up traditional risks with or without increased scanning risks. This way, we're making the best decision for our individual patients, or you're involved in making the best decisions for yourself with the information available. I'm going to wrap it up there. I really hope you found that this made some sense. It's incredibly important. I do appreciate you listening to me now. If you have any queries or questions, drop me a note at info@drwarwickbishop.online. As always, I'd like to wish you the very best, and I hope you live as well as possible for as long as possible. Take care and bye for now.