 Hi, I'm Joe Rogers, president and CEO of the Texas Heart Institute, and I have the pleasure today of speaking with Dr. Salim Varani, who's just given Grand Rounds at THI, and given us an update on the current status of lipid management. Salim is a professor of medicine at the Baylor College of Medicine and is a prolific writer in this space, in the space of preventative cardiology, particularly in lipid management. Salim, thanks so much for taking the time to visit after Grand Rounds today. Thank you for having me. It was a lot of fun presenting and taking the questions afterwards from colleagues. I'm very interested in all of the new approaches to the management of lipids, and it became clear to me as I was listening to you walk through the different choices and the interesting mechanisms of the drugs. As you look forward in the world of lipid management, how is the practicing clinician going to keep this straight? Because we're going to have to go from a group of statins to all of these really interesting drugs that have complex mechanisms. What does that look like for the practicing physician and equally importantly for the patient who has hyperlipidemia? No, that's a great question. Even now, I struggle with things in prevention. There's so much to keep up with. Then for a practicing cardiologist who just doesn't have lipids, there's a lot going on in heart failure space, diabetes space. Even in hypertension, there's a lot going on. Then DAP therapy, the duration keeps changing of when we need to use what. It's a lot to keep up with. I think the important thing is at an institution level, I think we'll all have to make sure that those things are provided to our clinicians. The Grand Rounds we have, the discussions we're having now, I think even having something in EMR that gives you that cognitive support, that's active cognitive support that, okay, these are the medications that are at your disposal. This is how they work. These are the things you should be careful with. Then I think the guidelines will also have to become more nimble. There is a national effort to actually harmonize guidelines and have regular updates as well. But at the end of the day, none of this will work if it's not made easier for clinicians to implement. I don't think I have any major solutions to this. I think we'll have to see there are some clinicians, and now we have younger clinicians who are becoming part of this. They may not read the books or read the articles that you and I did for a very long time. Now it's these small nuggets of information. How do you use social media to give that information? And even that comes in various flavors. But then even the way we do continuous medical education perhaps needs to evolve a little bit. And some of these things we're doing now is probably an evolution of that as well. You know, the other thing that struck me is we spent a lot of time talking about, obviously, about lipid lowering, and you talked about some of the outcomes, trials that have been done. I was, as I was watching the data, I was thinking about the times that you and I oftentimes engage with patients, and it's after we know they have atherosclerotic vascular disease. With some of these newer therapies, what are your thoughts about the potential for plaque regression? Because you sort of talked about this idea of treating in a primordial state, you know, getting to it really early and preventing the development. But oftentimes that's not when you and I get engaged with the patient. So what do we know, or what are you projecting about regression of plaques with some of these more interesting, aggressive therapies that really lower LDL cholesterol levels? I think that's a great question. And the way I look at this is that the regression of the plaque will also depend on whether you have enough lowering of the LDL cholesterol. And then that can be combined with a lot of these other parameters that we talked about, whether that is parameters that are targeting triglycerides like little a, we talked about those. But then there is this huge field of anti-inflammatory therapies as well. So I have a feeling that when we see these patients in the secondary prevention space or in high-risk primary, when they already have a lot of subclinical athero, there is this opportunity to even show regression. But in those cases, a lot of that is going to be dependent on magnitude of reduction for each of those risk factors that we talked about. And perhaps I think one of the other unexplored areas is that when you use a very potent LDL cholesterol lowering therapy with something that also lowers LDL pylitol A in a major way, what happens, right? Classic example is that we know that in some of the trials of PCS-canine inhibitors, almost 47-48% of the patients who were on high-intensity statin therapy actually showed a regression of athero as assessed by IWIS. But when we gave PCS-canine inhibitors, that went up quite significantly. In a lot more patients, we saw regression than statins only. Now, the question is, it's showing us that further LDL cholesterol reduction reduces, stabilizes back and regresses it quite a bit as well. Now, what if we were to combine therapies and then we don't even know what happens when you give SGLT-2s and GLP-1s and look at the plaque stabilization and perhaps more regression of the plaques as well? So, I think that area is very open to studies, whether it's done via IWIS, OCT or noninvasively using CTA, which now we get pretty decent images to actually do a lot of these analysis. I was really struck by the size of the trials that have been done. You showed a number of trials where the enrollment was between 10 and 20,000 people. And a lot of that was predicated on the demonstration of outcomes, but reductions in LDL cholesterol. Are we to a point now in this space where we have a clear understanding of the firm relationship between LDL reduction and outcomes so that we could do shorter, smaller clinical trials to really prove safety and LDL lowering, at least in the short term? And what do clinical trials look like going forward with some of these newer agents? Because the number of agents that you described today was legion. And I think that we're going to have to really rethink how we approach understanding the drugs going forward with a different kind of clinical trial design. Yeah, I think one trial design that there is a lot of discussion on is to identify those high-risk patients using imaging. So if you're in primary prevention, can you identify patients based on a carotid plaque presence or presence of very high calcium scores or CTAs and look at the plaque morphology and say, okay, these are the patients that I can enrich my trial with, so I don't enroll as many. Duration-wise, it's a little tricky. And we saw that PCS, PCS can have inhibitors that when we did those two trials, one for 2.2 years, one for 2.6 years, the relative risk reduction was not as much as we expected with that significant LDL cholesterol reduction. And that's a lesson from the statin trials as well. For the first two years, the relative risk reduction was not as high as in the next three years when we're talking about those five-year trials. So we can do that, but we'll need to make sure that there's enough time given with these trials for us to see the real positive benefits that these trials bring to the patients. Now, of course, there's this big move towards having these 20,000 patient trials. So the industry doesn't have to spend five years following these trials because you get enriched with events. But I do believe that in some of these cases, we have to be a little bit patient because then the data we get, it guides practice for the next few decades versus we're still struggling, well, why did we not see as much event reduction with Fourier or Odyssey outcomes as we should? Well, most likely answer is we just did not follow those patients for long enough. So there's a fine balance, but I think enrichment will probably help. We may even have genetic markers. I mean, that might guide us that these are the patients who are high-risk patients, and then we have the imaging markers. But then I do believe there is this tension whether we can just do these trials for two years and be done with it, or should we do five-year, six-year long trials? Well, listen, I thought your talk today was absolutely wonderful. And thanks for giving us a view into the future of what we can anticipate with new pharmacotherapies for the management of people with hyperlipidemia. Sling, thanks very much for joining us today. Thank you.