The journey from hypothesis to reality on inflammation in CVD

So Paul, we've been working together for decades me with one foot in the basic science laboratory, you in epidemiology, and then in clinical trials. And so, we've been thinking about inflammation and their whole reason for our focus on this is to try and get something that'll change practice. So, for practicing cardiologist today, should they be screening with C-reactive protein? And if they find inflammation, what should we do about it today?

Okay. First of all, you're right, we've been working together for a long time, but it's really very exciting, isn't it? I mean, we're finally, at a point where people are paying attention at a clinical level, and I think that's an enormous change that has happened over the last 25 years. Yes. We went through the stage of loneliness and the stage of skepticism. And then now everyone thinks they thought of it first. Well, that's okay. That's actually fine with me.

So, to answer your question. First of all, all guidelines internationally now, talk about C-reactive protein and they all say, look, if you're on the fence, and you're not really sure what to do. Go ahead and measure CRP and try to figure out: Is this going to push a patient over or under some risk? Now, lots of places, including my own clinic, measure this pretty much routinely in primary prevention, because you're learning something about the patient you don't already know and that helps me to figure out what I'm going to do. So, what am I going to do?

Well, the first is, I'm going to use it to motivate, good lifestyle, right? So, diet, exercise, and, smoking cessation all are good for you. They all lower this inflammatory cascade and really, can be very effective as a tool to say to someone: Hey, you really need to get with the program on that level.

The second question then becomes who am I going to give a statin to in 2022? as you know, in JUPITER, you helped design the study. We gave a high-dose statin to people whose LDLs were only 100 and we started that back in 2000. So that was 20 years ago. You and I already decided high-intensity statins are the way to go. So in my practice in primary prevention, if your CRP is high, and you have pretty much any other risk, I'm putting you on a statin. I'm probably going to start you on a high-intensity statin. Now, the guidelines are a little softer than that, but the good news is they've greatly expanded statin use for large populations. And I think we should be proud of that.

And sure, having the inflammatory marker helps with the shared decision-making, the kind of practice that you and I have, we have a lot of statin reluctant patients. And so it really gives us an additional ticket to try and move people forward in prevention, and I'm so glad that you emphasize that the first step isn't reaching for a prescription pad, but it's lifestyle, lifestyle, lifestyle. That's great.

So, thinking beyond statins, which your own work and work of us and our collaborators has shown has direct anti-inflammatory effects. In addition to its lipid-lowering effects. What can a clinician do today, therapeutically, to lower inflammation has been a great deal of interest in the trials of colchicine, which is a very venerable anti-inflammatory intervention. Some of this action may be on the same pathway that you and I have been mining for the last several decades. So, with COLCOT and LoDoCo2, What should we be doing today? Sure. and if there's been some reluctance, what's behind the reluctance to really implement the results of COLCOT and LoDoCo2?

Sure. So let's be clear about what's going on here. CANTOS proved the point, but you can't give canakinumab. It's being used, it's being developed for other purposes at this point and the cancer findings that came out of CANTOS really is what's driving that whole development program. So colchicine, we've had this drug around for 60 or 70 years and it's been in history of medicine for far longer than that. Used to treat Familial Mediterranean fever, used to treat a variety of other interesting inflammatory disorders. We have a little care for what mechanism. I think it does have some properties in this pathway has some other properties as well, but the bottom line is, you've got two trials, both randomized, both double-blind saying, hey, it also lowered event rates in basically stable atherosclerosis and if given within a month or so of acute core ischemia. The European guidelines have already endorsed this. So good for the Europeans. Canada has really made a big push to get this done. I think our own guidelines, I hope do change, reflect this.

The reluctance has to do I think with two factors. The first is that there is no reduction at least so far in all-cause mortality, but that's also true of a lot of drugs that we do use. So I think that's not a fair issue. And there's a little concern that maybe we don't want to give colchicine in the setting of renal disease, where some patients were randomized, but over time since this is renally excreted, you might get in trouble. Okay fine. That's one of the reasons why in ZEUS we're actually focusing on people with CKD, but for my standard atherosclerosis patient, what I call my frequent flyer, someone who is already on a high-intensity statin, someone who's LDL is already down to seventy. So, do I really want a PCSK9 inhibitor there? Probably not. But I think I might add colchicine there, for someone that keeps coming back. Those patients with recurrent angioplasties. I think it's what we should be doing, I think is what we should be doing particularly if their CRP is high.

In the future, in the future, Peter, I think we're gonna see bispecific monoclonals we're gonna see drugs that are specifically saying look, this schism that you introduced with; lipids over here, information over here. Let's bring it back together. Let's just drive everybody's LDL down very far. Let's drive everybody's inflammation down very far. We know, we can do it safely. The question is, How do we get there?

So anti-TNF strategies have really transformed the practice of rheumatology. and been used in skin diseases and been used in inflammatory bowel disease. Why haven't we adopted

anti-TNF strategy? Something that you and I toyed with 15 or 20 years ago. Well, I think it was a good idea. It just didn't actually work in terms of toxicity issues and in terms of risk reduction issues, but Peter you've recently written about Jak kinase inhibitors. We hear a lot of discussions out there about novel, other ways of getting information. So let me put it this way, the work that we've both done together, has defined one particular pathway that clearly works, but I suspect there's others. We're gonna figure this out. There are a balance here between Immunosuppressive and anti-inflammatory, that's a tricky one, clinically. It's actually a tricky one for regulators. Because say, for example, within CANTOS. We actually had no increase in opportunistic infection. We had a small increase in fatal infection. That's true, but it was all Staph and Strep. And once we knew about it, we pretty much took care of it. So we're learning what's going to happen here. About these different kinds of drugs, but there's many new agents, also being created, direct NLRP3 inhibitors. That Charles Dinarello, as you know well is thinking about and we have a variety of other directions to go. It's going to be an exciting future.

So it's exactly what you said at the beginning. We've been on this journey for several decades together and started out in theory. We had to plead in cajole to get support to test the hypothesis. The hypothesis is now reality. And now what we really have to do is all work together, the entire community. To test various novel agents and existing agents. Find the right balance between unwanted effects and beneficial effects. And ultimately, I think that the inflammation hypothesis is going to yield great dividends for our patients. And that's really the bottom line. Isn't it? Peter, It's great that we're doing this symposium. I think, the fact that Tom Lüscher and Filippo Crea and you and I are all together in this. It's a change. It's a real sea change in thinking about it, and it's been fun to be part of it.