MedEvidence! Truth Behind the Data

Beyond Cholesterol: Inflammation and Heart Health Trailer

• Dr. Michael Koren • Episode 338

Share episode

Send us a text

Be a part of advancing science by participating in clinical research.

Have a question for Dr. Koren? Email him at askDrKoren@MedEvidence.com

Listen on Spotify
Listen on Apple Podcasts
Watch on YouTube

Share with a friend. Rate, Review, and Subscribe to the MedEvidence! podcast to be notified when new episodes are released.

Follow us on Social Media:
Facebook
Instagram
X (Formerly Twitter)
LinkedIn

Want to learn more? Checkout our entire library of podcasts, videos, articles and presentations at www.MedEvidence.com

Music: Storyblocks - Corporate Inspired

Thank you for listening!

SPEAKER_01:

Inflammation, which is really how our body fights infection, how our body deals with foreign objects, things that aren't supposed to be there, and how you mount a response to that is really important for ultimate survival. So I'm gonna try to avoid getting jargony on you here, but we take back about 30,000 years. Imagine you're living in a cave somewhere, um, and you just want to survive. I still live in a man cave, by the way. Yes, I can tell. But 30,000 years ago, childhood infection would kill the vast majority of people who were born. Measles, malaria, mumps, schistosomiasis, you name it. You need a pretty good innate immune system to survive that. The second thing that killed a lot of our forebearers was um a saber-toothed tiger, if you like. You had to have a coagulation system that would survive bleeding. Very important for women who used to die so commonly in childbirth because of hemorrhage. And the third piece that people may not think about is in a pre-agriculture universe, uh, starvation. So starvation would kill a lot of people. And what do those three things have in common? Well, it's a insulin resistant, that's how you get by the starvation, pro-coagulant, that's how you get past the saber-tooth tiger. Uh, and pro-inflammatory, that's how you get past these infections. So our immune system is designed to help us survive these challenges of life when humans began. But you know, I live in Boston. Uh we don't have a lot of saber-tooth tigers. Uh women now survive childbirth because we have fantastic medical care. Uh, and childhood infections are largely dealt with with uh immunizations and vaccines. But that survival benefit of having this activated immune system in midlife becomes a hindrance. From a strictly evolutionary biology perspective, all we're really supposed to do is live long enough to reproduce, have kids, get our children launched, and then, as I laughingly sometimes say, everything else is extra genetic debris. But it's it's it's debris we all want in midlife and later. So the question is, how do we dampen down this inflammation that was so useful to survive early life that's coming back to haunt us in later life? And the reality, Mike, is that almost all the diseases of chronic aging, and in particular as cardiologists, we focus on heart attack and stroke, but it's equally true of cancer and other things, they all turn out to be driven, at least in part, by this chronic inflammatory response. We had recently shown that these statin drugs, not only do they lower cholesterol, they also lower a biomarker of inflammation. This is a mouthful. It's called high sensitivity C reactive protein or HSCRP. That's gonna be important because that's the thing that we actually measure in clinic to say, aha, my patient has a little bit of inflammation, a moderate amount of inflammation, a lot of inflammation. So that HSCRP test, we're gonna come back to it, I'm sure, is gonna be quite important. But the point is we had shown that statin drugs actually lower this inflammatory marker, the HSCRP. And we had tantalizing evidence that maybe people with a high CRP would benefit from being on a statin, even if their cholesterol levels were low when they didn't even qualify for a statin. Anyway, fast forward, we published these data in 2008. It's a nearly 18,000 patient multinational global trial, critically of people who were primary prevention, so no prior heart attack or stroke, healthy men and women, middle-aged folks, who would never qualify to be on a statin because their cholesterol levels were actually pretty low. But they all were selected because they had this marker of inflammation, they all had an elevated HSCRP, a level greater than two, uh, to qualify for the trial. And what's so remarkable is that in this study where nobody would have gotten a statin, because again, the whole idea from the guidelines was to lower the cholesterol uh and only given a high cholesterol, uh, in this group of people with high inflammation and low cholesterol, we had a 44% reduction in heart attacks and strokes, a 63% reduction in heart attacks itself, and quite remarkably a 20% drop in all-cause mortality. Right. It's crazy. And it was really a real revelation.

SPEAKER_00:

Yeah. So again, to kind of fast forward again, between the years of say 1980 and 2010, cardiologists were making huge strides in reducing cardiovascular morbidity mortality. And that curve has flattened. In fact, maybe hasn't changed at all in the last 10 years, which is of great concern. So it leads to the idea that maybe we should be looking at other things. And this gets into some research that you and I are working on together as we speak.

SPEAKER_01:

Well, that's right. So uh we learned during COVID that sometimes rates can actually go up. And that was a little scary. Uh but I think you're right, Mike. The the constant decline of the last 35, 40 years has really flattened out, telling us we now need to focus on some of these newer biologies. So, what's been a lot of fun, and again, working with you has been great. Um, we're trying to figure out can we target this inflammation directly? I must be a little careful there. That Jupiter trial we talked about was giving a statin. It's a drug that lowers cholesterol and has anti-inflammatory properties. Could we give a pure anti-inflammatory drug to lower risk? We actually did a clinical trial uh called Cantose, which used a very specific kind of inflammation inhibitor, and it really worked really well. But that drug's not available, unfortunately, for our patients for some complicated reasons that actually had to do with cancer prevention.

SPEAKER_00:

So that's a molecule called canicinemab. Is that still used for certain pediatric arthritic conditions? I know it's briefly on the market for that.

SPEAKER_01:

Well, it's still on the market for that. So kinikiniumab, which is another mouthful, uh, these are drugs that are called monoclonal antibodies. Um, they target a very specific piece of this inflammation pathway. And we showed it could lower the risk of a heart attack or stroke by about 15 or 20 percent, which is great. But uh the drug also has some great benefits in cancer. So it's being repurposed into the oncology community. Um, and so we need to find another way of targeting this.

SPEAKER_00:

Sorry for that aside. Uh just for our audience, one of the little tricks of the trade is if you hear a molecule or a chemical that ends with MAB, it's a monoclonal antibody. So you can surprise your friends uh at a dinner conversation that you know the nature of their particular medicine. So sorry, sorry about that.

SPEAKER_01:

No, that's a that's that's a great pearl even for those of us who live in this world uh on a daily basis. Um so the question was: could we find another one of these MABs uh that hits a different part of this particular immune system? Um and actually another mouthful, that drug turns out to be called Ziltaveca Mab. It starts with a Z. Um and we designed a series of clinical trials which are ongoing right now using this particular kind of inflammation inhibitor, which, by the way, is already commonly used. It's in a class of drugs that are commonly used to treat rheumatoid arthritis. Uh, some patients take it to treat inflammatory bowel disease like Crohn's disease or ulceritis. So the class of drugs has been around for 20, 25 years. We know it's pretty safe, but it's been used to treat classical autoimmune anti-inflammatory disorders. The trick is, can we use it to actually improve outcomes for patients with heart disease? We're going to focus a bit on Hermes, which is, again, it's a heart failure trial. That's a particular kind of heart failure. It's something that we call, cardiologists call HEF-PEF, which is heart failure with preserved ejection fraction. What's that really mean? That means that uh your heart's pumping and it looks pretty good on a standard echocardiogram, but it doesn't work really all that well. And you get the symptoms of heart failure, shortness of breath, a feeling of congestion, a feeling of not being able to walk as far as you used to be able to, even though the heart seems to pump okay, but the heart's actually too stiff. I think that's the easiest way to understand what this is. When we talk about inflammation, we're not talking about a sprained ankle. We're not talking about drugs like Advil or ibuprofen or even aspirin. We're talking about the kind of inflammation that classically would lead to things like rheumatoid arthritis or um inflammatory bowel disease or psoriasis, more severe disorders that go under the rubric of auto-inflammatory or um uh, you know, things like that. And there's certain specific pathways of this immune system that impact on some of these disorders more than others. And we're going to get very jargony very fast, but I think actually it makes sense. There's one particular pathway that all of us have. Understand, everybody has this because I said at the beginning, you need these things to survive childhood and get into early adulthood, but it kind of comes back to haunt us later in life. One of these pathways upregulates a certain cytokine. Now, a cytokine is a chemical molecule that tells cell A to talk to cell B. It's a communication system. That's all it is. It says, hello out there, this cell is doing this, you better do that. I see something over there that's not good. Let's go attack that. That's right.

SPEAKER_00:

Yeah, kine means means to move. So cytokine means move cells. It's a chemical that moves cells in one direction or another. That's exactly right.

SPEAKER_01:

It's just telling them move over here because there's something over there we got to deal with. It's just an infection, it's a bug, it's a virus, whatever. One of these cytokines has a name, interleukin 1. It's the first one that was ever discovered. It's at the top of the chain. The drug you mentioned before, kennakinumab, remember that MAB, that blocks the function of interleukin 1. Actually, it's even more technical than that. It blocks the function of interleukin 1 beta, but let's skip over that. Um, and that turns out to lower the risk of heart attack and stroke without changing cholesterol. In fact, that's the proof of principle that this whole thing actually works, came out of that cannokidomab trial. Now, the study with Hermes, as well as the Zeus study and the Artemis study, remember that's the chronic kidney disease study, the heart failure study, and the acute cornea ischemia studies. They're all using this drug, another MAB, Ziltefeca MAB. It targets a downstream cytokine. So again, a cell-moving molecule called intraleucin 6. Intraleukin 6 is the central cytokine. It's it's it's the biggest player. It's the one that we think is most involved in this process. And what's really interesting is there's several drugs on the market that block IL-6 that already work for several of those more serious inflammatory diseases that patients actually know they have because they have symptoms. The question being asked, particularly in the Hermes study, the heart failure study we're talking about, is can we use this inter-leucin 6 blocker to improve the outcomes in heart failure patients where they don't feel their inflammation? Mike, I think that's probably the most important thing we're talking about today. This is silent inflammation. If a patient has rheumatoarthritis, their hands and joints hurt. If they have lupus, their skin hurts. If they have psoriasis, they have issues, they know about. The inflammation we're talking about for all of these heart disease conditions, it's silent. You don't know what's there. And that's why running this blood test, the high sensitivity C-reactive protein, the HSCRP is so important because this is just like cholesterol. I can't feel my cholesterol. I can't really feel my blood pressure either. I need my physician to measure my blood pressure, to measure my cholesterol, to measure my inflammation, my HSCRP. So I now have information about the silent things that might well be big problems for me. And it's that silent inflammation we're trying to reduce to see if we can benefit our patients.

SPEAKER_00:

Yeah, that's an incredibly helpful description. Thank you for that. I'm going to ask you one more question that is sometimes a source of controversy and confusion about HSCRP, which historically was something that was originally discovered related to streptococcal infections, particularly pneumococcal pneumonia. And what happens and what confuses people is sometimes they have extremely high levels that are not related to vascular disease. And people get very confused about this when we talk about, quote, HSCRP as a risk factor. You gave a brilliant discussion about this at a recent meeting. I think it'd be extremely helpful if you can break that down for folks.

SPEAKER_01:

Sure. So, Mike, your your memory is very good on this. Many physicians, unfortunately, only knew about C-reactive protein uh as something called an acute phase reactant, which is again a fancy word for it goes up when you're sick. And that has been a problem because physicians, again, don't always get as much new education as they probably should. And people remember that. Um we recently published a very big study. It was actually 28,000 initially healthy American women that we've tracked since 1993. So in 1993, we took a random blood drop and we measured this HSCRP. And 30 years later, that value, that random value, is a stronger predictor over 30 years of who's going to develop a heart attack, a stroke, or die from a cardiovascular event than was LDL cholesterol, the thing we all measure all the time. Now, what's really interesting, Mike, is that when there's a biomarker like the CRP that in theory has some extra variability built into it, uh the epidemiologist would say, well, variability is what we call a bias towards the null. It actually makes it harder to see a true effect, not easier. So if CRP is already outperforming our standard go-to LDL cholesterol, that means we're underestimating the true impact of inflammation long term. Uh, I've said this before, I'll repeat it here. Many of your listeners today, their physicians may not actually know this. Uh, I've told a lot of people go to the New England Journal of Medicine website. It's free, it's on the internet. You can download this recent manuscript and take it to your doctor's office. They may need to actually read it and think about it. Because part of the education for physicians honestly comes from family members and caring, you know, people who just want to do the right thing. Um, all of us need lifelong education.

Head Shot

Dr. Michael Koren

Host