Marios Georgakis: Why Did Two Major Clinical Trials for Heart Disease Fail?

Eric Topol (0:01)

Okay, I'm Eric Topol, and this is Ground Truths. I'm thrilled that you're joining us today. I have the real delight to have this discussion with Marios Georgakis, the University of Munich, who is a physician scientist, actually a neurologist who studies atherosclerosis, genomics, particularly the cerebral vascular, but he certainly has tuned in to the coronary atherosclerosis anywhere in the body.

And he wrote a brilliant book in his own sub-stack called The Codon, about the Zeus Trial, and we're going to discuss these two trials, big trials, pivotal trials that failed. So welcome, Marios.

Marios Georgakis (0:44)

Thank you, Eric. Nice to be here. Thank you again for the invite.

Eric Topol (0:48)

Yeah, I know it's going to be great.

So this is kind of unprecedented in my many decades as a cardiologist to see two pivotal trials, one with over 6,000 patients, one with over 8,000 patients, and they both failed. And maybe there's common threads here, maybe not. But let's first, before we get into that, talk about atherosclerosis and inflammation. What's your sense about, people are talking, oh, well, this proves the inflammation hypothesis is wrong. What's your sense about the process of atherosclerosis?

Marios Georgakis (1:34)

Yes. Thank you, Eric.

So I think the history of inflammation in atherosclerosis actually goes a little bit back, right? So over 100 years in principle. It was the beginning of the 20th century when Nikolai Anitskvf, a pathologist who fed rabbits with high levels of cholesterol, and he observed under his microscope atherosclerotic lesions in their aorta at the time. He was able to see this, what we call today foam cells, right? So macrophages filled with cholesterol and lipids, and he already assumed at the time that these are in principle phagocytes, macrophages. So this was the first connection to an immune response, if you will, and that's already early 20th century, so over 100 years ago, and of course since then we've done massive progress, right? So after that, for decades, immunohydrinochemical studies confirmed in principle that those are immune cells, macrophages, T-cells.

Through quantification of cytokines within human plaques, we were able to see that there are high levels of inflammatory mediators. And then even more recently with high throughput technologies like single-cell RNA sequencing, special transcriptomics, we just came close to recognize the very complex immune microenvironment. I mean, we're talking about multiple different types of macrophages, T-cells, neutrophils, mast cells, dendritic cells, and so it's a really complex and mature immune microenvironment. And so I don't believe that anybody doubts that inflammation and inflammatory response is actually taking place within the vessels, within atherosclerotic plaques. But I think the big question was always whether targeting these processes would actually lead to any kind of therapeutic benefit. And yeah. And so-

Eric Topol (3:49)

That's good. I think no one will question, although some did. And like, for example, in the New York Times coverage of this Zeus trial, he said, oh, well, the inflammation hypothesis is wrong. It's not that there's lacking inflammation in arteries with atherosclerosis. It's just that we haven't found, at least so far, a target of inflammation that is going to be safe and highly effective. So also I want to mention all those that are joined. If you have any questions for Marios, don't hesitate to put them in the message. We'll try to get to them as we move along. All right, so we established that inflammation is a big part of atherosclerosis. In fact, even a paper this week was about the autoimmune aspects of this whole condition, which is interesting. But let's get into the idea that we have these markers.

High-sensitivity CRP has been out there for a couple of decades.

We got Paul Ritker, that's all he talks about, is high-sensitivity CRP. We have interleukin-6 that can be measured but isn't usually measured clinically so much as HSR CRP, and of course we have the lipids. We have LDL, HDL, triglycerides, ApoB, and Lp little a. This is what we have from blood tests. What did these blood tests tell us?

Marios Georgakis (5:20)

Yes. As you said, it's been now, I think, over two decades that the first large-scale epidemiological studies actually assessed the relationship of high-sensitivity C-react protein levels in the blood with risk of cardiovascular disease and actually showed pretty robust associations, right? So both case control studies later on also prospective cohort studies suggesting that people who have high levels of C-react protein, if you follow the map for several years, people with higher levels have higher risk of developing myocardial infarction and stroke or cardiovascular death. In principle, later on, more or less, we came to similar conclusions for interleukin-6 levels. So also interleukin-6 measuring in blood, both in primary prevention, so people who don't have cardiovascular disease, but also in secondary prevention settings, people who do have cardiovascular disease, they seem to be predictive of future cardiovascular events. And this seems to hold true even after we statistically adjust for other cardiovascular risk factors, including the markers you mentioned, LDL cholesterol, HDL cholesterol, triglyceride levels, but also other comorbidities that we know cardiovascular risk, like type 2 diabetes, blood pressure, BMI. So these associations have been out there for several decades and of course, it's the question, what do they tell us? I think in two different dimensions.