Juan Carlos Kaski:
Welcome to this educational programme on targeting inflammation in atherosclerosis and CKD, and gaining insight into the importance of inflammation in atherosclerosis, in general, and kidney disease, in particular. I'm J.C. Kaski, Professor of Cardiovascular Science at St. George's University of London, and my guest today is Dr. Paul Ridker the Eugene Braunwald Professor of Medicine at Harvard University and Brigham and Women's Hospital, where he directs the Centre for Cardiovascular Disease Prevention. Dr. Ridker's contribution to the field of inflammation in cardiovascular disease has been, and continues to be, truly awesome. Suffice it to say that his citations are over 400,000 and his h-index over 255. Really astronomical figures. Paul, thank you very much for joining us today to discuss unmet needs in atherosclerosis and CKD.

Paul Ridker:
Juan Carlos, it's an absolute pleasure to join you today.

Juan Carlos Kaski:
Paul, the concept of residual inflammatory risk in addition to the sort of cholesterol risk or residual cholesterol risk in atherosclerosis that you put forward many years ago, now, seems to be very important in CKD patients as well. Can you comment on this please?

Paul Ridker:
Sure. So, Juan Carlos, let's first start with the concept of residual inflammatory risk, which is an idea that we put together to help the clinical community understand what we're talking about. Most physicians are very comfortable with the idea residual cholesterol risk. So a patient who has had prior disease, they're on a high-intensity statin, but the LDL cholesterol is not low enough, say, it's not below a 100 or below 70. We call that residual cholesterol risk, and we might use a second drug, perhaps a PCSK9 inhibitor, perhaps ezetimibe, et cetera.

Paul Ridker:
The exact same thing is true with residual inflammatory risk, except in this case, the LDL cholesterol has come down quite dramatically with the high-intensity statin, but the high-sensitivity CRP, the biomarker of inflammation, has not come down. But the fundamental issue that most clinicians are not aware of is that we have 3 patients with residual inflammatory risk for every 1 patient with residual cholesterol risk. But if you're not measuring CRP, you don't know who they are.

Paul Ridker:
Now, with regard to kidney disease, it's even more important, because our patients with chronic kidney disease have enormous unmet clinical need. Those with atherosclerosis and a high CRP are more likely to succumb to a cardiovascular event than they are to kidney failure. So you're right. These are very important subgroup of patients. We see them every day in clinic, and the question is, what can we do for them?

Juan Carlos Kaski:
Thank you, Paul. Reduced glomerular filtration rate carries prognostic inflammation, as you showed in the CANTOS CKD sub-study, and in this particular group of patients with kidney dysfunction, there is also an increased risk, which is over and above that of impaired renal function that relates to inflammation. Do you mind, actually, refreshing our minds in relation to the findings in CANTOS CKD sub-study in relation to this?

Paul Ridker:
Sure. So, Juan Carlos, you're absolutely right. Our patients with GFRs between 35, 40, 45, and 55 are much higher vascular risk, and if they have known atherosclerosis and elevated CRP, we're quite concerned about them at the American College of Cardiology meetings, we presented some new data from CANTOS. Now, CANTOS already showed that giving an interleukin 1 beta inhibitor lowered the risk of cardiovascular events, actually as much as a PCSK9 inhibitor, that was the real interesting part, in the absence of any lowering of LDL cholesterol or apoB. But also in CANTOS, as you point out, we had previously shown that patients with CKD had an even higher absolute risk, and if anything, a greater absolute risk reduction with targeted anti-inflammatory therapy.

Paul Ridker:
The new data at the ACC can be summarised very quickly in patients with normal kidney function, a GFR above 60, as we would expect, CRP and IL-6 as inflammatory markers, LDL cholesterol and non-HDL cholesterol as lipid markers, all predict recurrent coronary events so far so good. But, among patients with reduced GFR, only the CRP and the IL-6 predicted the recurrent events. There actually was no predicted utility for LDL cholesterol. And these effects are magnified quite dramatically when you look at the endpoint of cardiovascular mortality or all-cause mortality.

Paul Ridker:
So the bottom line of the new data is, it emphasises, yet again, how important the chronic kidney disease population is with regard to residual inflammatory risk. But, right now, we as clinicians don't have a drug we can give to such patients, because the only real anti-inflammatory drug available to us is colchicine, which the LoDoCo2 trial and the COLCOT trial have shown is quite effective for chronic stable atherosclerosis. But, I would not give colchicine to a patient with chronic kidney disease because the drug is renally excreted. So we have a conundrum. We know these patients are at very high vascular risk in CKD, but how do we treat them?

Juan Carlos Kaski:
You mentioned colchicine, and that's quite interesting, because colchicine has been shown to be effective even without looking at CRP. I mean, I don't think that CRP was a key component in the major studies of colchicine. But, of course, there is a problem of kidney disease and the use of colchicine. So with ZEUS and RESCUE, you seem to be actually coming up with better options that can address the inflammatory component in CKD patients, without affecting renal functions. Would that be sort of fair to say, that this is really a key element in terms of treating CKD patients?

Paul Ridker:
Well, first of all, Juan Carlos, I would point out that neither COLCOT nor LoDoCo2 measured any biomarkers at all. So it's not like they measured it and didn't matter, they just didn't measure it at all. So I would argue, if you're going to pick patients who I would give colchicine to who have chronic atherosclerosis, in my practise, I'm giving colchicine to individuals who'd have an elevated CRP, despite having been on aggressive statin therapy, because I don't want to treat everybody. I want to make sure I can target the therapy to those individuals who I believe have the biologic problem. So I am measuring CRP in those patients and I'm giving some of them colchicine now.

Paul Ridker:
But you're right. In chronic kidney disease, we cannot use colchicine, it's renally excreted, and the toxicity gets worse as the GFR declines. And so I wouldn't want to put a patient on a chronic therapy that might get them in trouble. But the exciting new news is we recently did a clinical trial called RESCUE. It was a phase IIb study published last year, that used a novel interleukin 6 ligand monoclonal antibody called ziltivekimab. Now, we were able to show that ziltivekimab lowered CRP by 85-90%. That's twice as much CRP lowering as we got with canakinumab in CANTOS. And remember, the magnitude of benefit observed in CANTOS was directly related to the potency of the anti-inflammatory that they received. So we're very optimistic that this new drug will be able to lower levels substantially.

Paul Ridker:
RESCUE also showed that we lowered levels of fibrinogen, we lowered levels of sPLA2. Interestingly, we lowered levels of Lp(a), there's some biologic reasons why that's the case. But I think most important is that we had no effect on lipids at all. The apoB to apoA ratio did not change. That's important because the clinicians will know that other IL-6 drugs like tocilizumab can raise LDL cholesterol. We did not see that with ziltivekimab.

Paul Ridker:
So what we've done is launched a new multinational clinical trial called ZEUS, the ziltivekimab inflammation reduction study cardiovascular reduction study, in which over 6,000 patients worldwide who have residual inflammatory risks, so their CRP is above 2, they have known atherosclerotic disease, they're already on high-intensity statins, and they have stage 3 or 4 chronic kidney disease, so GFR between about 35 and 60. They're being randomly allocated to aggressive care plus ziltivekimab 15 milligrammes once a month or to aggressive care plus placebo.

Paul Ridker:
And, Juan Carlos, it's a very interesting clinical trial. There's really two fundamental endpoints. The primary endpoint is cardiovascular events, major recurrent cardiovascular events, and I'm the trial chair for that part of the study. But we also have a pre-specified endpoint of progression of renal disease, and our friend and colleague that you know well, Vlado Perkovic who's a nephrologist in Australia, is really in charge of the kidney part of the study. So again, we're learning how to combine understanding of biology of both the kidney and the heart in this new ongoing trial, and I'm very pleased that we've already randomised over 500 patients to date, despite just starting the study a few weeks ago.