PracticeUpdate: Cardiology - Winter 2018

EXPERT OPINION 18

Cholesterol, Inflammation and Immunotherapy: Current Implications and Future Directions Interview with Peter Libby MD by Jennifer N. Caudle DO

Dr. Libby is Mallinckrodt Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Dr. Caudle: Can you tell us briefly about the design and the outcomes for the CANTOS trial and how might these results change clinical practice? Dr. Libby: CANTOS stands for Canakinumab Antithrombotic Outcome Study, and lis- teners may wonder what’s canakinumab. Canakinumab is a biological agent. It is a monoclonal antibody that neutralizes a pro-inflammatory mediator, a cytokine known as interleukin-1 beta. In my basic science laboratory life over the last more than 30 years, I’ve been interested in the hypothesis that interleukin-1 can contrib- ute to atherosclerosis and atherosclerotic events. And I certainly am not going to take your time to talk about all of our basic science studies, but let me say that there is a con- cordant evidence base, not only from my own group but from many others world- wide, that interleukin-1 may be one of the instigators of inflammation that we believe is a driver of atherosclerosis. Certainly not to replace the traditional risk factors includ- ing LDL cholesterol but, if you will, a signal transduction mechanism that can sense danger in many forms, including from tra- ditional risk factors, and transduce them into altered behavior of the artery wall and beckoning some unwelcome visitors to the artery wall during the process of athero- sclerosis formation, and that would be the blood leukocytes. With that background, we have the oppor- tunity to design a clinical trial, which is actually the first large-scale clinical trial to test the proposition that intervening on inflammation might be able to improve

cardiovascular outcomes in selected patients. So, the study that we did, the CANTOS trial, enrolled over 10,000 people who had had a prior cardiovascular event – a myocardial infarction, acute coronary syndrome – but were stable afterwards at least a month out – and most were fur- ther out than a month – and that were fully equilibrated on everything that we know to do today in guideline-directed therapy including high-dose statin, high-intensity statin therapy, beta blocker, ACE inhibitor or angiotensin receptor blocker and, of course, aspirin. But these people had a little flag waving saying that they had residual inflammation despite being on all of those good things, including statins, which will lower high-sen- sitivity C-reactive protein, which is a gauge of the overall inflammatory status. So, we pick people out of the post-MI population on all of the standard of care medications but who had a C-reactive protein meas- ure for the high sensitivity test greater than 2 mg/L. And we randomized them to 1 of 3 doses of canakinumab or placebo. Canakinumab is a remarkable monoclonal antibody because it can be given only four times a year, one subcutaneous injection every 3 months. So, it’s quite easy for the patients to take and to tolerate well, and we counted up the hard cardiovascular events – myocardial infarction, stroke, or death due to cardi- ovascular disease. And at the end of the day we found that there was a statistically significant reduction of about 15% in cardio- vascular events, those hard cardiovascular events, in the patients who received the

middle dose of the monoclonal antibody canakinumab. This was a very impor- tant result for us because number one, it provided the first clinical proof that inflam- mation in atherosclerosis is actionable from a therapeutic perspective; it reinforced all of this basic science work and observa- tional work through the decades. But more importantly it gave us a new tool to deal with residual cardiovascular risk in patients treated with the full palate of contemporary standard of care. So, it was a big twofer for us and we think that it’s advanced not only for science but also for our patients. Dr. Caudle: It’s very interesting and given that you were using CRP levels in this par- ticular trial, my next question is about CRP level measurements. Do you feel that CRP is just as important as HDL-C and LDL-C in monitoring lipid profiles. What do you think about that? Dr. Libby: I could be provocative and say that I think it’s much more important than HDL-C. Matter of fact, why do we meas- ure HDL-C? Because we have no evidence that acting on the HDL can actually confer a benefit. But we do have evidence that is embryonic but which is very intriguing and provocative, that CRP can guide ther- apy both in primary prevention as we’ve

PRACTICEUPDATE CARDIOLOGY