Steven Nissen, M.D., Chairman of Cardiovascular Medicine at Cleveland Clinic, talks about a drug that is bringing cholesterol levels to a new low.
Interview conducted by Ivanhoe Broadcast News in November 2016.
We’re talking PCSK9 now.
Dr. Nissen: When I was in medical school longer ago than I wish to admit, we were taught that a total cholesterol level was anything under three hundred. Because you would look back at this, we now realize how much medicine has changed over these decades. We have developed drugs, the statin drugs, to lower the bad cholesterol LDL and gradually our guidelines have suggested that lower and lower levels of the bad cholesterol LDL are associated with the reduction in the risk of death, heart attack and stroke in patients that are at high risk. Now, there are tens of millions of patients that take these cholesterol lowering drugs the statins. But, we wanted to know whether we could do better. Within the last year and a half a new class of drugs has come to market. These are known as PCSK9 inhibitors, they’re injectable. Patients inject themselves every two weeks or once a month and they work in addition to the statin drugs to further lower the bad cholesterol, the LDL cholesterol levels. All we’ve really known about these drugs until now is that they do lower the blood chemistry measurements. They improve the levels of LDL cholesterol. But what do they do for the coronary arteries, where the plaque develops? That’s the whole reason why people have heart attacks. Is a plaque develops in the coronary artery it fractures, a blood clot forms and that’s what causes a heart attack. It’s also what can cause sudden cardiac death. We designed the glagoc trial to ask the question: can we do better than simply giving statins alone? Can we slow down the progression of the development of plaques in the arteries or can we even remove some of the plaque from the arteries by getting cholesterol levels down to levels we’ve never achieved before? We wanted to go where no man or woman had gone before, to levels of LDL cholesterol that had never been achievable in the past. In the trial, nine hundred and sixty eight patients were randomly assigned either to receive a conventional statin drug to lower their cholesterol and most of them got the high doses of very potent statins. The other half got a statin plus, this injectable drug known as evolocumab for once a month for eighteen months. The group that got the statin alone achieved an average level of the bad cholesterol, the LDL, of ninety three. The group that got combination therapy with a statin and a PCSK9 inhibitor got to LDL cholesterol of just thirty six point six milligrams per deciliter, a level that has not really been achieved in any substantial clinical trial. We used a little ultrasound probe, a technique that had been developed here over many years. We actually, at the beginning of the study, measured the amount of plaque in the coronary arteries and at eighteen months later we measured it again. In the group that got a statin alone there was no change in the amount of plaque in the coronary arteries. The disease did not progress but it did not regress either, it did not get smaller. In the group that got to an LDL cholesterol of thirty six there was highly statistically significant regression, there was less plaque at the end of eighteen months than at the beginning. The difference between the two groups was very, very statistically significant. For the first time, now have shown that this new class of drugs, the PCSK9 inhibitors, has a favorable effect on the development of plaques in the coronary and can actually regress those plaques. It turns out about two thirds of patients actually had less plaque at the end of eighteen months than they started with. But even more interesting in many ways we also looked at the subgroup of patients who started out with even lower LDL cholesterol levels. The lowest level recommended by any guideline anywhere in the world is to get below seventy for the bad cholesterol. If you took the people that were below seventy on a statin alone, gave them a combination therapy, they got to an LDL cholesterol level of just twenty four, really an unprecedented level. They had massive regression. Eighty one point two percent of them actually had their plaques get smaller during the course of eighteen months. Many of those patients had levels of LDL cholesterol down in the ten to twenty ranges. These are really low levels. We also looked at the relationship between the achieved level of bad cholesterol and the rate of progression. It looks like a straight line all the way down to twenty. We believe that the conclusion of the trial is that getting the bad cholesterol down to levels that we could never achieve before can in fact reverse coronary heart disease in a significant fraction of patients. Now this is of course not measuring the effect of these drugs on heart attack, strokes or death. It’s an end point of plaque but we’ve shown over the years that having less plaque generally results in having fewer heart attacks, strokes and less likelihood of dying. We think that when the large clinical outcome trials that are currently under way are completed, our study suggests that there will be a significant reduction in the risk of the things that people really care about which are the clinical events that occur. It’s an exciting finding. We used to say: “you can’t be too rich or too thin”; we now say: “you can’t be too rich, too thin or have too low of a cholesterol level.” Now what about safety, we saw no safety problems at these ultra-low levels of the bad cholesterol. There weren’t any more muscle problems, there weren’t any neuro cognitive problems, and there were few if any reactions at the site of injection. The safety in this modest size population was there was no problems with safety at getting levels down to these very, very low levels. We’ve really gone to a whole new level of bad cholesterol and we’ve seen some really pretty exciting results.
This sounds like a game changer, will this change how patients are treated?
Dr. Nissen: I think that most clinicians are going to wait for the clinical outcomes trial. Those trials are going to be reporting out in less than a year. The guidelines will then have to reconsider. We would project based upon what we saw, that those trials will be positive, that we have a favorable affect. But generally, it takes those larger studies that measure clinical outcomes to change guidelines. Some physicians, however, will look at our data and in very high risk patients they will choose to treat them more aggressively with this combination therapy. Now there is a down side and the down side is cost. The list price for these drugs is about a thousand dollars a month, fourteen thousand, twelve to fourteen thousand dollars a year. They’re not for everybody; they’re for the highest risk patients with particularly high cholesterol levels that are very high risk for having serious outcomes. But if you’re in that group of patients there is this new option and we’ve now provided some of the first evidence that these drugs don’t just lower cholesterol levels they change what happens in the artery. We think that’s very significant.
Main consumer friendly take home message?
Dr. Nissen: We were able to show that getting the bad cholesterol levels down to really low levels, down in to the twenties and thirties can actually remove plaque from the coronary arteries; going to levels that we’ve never been able to achieve before.
END OF INTERVIEW
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