Raising HDL Cholesterol: The Controversy
Dr. Nicholls: We have seen that if you infuse HDL, you rapidly regress plaque. And so that tells me that if you infuse it in large enough quantities, which don't necessarily raise HDL cholesterol -- and that is the big distinction here; the concerns with the failed studies have been about HDL cholesterol-raising drugs, and that may be different from targeting HDL -- and so if you infuse HDL, give a boatload of it into the plasma straight away, it seems to be doing the right thing. It is shrinking plaques. Ultimately, the HDL hypothesis will not be proven until an HDL drug reduces cardiovascular events, and we haven't seen that yet.
Dr. Harrington: We really need to see an HDL infusing agent in a large enough outcome study to tell us yay or nay.
Dr. Nicholls: To me, that is probably the purest hypothesis. You know, if you look at the other drugs that are out there, niacin has failed. Niacin does lots of other things. The CETP inhibitors, some of them failed already; they have got some baggage. There are 2 CETP inhibitors that are very potent that are in phase 3. They double HDL but they lower LDL 30% to 40%, so they may just work just because of that. We looked at an ApoA1 inducer here. It didn't work. It didn't have any incremental effect on HDL and it didn't regress plaque any more than placebo.
Dr. Harrington: Did it have any toxic effects?
Dr. Nicholls: It raised liver enzymes a bit so I think that is a challenge. But that, again, doesn't become a test of the HDL hypothesis because it didn't do anything above and beyond therapy, so to me the purest test would be to infuse it. We had some intriguing studies early with imaging they had to reformulate -- all those companies.
Dr. Harrington: Are you talking about IVUS imaging?
Dr. Nicholls: In IVUS imaging, ultimately it is going to be about events. That is what we care about for our patients, and so we need better formulations. But we need them to get to the clinical trials to evaluate them.
Dr. Harrington: Renu, let's go back to you and mechanism, mechanism, mechanism.
Dr. Virmani: You know, it is very nice to say that animal studies worked and the animal plaque resembled human plaque -- absolutely not! It is very rich in macrophages and, yes, you can convert, and not many necrotic cores. Therefore, your animal studies are not appropriate. Remember: We do it with very high cholesterols and therefore we can reverse things in the animal. I think human [disease] is a different disease which takes decades to develop, and now you want to put a regression on it and you are going to try and do it in a year or 2 years. I just don't see how you are going to see it.
Dr. Nicholls: So we saw 3 imaging studies in humans, all with an acute coronary syndrome within the preceding 2 weeks, weekly infusions of delipidated HDL on 4-6 occasions over the next 2 months, rapid regression of disease. Whether those therapies get to the clinic or not, it at least supports the hypothesis, but until we have a drug that targets HDL and it reduces cardiovascular morbidity and mortality, we will not have proven the hypothesis.
But I think the argument, that the hypothesis is dead on the basis of the evidence we have seen, is a little premature.
Dr. Harrington: Can I push here, Renu? Are you saying it is dead or are you saying that there is still life here and that Steve is making some points that have to be addressed?
Dr. Virmani: I think Steve is making some good points and I think they have to be addressed. I totally agree that infusion is going to be different as compared to what is currently being done. I also think that imaging with IVUS has its limitations, so you cannot rely on IVUS alone. We have better tools today. Maybe we would be able to show some regression if we can show, for example, that the area of cholesterol becomes much less, or if we can show by optical coherence tomographythat we start seeing fewer macrophages -- that will be something that will be encouraging, but I need that kind of encouragement.
Dr. Nicholls: I think the other thing that we are in complete agreement about is that cholesterol is important. We have seen major advances by lowering LDL cholesterol. We have now got these new drugs, which are now going into phase 3 trials.
Dr. Harrington: Are you talking about the PCSK9 inhibitors?
Dr. Nicholls: PCSK9 inhibitors. They are going to lower LDL another 50%, and it is just mind-boggling to think that if you get an LDL of 30, what is going to happen there? So there are 2 large outcome studies, and we have the good fortune to be able to do an IVUS study in parallel and ask whether we will see more regression than we have seen in the studies where we have been able to get LDLs to 60. We have to do the studies.
Dr. Harrington: The PCSK9 story is an interesting one, isn't it, because it is all based on this hypothesis where events decrease as LDL decreases, and what we don't know, as you know well, is whether that curve plateaus.
Dr. Nicholls: We talk a lot about residual risk, and I think we really need to change the whole topic to modifiable risk. The question is, at what point on that line do we stop being able to modify the risk? We just don't know that.
Dr. Harrington: But with these new studies, as you say, it is the data that has been presented thus far at these meetings, at AHA, at ACC. It is extraordinary, the effect on lipids that these agents have.
Dr. Nicholls: Yes.
Dr. Virmani: If you look at IVUS studies, I think it is interesting that with statins they can show very nicely that calcium goes up. Now, once you have high calcium, are you going to be able to show a further benefit? That is going to be the problem with these.
Dr. Nicholls: We looked at that data a number of years ago and looked at people according to how much calcium they had. If you had a lot of calcium, you didn't progress and you didn't regress.
Dr. Virmani: Yes.
Dr. Nicholls: They had a modifiable disease. They have stable plaque.
Dr. Virmani: That is why stable plaque, I believe, should not be treated percutaneously.
Dr. Harrington: That may be a hypothesis that we choose to test, and that is an interesting question.
Dr. Nicholls: One of the questions that will come with all of these imaging advances is, ultimately, how we are going to use it in clinical practice and whether this is exactly the right way to use it. Can we use it as a biomarker that says that this person has got modifiable risk and this person doesn't, and so we should be more aggressive with that person?
Dr. Harrington: That's the notion of taking the population-level data and applying it to a personalized level. But we have got the big piece of data that says that, yes, the drugs are associated with an improvement in outcome, but we know that most of that effect is concentrated in a certain group of patients that we can detect with this biomarker. That is the way to go.
Dr. Harrington: This has been a terrific discussion. I am glad that we maybe agree somewhere in the middle here. It is good to be skeptical. I think it is also good to say that this is a hypothesis that is not yet dead, that has some life in it, and we look forward to new studies. Dr. Steve Nicholls, Dr. Renu Virmani, thanks for joining me here at ESC in Amsterdam.
Infusing HDL
Dr. Nicholls: We have seen that if you infuse HDL, you rapidly regress plaque. And so that tells me that if you infuse it in large enough quantities, which don't necessarily raise HDL cholesterol -- and that is the big distinction here; the concerns with the failed studies have been about HDL cholesterol-raising drugs, and that may be different from targeting HDL -- and so if you infuse HDL, give a boatload of it into the plasma straight away, it seems to be doing the right thing. It is shrinking plaques. Ultimately, the HDL hypothesis will not be proven until an HDL drug reduces cardiovascular events, and we haven't seen that yet.
Dr. Harrington: We really need to see an HDL infusing agent in a large enough outcome study to tell us yay or nay.
Dr. Nicholls: To me, that is probably the purest hypothesis. You know, if you look at the other drugs that are out there, niacin has failed. Niacin does lots of other things. The CETP inhibitors, some of them failed already; they have got some baggage. There are 2 CETP inhibitors that are very potent that are in phase 3. They double HDL but they lower LDL 30% to 40%, so they may just work just because of that. We looked at an ApoA1 inducer here. It didn't work. It didn't have any incremental effect on HDL and it didn't regress plaque any more than placebo.
Dr. Harrington: Did it have any toxic effects?
Dr. Nicholls: It raised liver enzymes a bit so I think that is a challenge. But that, again, doesn't become a test of the HDL hypothesis because it didn't do anything above and beyond therapy, so to me the purest test would be to infuse it. We had some intriguing studies early with imaging they had to reformulate -- all those companies.
Dr. Harrington: Are you talking about IVUS imaging?
Dr. Nicholls: In IVUS imaging, ultimately it is going to be about events. That is what we care about for our patients, and so we need better formulations. But we need them to get to the clinical trials to evaluate them.
A Dead Hypothesis?
Dr. Harrington: Renu, let's go back to you and mechanism, mechanism, mechanism.
Dr. Virmani: You know, it is very nice to say that animal studies worked and the animal plaque resembled human plaque -- absolutely not! It is very rich in macrophages and, yes, you can convert, and not many necrotic cores. Therefore, your animal studies are not appropriate. Remember: We do it with very high cholesterols and therefore we can reverse things in the animal. I think human [disease] is a different disease which takes decades to develop, and now you want to put a regression on it and you are going to try and do it in a year or 2 years. I just don't see how you are going to see it.
Dr. Nicholls: So we saw 3 imaging studies in humans, all with an acute coronary syndrome within the preceding 2 weeks, weekly infusions of delipidated HDL on 4-6 occasions over the next 2 months, rapid regression of disease. Whether those therapies get to the clinic or not, it at least supports the hypothesis, but until we have a drug that targets HDL and it reduces cardiovascular morbidity and mortality, we will not have proven the hypothesis.
But I think the argument, that the hypothesis is dead on the basis of the evidence we have seen, is a little premature.
Dr. Harrington: Can I push here, Renu? Are you saying it is dead or are you saying that there is still life here and that Steve is making some points that have to be addressed?
Dr. Virmani: I think Steve is making some good points and I think they have to be addressed. I totally agree that infusion is going to be different as compared to what is currently being done. I also think that imaging with IVUS has its limitations, so you cannot rely on IVUS alone. We have better tools today. Maybe we would be able to show some regression if we can show, for example, that the area of cholesterol becomes much less, or if we can show by optical coherence tomographythat we start seeing fewer macrophages -- that will be something that will be encouraging, but I need that kind of encouragement.
PCKS9 Inhibitors
Dr. Nicholls: I think the other thing that we are in complete agreement about is that cholesterol is important. We have seen major advances by lowering LDL cholesterol. We have now got these new drugs, which are now going into phase 3 trials.
Dr. Harrington: Are you talking about the PCSK9 inhibitors?
Dr. Nicholls: PCSK9 inhibitors. They are going to lower LDL another 50%, and it is just mind-boggling to think that if you get an LDL of 30, what is going to happen there? So there are 2 large outcome studies, and we have the good fortune to be able to do an IVUS study in parallel and ask whether we will see more regression than we have seen in the studies where we have been able to get LDLs to 60. We have to do the studies.
Dr. Harrington: The PCSK9 story is an interesting one, isn't it, because it is all based on this hypothesis where events decrease as LDL decreases, and what we don't know, as you know well, is whether that curve plateaus.
Modifiable Risk
Dr. Nicholls: We talk a lot about residual risk, and I think we really need to change the whole topic to modifiable risk. The question is, at what point on that line do we stop being able to modify the risk? We just don't know that.
Dr. Harrington: But with these new studies, as you say, it is the data that has been presented thus far at these meetings, at AHA, at ACC. It is extraordinary, the effect on lipids that these agents have.
Dr. Nicholls: Yes.
Dr. Virmani: If you look at IVUS studies, I think it is interesting that with statins they can show very nicely that calcium goes up. Now, once you have high calcium, are you going to be able to show a further benefit? That is going to be the problem with these.
Dr. Nicholls: We looked at that data a number of years ago and looked at people according to how much calcium they had. If you had a lot of calcium, you didn't progress and you didn't regress.
Dr. Virmani: Yes.
Dr. Nicholls: They had a modifiable disease. They have stable plaque.
Dr. Virmani: That is why stable plaque, I believe, should not be treated percutaneously.
Dr. Harrington: That may be a hypothesis that we choose to test, and that is an interesting question.
Dr. Nicholls: One of the questions that will come with all of these imaging advances is, ultimately, how we are going to use it in clinical practice and whether this is exactly the right way to use it. Can we use it as a biomarker that says that this person has got modifiable risk and this person doesn't, and so we should be more aggressive with that person?
Dr. Harrington: That's the notion of taking the population-level data and applying it to a personalized level. But we have got the big piece of data that says that, yes, the drugs are associated with an improvement in outcome, but we know that most of that effect is concentrated in a certain group of patients that we can detect with this biomarker. That is the way to go.
Conclusion
Dr. Harrington: This has been a terrific discussion. I am glad that we maybe agree somewhere in the middle here. It is good to be skeptical. I think it is also good to say that this is a hypothesis that is not yet dead, that has some life in it, and we look forward to new studies. Dr. Steve Nicholls, Dr. Renu Virmani, thanks for joining me here at ESC in Amsterdam.