The Role of CETP Modulation and Inhibition in the Progression of Coronary Heart Disease

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DR. NICHOLLS: Well, I think that they should be optimistic that the field has moved forward. If you go back to the end of 2006, early 2007, the rug had really been pulled out from under all of us. It was certainly quite conceivable that there wouldn’t be a path forward for a CETP inhibitor at all.

Keep in mind that the cardiovascular field in general has numerous examples of therapeutic classes where the first drug failed. In fact, the very first statin failed. It was important for us to be able to elucidate what we did about torcetrapib so that we could get this moving forward. Investigators and clinicians who are watching from the sidelines could be confident that we were moving forward with a class of drugs that is potentially safe, and potentially effective.

I think that’s what we’ve seen. DEFINE was a very elegant study; it was almost the first of its kind. It’s almost a small outcome study. It’s not quite a Phase II study; it’s not quite a Phase III study. It gave a pretty clean bill of health to anacetrapib. This drug has impressive lipid effects and there is a lot of confidence not only in its ability to raise HDL, but its ability to lower LDL. As Christie said, just purely its LDL lowering of 35% to 40%, is something that I think would be attractive in clinical practice.

The dalcetrapib program includes several programs where we’ll see the results in the next few years. This drug, while it raises HDL-C less than anacetrapib, still has a fairly robust increase in HDL-C levels. Ultimately we have to see if they prevent cardiovascular events. If they do that then we will have an additional class of drugs on top of the statins to help reduce cardiovascular morbidity and mortality.

DR. DAVIDSON: You want to mention the third CETP inhibitor, evacetrapib?

DR. NICHOLLS: We performed a 12-week lipid study15 to define the effects of the compound on both HDL and LDL levels, both as mono-therapy and in combination with a range of statins at their commonly prescribed doses. What we observed was a dose-dependent increase in HDL by up to 129% and decrease in LDL by up to 36%. We observed robust changes with the submaximal dose in combination with the most commonly prescribed statins at their typically used doses. We did not observe adverse effects on blood pressure or mineralocorticoid activity. I suspect that ultimately, like the statins, we’ll end up with a number of CETP inhibitors.

DR. DAVIDSON: Let’s close by reviewing what’s going to happen over the next several years as the CETP inhibitor outcome trials complete. Christie, I’ll start with you.

DR. BALLANTYNE: Well, the first thing we’re going to find out now is clinical outcomes. Will there be a reduction in events? Will we see any safety signals? I think that there are enough differences between the drugs we have discussed, that one cannot assume that the results with dalcetrapib will be applicable to anacetrapib.

We will have to wait until the results of the outcomes for all the studies, including anacetrapib and evacetrapib to really know the differences in these drugs. It’s one of these things where it’s truly the scientific method. One does experiments and you don’t know what the answer is going to be until they are completed.

DR. DAVIDSON: It’s fair to say that even if one doesn’t work, another one might. It’s really different than the statins. Each of these CETP inhibitors act differently and so we’ll have to see how each one turns out. It might not be a class effect at all for CETP inhibitors. We know the first drug of the class, torcetrapib was toxic but hopefully the new CETP inhibitors that do not share the adverse effects of torcetrapib on blood pressure and steroidogenesis will be beneficial.

DR. BALLANTYNE: Yes.

DR. DAVIDSON: We have explanations about why it was toxic, but yet I think each of the other CETP inhibitors in development have differences that may affect their outcomes as well.

DR. BALLANTYNE: Correct.

DR. DAVIDSON: Bob, how do you see things comparing going forward in the next five years with the field?

DR. ROSENSON: The clinical trials are key and clearly the different CETP inhibitors vary with respect to their lipid and lipoprotein effects. Dalcetrapib is an agent that will allow us to more adequately test the HDL hypothesis than any other therapy that we have had other than the apoA1 mimetics and apoA1 inducers because this agent works essentially on HDL particles. Thus far, we have not discussed the effects of dalcetrapib on increasing the pre-beta HDL fraction, which is the HDL fraction that interacts with the quintessential ABCA1 transporter. We know how important the ABCA-1 transporter is for macrophage cholesterol efflux. At the same time, we also know from work by Laurent Yvan-Charvet and Alan Tall that the heterotypic CETP inhibitors form very large HDL particles that can remove cholesterol from the cell membrane via the ABCG1 pathway. These data provide another example as to how these agents differ even at the level of the cholesterol transporters.

Moving forward, it will be interesting to see how these different CETP inhibitors impact clinical cardiovascular events. Through its effects on HDL, dalcetrapib works mainly on the anti-atherothrombotic side of cardiovascular risk, whereas anacetrapib works on reducing atherogenic lipoproteins. In statin-treated patients with the metabolic syndrome and type 2 diabetes, anacetrapib may be very useful to reduce residual risk.

Whether anacetrapib will be effective because of its effects on increasing HDL-C is not necessarily clear to me, whereas the potential benefits of reducing the atherogenic particles is more widely accepted. The translation of these clinical trials into different subgroups of individuals who may benefit from one agent compared to another is going to be one of the great challenges that we have as clinicians and educators.

DR. DAVIDSON: This has been a fascinating discussion about a novel class of therapies on the horizon that may not be pertinent to your practice today as clinicians, but addresses an important topic by focusing on the HDL pathway for reducing atherosclerosis.

I want to thank everyone. It’s going to be an exciting several years in this field. Thank you very much.

 

 

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