The Role of HDL-C in the Management of Atherosclerosis

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Anacetrapib is going to be the competing drug. Dalcetrapib is capable of regenerating pre-beta HDL.26 This regeneration of pre-beta HDL potentiated a significant increase in the recovery of fecal bile acids and neutral sterols, whereas anacetrapib, another inhibitor, which did not regenerate pre-beta HDL, did not result in a significant increase in the recovery of bile acids or neutral sterols in the gastrointestinal tract.

Despite the fact that dalcetrapib raises HDL somewhat modestly compared to the anacetrapib (which raises HDL-C about 140%),30 consistent with what Bryan had said earlier, we are probably shooting for the augmentation of RCT rather than some absolute level of HDL-C targeting.

DR. RADER: Could you please briefly cover dal-VESSEL,31 dal-PLAQUE,32 and then maybe just sort of give a description of the dal-OUTCOMES trial33 in terms of the general design?

DR. TOTH: In order for any of these drugs to be approved, they are going to have to have hard cardiovascular outcome data coupled with demonstrable long-term safety. dal-OUTCOMES is enrolling about 15,600 patients with established CAD and they’re being randomized to dalcetrapib plus statin versus statin alone.33 Hopefully this trial will constitute a rigorous test of whether or not the addition of dalcetrapib to statin in patients with established CAD will provide incremental risk reduction.

It is important to point out that dal-OUTCOMES will not be a rigorous test of the HDL hypothesis. If it works it’s just going to show that dalcetrapib provides incremental risk reduction. dal-VESSEL basically turned out to be a safety study. What the investigators were hoping to show was that the use of dalcetrapib will impact endothelial function and promote vasodilatory capacity. In the end it turned out to be a neutral study. dal-PLAQUE used a variety of imaging modalities to determine whether or not dalcetrapib impacts plaque volume and configuration. But again, the impact was relatively modest.

DR. RADER: You referred to anacetrapib, a very different CETP inhibitor with a different profile. Can you summarize anacetrapib’s lipid effects and the outcome trial that’s currently going on?

DR. BREWER: Anacetrapib is a more potent inhibitor of CETP than dalcetrapib. As a result of the more consistent inhibition of all of the facets of CETP’s functionality, anacetrapib increases HDL about 140% and reduces LDL approximately 35%. In the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) study34,35 anacetrapib was not associated with the adverse side effect previously observed with torcetrapib. Based on the positive safety profile in DEFINE, a 30,000 patient morbidity and mortality trial, Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL),36 has been initiated to determine if CETP inhibition is associated with a decrease in cardiovascular clinical events.

There is also the development of a third CETP inhibitor, evacetrapib,37 which has a similar lipoprotein profile to anacetrapib. There will ultimately be several CETP inhibitors developed, and we will have the opportunity to see if these inhibitors will reduce the residual cardiovascular risk in our patients that are taking statins.

DR. RADER: And I’ll just add briefly they also seem to lower lipoprotein(a) (Lp[a]) levels for reasons that are totally unclear. 

DR. BREWER: I think that’s really a very exciting facet of the CETP inhibitors, in that they also lower LDL as well as Lp(a). We still do not know the definitive mechanism for the reduction in LDL or Lp(a). However, for the first time we may have a drug that will lower LDL, increase HDL and lower Lp(a), which should be of great use in the treatment of the high risk patient with cardiovascular disease.

DR. TOTH: It is a continuous linear relationship as a function of time. It will be interesting to see how low Lp(a) goes over the course of 3–5 years.

DR. RADER: So as you all have pointed out, these two CETP inhibitors are actually very different drugs which have very different effects on the lipid profile, and it’s important that they’re both being tested in large clinical trials. The only thing we’re missing is they’re not being tested head-to-head.

But having said that, Jean-Claude, you get the fun question. There’s a lot of discussion about whether you would want to inhibit CETP more or less. No one knows the right answer. But what’s your take on the concept that maybe there’s a sweet spot for CETP inhibition and maybe it’s not the more inhibition the better. I mean, is there validity to that?

DR. TARDIF: Well I think you already said it. These are very elegant hypotheses and positions, but it’s dal-OUTCOMES and REVEAL38 that will really tell us the clinical significance of this. The only thing I would add is that, yes, people are saying, do you need more potent or less potent inhibitors? I think the question is whether or not we need complete inhibition versus selective modulation.

So said differently, is it more beneficial to simply block or only block the transfer of cholesterol esters from HDL to apoB containing lipoproteins, and let CETP do its work on the remodeling of HDL particles that generate pre-beta particles? Or is it better to get complete CETP than blockade in terms of its effects on transfer to apo B containing lipoproteins and the effects of CETP on HDL remodeling. I think nobody really knows; certainly anacetrapib not only has effects on HDL-C, but has major effects on LDL-C.

Most people would think that this is a good thing, but you could argue that perhaps the reason by which it’s doing that may not necessarily be a good thing. We don’t really know the clinical significance of these different mechanisms.

DR. RADER: Peter, do you have any comments on CETP inhibition?

DR. TOTH: I just want to add a little bit of sense of balance to the whole CETP discussion because I want them to work, because we need novel therapies. But on the other hand we have to introduce a little bit of a note of skepticism just because we’ve got so many recent studies that have interjected notes of caution.

The Framingham Offspring Study recently showed that low CETP activity was associated with increased risk for cardiovascular events in Framingham.17 The Prevention of Recurrent Venous Thromboembolism (PREVENT)42, the Ludwigshafen study in Germany and then the Copenhagen City Heart Study40-42 all have shown that decreased CETP activity is associated with increased risk in their studies. Counterbalancing some of these findings are other studies like the Womens’ Health Study,43 and then the Emerging Risk Factors Collaboration,44 which showed modest reductions in risk if CETP activity was low.

It’s a very messy area and I think one particular concern for me is recent data from the Regression Growth Evaluation Statin Study (REGRESS),45 where they showed if you were on a statin and your CETP was below the median, your risk for disease progression and for cardiac events increased dramatically compared to people whose CETP activity was above the median. It’s all going to come down to the dal-OUTCOMES34,46 and then also to REVEAL36 and Heart Protection Study 3 (HPS3).

DR. BREWER: I think that’s good, because I think that we need to put in the appropriate problems associated with the simple conclusion that raising HDL is a great target. Although that makes it more confusing to the cardiologist, we still don’t know the answer based on anything other than the outcomes studies.

DR. RADER: I’d like to take one more minute just to briefly touch on a few other things that are much earlier in potential clinical development and then we’ll wrap things up.

Jean-Claude, let’s start with apoA-1 infusions since you have a history with that. Can you tell us something; what’s going on with the concept of apoA-1 infusion?

DR. TARDIF: Very simply put, there have been three small clinical studies, all less than 200 patients that have all shown the same thing. One with a mutant form of apoA-1, called apoA-1 Milano, 47 patients47; one with the wild type form of apoA-1 called the Effect of Reconstituted HDL on Atherosclerosis and Efficacy (ERASE) study;48 and a third approach called HDL delipidation that was led by Bryan Brewer.49 All studies basically came back with almost identical results; that is significant reduction of plaque burden versus baseline, but not significant compared to placebo because these studies were too small.

And in the study we did, ERASE, we saw favorable changes in plaque composition and position.47 I think none of these studies are definitive. We’re doing a large study now, 500 patients called the Can HDL Infusion Significantly Quicken Natural Atherosclerosis Regression (CHI-SQUARE) trial. Next year we’ll be able to tell you whether it works or not.

DR. RADER: Exciting. So there’s also endogenous up-regulation of apoA-1. Peter, are you comfortable talking about what’s happening there?

DR. TOTH: Yes, RVX-20850,51 is an interesting novel compound, and it exerts a variety of effects including increasing hepatocyte driven apoA-1 production and HDL biogenesis. The other facet of this is it has also been shown to stimulate ABCA1 expression on the surface of macrophages, and the combination of these two effects may provide for a powerful approach toward altering HDL metabolism and RCT kinetics. In the safety studies done to date by Jacques Genest and co-workers, it also appears to have some promise that will have to be tested in larger scale trials.

And there is an ongoing IVUS trial, too that will be interesting.

Finally, Bryan, you know the concept of getting the macrophage to up-regulate efflux pathways is attractive. If you could comment briefly on two approaches; one would be LXR agonists; are they dead or is there still a possibility? And the second would be miR-33 antagonism.

DR. BREWER: I think both of these new approaches are very exciting ways to further look at the question of reducing cardiovascular disease. It would be interesting to be able to specifically increase macrophage ABCA1, which could be achieved with macrophage specific LXR agonists. I don’t think that LXR agonists are dead and further research in this area may provide some new drugs with greater macrophage specificity.

A very exciting new area for modulation of HDL-C levels and cholesterol metabolism are microRNA antagonists; microRNAs are short, double-stranded RNAs that bind to complementary target sites in the three untranslated regions of mRNA, resulting in translational repression of gene expression. Of particular interest is miR-33, which down-regulates expression of ABCA1 and ABCG1, as well as reduces fatty acid degradation. An antagonist to mi-R33 is a potential novel mechanism to regulate HDL metabolism and atherosclerosis.52

DR. RADER: What I’ve heard in this time is that despite the setbacks and despite the uncertainty, the HDL therapeutic field is alive and well. If the CETP inhibitor trials are positive this class is going to be a big deal. We’re still waiting for the final word on niacin. And then they are several other things that are in an earlier stage of development, so it will be fascinating to see how all of this pans out over the next decade. Thanks very much everybody.