DR. WENGER: Again, the message is that we need information on the combination of a fibrate and a statin in a randomized study, in people who have high triglycerides. That information was not truly imparted by the full ACCORD cohort.
DR. BALLANTYNE: It’s frustrating for those of us who are in this field that we’ve yet to have a true triglyceride trial. Hopefully we’ll finally get one in the near future.
DR. WENGER: This is the concern that so many have voiced of the difference between trial populations and community populations. Here we see the trial data being extrapolated to the community, where often the community (these are patients we see in our offices) differs markedly from the highly selected group in clinical trials.
Let me ask you to return to another trial, though, and that is the VA-HIT11 trial. Obviously, the concern with VA-HIT is that it was a single-sex trial, confined to men, but tell me what have we learned from VA-HIT that’s applicable to our male patients.
DR. BALLANTYNE: I think this is consistent, when you have people who enter into a trial with low levels of HDL cholesterol. In the VA-HIT study, a different fibrate was tested, gemfibrozil and there was benefit in regards to cardiovascular event reduction. So gemfibrozil worked when there were low levels of HDL cholesterol. An old study with fibrates was the Helsinki Heart Study.12 Interestingly, these patients were enrolled by high levels of non-HDL cholesterol, not by high levels of LDL cholesterol. In that trial, the group that had the greatest benefit were individuals with high triglycerides and low HDL cholesterol.
Overall, there’s a fairly consistent theme that, at least in regard to fibrates, the patient population that benefits needs to have a low HDL cholesterol and high triglyceride. So there are some differences compared to statins. These have benefitted in a wide variety of patients. They’re uniquely easy agents to use as compared to fibrates. I think fibrates are like some other therapies—you’ve got to target more specifically the patients to get benefit.
DR. WENGER: What’s fascinating, if you recollect the history of statin use and review the early requirements for substantial laboratory testing that had to be done pre-therapy, and with change of therapy, etc., virtually all those test requirements have proved unnecessary as we’ve increasingly used statins in clinical practice. The clinical use of statin therapy today is totally different than it was a decade ago.
Let’s proceed to another category of drugs. Dr. Davidson, the CETP drugs and raising of HDL cholesterol levels. There has been a longtime interest in trying to raise HDL cholesterol. It’s been an elusive target. Should we be excited or should we be worried about the recent clinical trial data?
DR. DAVIDSON: CETP inhibition is an interesting target. CETP is the protein that transfers cholesterol from HDL back to the ApoB containing particles VLDL and LDL. So by blocking CETP, HDL increases significantly and if you block it enough, LDL also decreases significantly. Animals that lack CETP, such as mice, rats, and dogs have very high HDL and low LDL. So in that sense, it’s a very attractive target.
The first CETP inhibitor that went into human trials was torcetrapib, and, as expected, it raised HDL and lowered LDL, but also raised blood pressure. A very large outcome study with this agent (ILLUMINATE),13 was stopped early due to increased mortality, so that cast a pall over the whole CETP inhibition mechanism as a target of therapy. There was concern that by inhibiting CETP, HDL becomes large and dysfunctional and no longer athero-protective.
Fortunately, two additional CETP inhibitors are being studied. One is called dalcetrapib that’s produced by Roche Genentech. It works by modulating the actual protein itself. It does not bind HDL and leads to about a 30% increase in HDL. The drug has been studied and does not raise blood pressure. There is now a large outcomes study with this agent that will be completed in 2013. The study dal-HEART14 is designed to look at high-risk acute coronary syndrome patients and see if the drug improves outcomes in all patients, regardless of their baseline HDL. Dalcetrapib is also being evaluated for the effects on atherosclerosis as measured by carotid MRI and coronary IVUS. We’ll be seeing more data in the near term in regard to its effects on blood pressure and endothelial function. From what we can tell from the data so far, there has not been an adverse effect on blood pressure. Because it works with a different mechanism from torcetrapib, it might maintain better HDL functionality. We’ll have to wait and see what happens as the clinical trials proceed over the next few years.
The second CETP inhibitor is anacetrapib. It’s a potent CETP inhibitor. It raises HDL by about 100% and it lowers LDL by about 30%. So it’s very effective in modifying the values of HDL and LDL on the lab sheet. The question about anacetrapib—because it is closely related to torcetrapib in structure—is safety. Anacetrapib was evaluated in a very large safety trial called DEFINE.15,16 There were 2757 high-risk patients in the study, comparing anacetrapib with placebo for 18 months. The study showed that there was no torcetrapib-like effect on blood pressure, and, in this patient population, that the drug was safe.
DR. WENGER: No increase in blood pressure.
DR. DAVIDSON: No increase in blood pressure, there was no increase in cardiovascular events, no increase in mortality. So the DEFINE study ruled out a torcetrapib adverse effect on cardiovascular events. On the positive side, the cardiovascular events seemed to go in the right direction, especially revascularization, which was eight events on anacetrapib, compared to 28 events in the statin control group. We’re talking about those already at their well-treated LDL targets. The DEFINE study has given us a lot of confidence that the problems with torcetrapib may have been molecule-specific and not mechanistically based.
It doesn’t necessarily mean that CETP inhibition is going to work on reducing cardiovascular events, but we now have more optimism that these drugs may, in fact, provide significant cardiovascular benefits. If anacetrapib does work, and it appears to work in relationship to how much it lowers LDL, we still may not know whether it’s the HDL raising affect that causes the benefits. This is a complex field, and we may not have an answer to whether raising HDL is beneficial with CETP inhibition.
There are going to have to be drug-specific studies, because the drugs are different in how they work. We’re not going to be able to draw any broad conclusions about raising HDL and what this means when it comes to cardiovascular benefits. This is truly a situation where I believe in a class effect for supporting the LDL hypothesis, but when it comes to this particular area, we’re going to be basing more of our evidence on the specific drug that was used in the trial.
DR. WENGER: The challenging aspect is that we now see HDL raising through two different mechanisms by these two different drugs. It opens a new vista. Let me ask you to continue from the viewpoint of the clinician. For the clinician in practice, what should he or she be alert for as research data begin to emerge? On one hand, we see trials in acute coronary syndromes. Other research trials are outside the setting of an acute event, more comparable to office practice. What should the clinician look for as lipid trial data emerge in the next several years?
DR. DAVIDSON: I think the key thing is not to over-interpret things that may not be powered sufficiently to give us an answer. For example, we’re going to have the dal-VESSEL17 study come out first, which is an endothelial function trial with dalcetrapib. That really was a safety trial to make sure there was no adverse effects on blood pressure or endothelial function. So if it doesn’t work on improving endothelial function, I don’t think we should jump to the conclusion that it’s not going to work when it comes to cardiovascular outcomes.
One word is caution. We need to make sure the trials are designed appropriately to answer questions that we want answered in regard to HDL therapies. The key thing is, we have to be patient, and I know that’s hard sometimes, but we have to be patient for the studies to finish and give us the right answers for how these drugs can be most effectively utilized.
We do have two niacin trials that will be coming out in the next few years, too. One is AIM-HIGH,18 with 3,000 patients, looking at niacin on top of a statin, compared to a higher-dosed statin. The LDL cholesterol levels should be about the same in both arms, but we’ll be able to compare the effects of triglyceride lowering and HDL cholesterol raising to that of the equivalent LDL cholesterol levels. Whether it will have enough events is hard to say, but as we mentioned early on, that group of patients that does have high triglycerides, low HDL, metabolic syndrome and heart disease, do have a high risk even on a statin. My hope is it will be sufficiently powered to see enough event difference and that in the absolute event differences. To me, this is probably the most interesting trial evaluating niacin treatment.
The other trial is Heart Protection II, or THRIVE.19 The study will compare a statin in the control group to a combination of niacin and laropiprant to reduce the flushing with the niacin. The study will evaluate a similar population as HPS I,7 which includes those with CVD, diabetes and high Framingham risk. The THRIVE population will not have only low HDL/metabolic syndrome patients like AIM-HIGH, and therefore it may be hard to compare the two trials. I think when someone looks at those two trials, they shouldn’t jump to the conclusion that one niacin formulation is better than the other because they were treated in different populations. With AIM-HIGH focusing on the more at-risk group that can benefit the greatest from a niacin product, they may likely have a greater relative risk reduction. While the other study will hopefully show still a benefit, the relative risk reduction won’t be quite as robust. So we need to be careful again how we interpret the difference in these trials and what it means for us to use these drugs clinically.
DR. WENGER: It’s fascinating to see the resurgence of interest in niacin, which was really the only drug that survived and thrived following the age-old Coronary Drug Project. Now we see niacin as the focus of many clinical trials. I expect that for clinical practice, clinicians are now looking askance, actually, as are the regulatory agencies, at intermediate or surrogate trial outcomes. What we really require is clinical outcome information. That will be important.
But I expect that clinicians also have concern in terms of the trial populations because many patients seen in clinical practice may be older. Of course, this group has either been systematically excluded from or underrepresented in many clinical trials, and in particular if they have comorbidities. That’s one of the challenges that clinicians face daily in the office. How are they to make decisions for an elderly population, which is the most rapidly growing component of our cardiology practices, with limited data. I hope that the newer trials at least will have a representative component of older people.
Dr. Ballantyne, let’s return to some of the historical data from the Framingham Heart Study,20 which was the landmark prevention study. Many years ago, Framingham showed us that determination of HDL was important in the risk evaluation for cardiovascular disease and that the total cholesterol to HDL ratio was probably the best indicator of risk. In Framingham, for example, a ratio of more than four of total cholesterol to HDL was defined as a good indicator of high risk. Somehow, this observation seems either to have been lost or to have disappeared from view over the past 20 or 30 years because of our focus on LDL reduction. How do you view this?
DR. BALLANTYNE: I think we’re coming back to it. One of the things that’s always been fascinating is, why does that ratio do so well? Mathematically the ratio of total cholesterol to HDL cholesterol is exactly the same as non-HDL cholesterol to HDL cholesterol. It’s not the same as using LDL cholesterol. Basically, what drives the ratio is the non-HDL cholesterol and HDL cholesterol. So that’s one of the reasons as we begin to focus on non-HDL cholesterol, as Mike’s already mentioned, it’s a better marker for risk and probably a better target for therapy than LDL cholesterol.