The other one that is coming back is the focus on HDL. I’m hopeful that at the ACC in 2013, we might be hearing the results of some of these studies with niacin and our first CETP inhibitor, and there’s more in the pipeline beyond this. The challenge has been, as you know, that it hasn’t been very easy to raise HDL. Niacin is not the easiest drug to take. We do have an extended release formulation, and there’s a development of a niacin flushing pathway inhibitor available in Europe. But the challenge has been to achieve major increases in HDL cholesterol or improvements in HDL function, and the therapeutics for this have lagged far behind that for reducing LDL and non-HDL cholesterol.
DR. WENGER: Dr. Davidson, do you think this concentration on LDL was because we did not have an HDL enhancer that could be taken with reasonable safety or was there just loss of interest in the molecule?
DR. DAVIDSON: I think that’s right. I believe that every risk factor becomes more and more important once we find effective treatments to modify that risk factor, and modification of that risk factor yields outcome benefits. So I think that once we find that effective HDL-raising or triglyceride-lowering therapies provide clinical benefits, we’ll start focusing more and more on those particular risk factors. We can say with certainty that the LDL cholesterol lowering with multiple types of approaches results in cardiovascular benefits. If we could demonstrate that HDL-raising-specific therapies or triglyceride-lowering-specific therapies also provide clinical benefits, then we could start addressing this high residual risk that people do have on statins.
In the ACCORD trial, there was 17.3% primary outcome rate in the placebo group who had high triglycerides, low HDL, compared to 10.1% primary outcome rate for those that did not have a high triglyceride, low HDL in both study groups.10 That’s a 70% higher event rate in that one subgroup, which represented about 20% of the patients. We know that they are high risk, so once we can identify effective therapies that can modify that risk, it will become much more important when it comes to management of the overall global risk for patient with diabetes or cardiovascular disease.
DR. WENGER: Dr. Ballantyne, obviously, with a low HDL and high triglycerides as important components of the metabolic syndrome, we have to correct these, if we are to reduce the risk. Are there trials that provide any relevant information?
DR. BALLANTYNE: We do have some data. For example in AFCAPS/TexCAPS,21 patients were recruited by low HDL cholesterol levels and they had benefit with statin therapy. There were a large number of people with metabolic syndrome in the JUPITER trial who did not have high LDLs.4 They benefitted from statin therapy. So I think we have pretty good indicators that patients with the metabolic syndrome benefit from statin therapy if their risk is sufficient to be treated.
Unfortunately, what we don’t have is therapies with drugs that really to target triglyceride, HDL or even obesity. In fact, we are still waiting for the results of Look AHEAD,22 which is our lifestyle trial on obese diabetics. So it’s a case where we recognize there’s a terrible problem here. I would point out we do have pretty good data with regard to lifestyle changes. These patients have high risk for heart disease and diabetes. We have data that lifestyle modification is terrific for reducing the onset of diabetes.
DR. WENGER: Again, certainly that was important, but would you like to comment on lifestyle modifications for raising HDL?
DR. BALLANTYNE: I think this is something that we have to look at more seriously. For example, we have gotten very aggressive with statin therapy. We’ve seen that with more aggressive therapy, you get greater benefits. Now in terms of HDL raising, lifestyle modifications usually are fairly modest, but the more exercise you do and the more weight you lose, the greater the benefits. There is a dose response for diabetes prevention and also some for exercise. It takes a lot, but I think our concepts of prescribing exercise in the past would say, 30 minutes a day, six days a week. That’s really the minimum. It’d be like prescribing ten milligrams of lovastatin.
In fact, you see better efficacy with around an hour a day of exercise. People say that’s not realistic. In my case, I have a family history of both heart disease and diabetes and I find the time to get an hour a day of exercise, on average, in a week. It is a choice that busy people can make. I think the benefits are great, if we look at diabetes prevention, blood pressure control, improving the lipid profile and also probably in my case, mental health when you have a high stress job, there’s nothing better than a vigorous workout.
DR. WENGER: Dr. Davidson, what about the women who have very high HDL levels, in the range of 80 or 90, and consequent elevated total cholesterol levels? Should they be treated with medication despite their high levels of HDL? Do we have any data that could guide those decisions?
DR. DAVIDSON: We really don’t have data. I actually believe that this is a situation where it’s very valuable to talk to the woman yourself and get a feeling for where she stands on the issue of drug treatment. I know a lot of people don’t like you to do that. They’d rather you tell them what to do, but I think the situation where when you have a high HDL and a high LDL, your risk is actually quite low—lifetime risk is low, and often we find these people live to be quite old and live healthy lives. We need to be cognizant of that issue, that there is no evidence of benefit. The risk is generally quite low in these women.
What frequently is kind of a tiebreaker is that if the LDL is above 190 mg/dl, then you’re kind of above the threshold of where the ATP guidelines say you should initiate therapy. Or if you have another risk factor—hypertension or a bad family history or high LPa, that I think would also weigh more towards treatment. Then if you want to do an assessment, such as carotid IMT or coronary calcium and look for evidence of subclinical disease, that can help you if the woman is old enough. A woman with high HDL should be at least 50 before considering a coronary calcium scan to assess risk.
But my general view is very conservative in how I treat women in that situation. I try to be cognizant of the fact that they are at low risk. We should try lifestyle approaches first, and then if necessary have them go onto treatment, but in general, I like to hear what the woman has to say, too, before I decide which way to go.
DR. WENGER: The final question, actually for both of you, is given the variety of rather powerful statin drugs that enable reducing LDL cholesterol levels to be extremely low values, is there any level of LDL below which any other interventions may not provide significant benefit?
DR. BALLANTYNE: There are a few things. First of all for the clinician, at least, using therapies lowering LDL cholesterol to brittle levels like 20 or 30 mg/dl does not seem to cause harm to the patient. Now the question that comes up is, are there ever people in whom you have treated LDL to very low levels and they are still at increased risk for CHD? Unfortunately the answer is yes. These tend to be people with other comorbidities, such as low levels of HDL cholesterol, high triglyceride, diabetes, or kidney disease. But we don’t really have the answer yet, in regard to whether, if you have LDLs on average down to 25 or 30, you would still have much risk from other lipoprotein abnormalities such as involving HDL.
From what we saw in the large collaborative trial—and they looked at more intensive compared to less intensive statin therapy—and these were LDLs that were in the 70s and 60s—there was still benefit for the patients who got aggressive LDL treatment, but they still had the increased residual risk by having a low HDL. So there appears to be some risk still with low HDL even with intensive statin therapy and that was seen in TNT.
DR. WENGER: Dr. Davidson, your comment?
DR. DAVIDSON: I agree with everything Christie said. I think lower is better, as a general rule of thumb. Sometimes when I have really low HDL cholesterol, I just drive the LDL cholesterol down to equal to HDL cholesterol as a target in these very high-risk patients. So there’s one approach to take. I really can’t say what’s better, an LDL cholesterol of 30mg/dl with HDL of 30 mg/dlor LDL of 60 mg/dl with and HDL of 60 mg/dl. They both have the same one-to-one ratio. So one strategy for a very low HDL cholesterol is to really drive the LDL cholesterol down quite low, and as Christie mentioned, we don’t have any evidence that there’s harm. We have a lot of evidence that these people do fine. In the JUPITER trial, what was reassuring was that when the LDL cholesterol was treated to below 50 mg/dl, people actually had lower mortality including lower cancer mortality. So it shows that treating to lower levels of LDL does not appear to increase your risk of any adverse effects.
DR. WENGER: That’s a very short-term trial, though, remember.
DR. DAVIDSON: Right.
DR. WENGER: This concludes a roundtable that has probably posed as many questions as it has answered. Nonetheless, there appears to be promise from ongoing clinical trials. I thank both of you for participating in this discussion.