Raising HDL: It's a Question of Context

[Guest guest]

I'm Weintraub. I'm a cardiologist at New York University Medical

Center where I am a Clinical Associate Professor in the Department of

Medicine. I'm also the Clinical Director of the NYU Center for the

Prevention of Cardiovascular Disease.

I'm here at the request of Medscape to speak about a very moving target, it

appears, in cardiology and that is high-density lipoprotein (HDL)

cholesterol, the good cholesterol. There have been several articles that in

the past have always informed us that HDL cholesterol is something that you

want to get as much of as you possibly can, and the data from Framingham

certainly supported that. When your HDL cholesterol was high, for every 1

mg/dL it went up, you lowered your risk some 2%, so it stood to reason that

as we improved HDL cholesterol, that risk would get better.

There's an article that was published last year in *Menopause* that became a

topic of interest actually a few months ago, and there was a piece on this

in Medscape relatively recently.[1] This large study in menopausal women

identified that HDL changed its character. Instead of being the white knight

that tended to protect against carotid calcification and aortic valve

calcifications, what they found was that HDL cholesterol in higher levels

was actually associated with more atherosclerosis and more calcification of

the aortic valve. This became a conundrum and a lot of people were wondering

why this would happen.

I think we need to step back and take a look at this in a way that Tom

Dayspring did in a very good review that he also published a few months ago,

[2] and that is to recognize that postmenopausal women tend to be different

from premenopausal women: they're more insulin resistant; they tend to have

higher triglycerides; they also are more likely to be hypertensive. So,

you're creating a more inflammatory milieu that HDL lives in. HDL may be

asked to do a job that it's no longer capable of doing, and the character of

the HDL may also change because in the setting of higher levels of

triglycerides you have a smaller denser HDL that may not be quite as good a

participant in reversed cholesterol transport. This is likely to be one of

the explanations and certainly what it tells us is that in postmenopausal

women we should be very, very cautious in attributing a negative risk --

meaning to give a protective factor when HDL cholesterol levels are high.

We've all seen many postmenopausal women with high levels of total and

low-density lipoprotein (LDL) cholesterol whose HDL cholesterols are high

and they have rampant atherosclerosis. And we see this too often as

cardiologists, particularly myself as a lipid specialist, so I would caution

primary care clinicians as well as cardiologists to be very concerned about

people who gave a good story for angina, they hear a bruit, or there are

other issues that make them believe that this person is at risk. The other

thing that they should look for is body habitus. If they look insulin

resistant, they probably are, and if their HDL cholesterol was high, do not

assume that it's routinely protective.

The topic of HDL has come under further fire in a much more recent

contemporary study called AIM-HIGH. AIM-HIGH was a National Institutes of

Health trial that looked at whether or not HDL cholesterol elevation could

reduce cardiovascular risk as we had assumed it would.[3] This focused on a

group of individuals, most of whom had coronary disease, half of whom had

myocardial infarction, about a third had diabetes, and 80% had metabolic

syndrome. What they wanted to do was evaluate whether adding

extended-release niacin (Niaspan®) would actually reduce cardiovascular risk

in the setting of existing statin therapy. What they were able to identify

in this trial was, unfortunately, that there was no appreciable benefit and

this trial was stopped due to futility. Futility meaning that there was no

difference in the risk attributable to either using Niaspan added to statins

vs taking statins alone, So why would this possibly be?

We've always been told that LDL cholesterol is our target for therapy, and

in the people taking the statins, existent LDLs were 71 mg/dL, which is a

pretty good level. HDL cholesterol was 34.9, triglycerides averaged about

161 to start with, and they lowered considerably with therapy. However, I

think we need to focus on that once again we're asking HDL to do a job in

the setting of very, very low LDL and it's very, very difficult for there to

be an appreciable difference in cardiovascular risk in the setting of such a

low level of LDL.

We have seen numerous studies in which LDL cholesterols were lowered

considerably and the effect of HDL was reduced even though it may have been

partially present. Some of this has been seen in the PROVE-IT trial where

HDL was still seen to be a movable risk, if you will.[4] This is in Phil

Barter's study[5] that was published after the release of the trial. But I

think we need to recognize that it's just not as easy as we'd like to

believe that if you just keep raising HDL that everything is going to be

fine. I think we need to recognize that HDL cholesterol is a very important

lipoprotein. I think what we are going to find in subsequent analyses of

AIM-HIGH is that in those individuals with low levels of HDL and higher

levels of triglycerides there would probably be news that will reinforce our

previous thinking that Niaspan was in fact beneficial.

This is not too dissimilar to what we saw in the ACCORD trial.[6] In ACCORD,

the triglycerides are almost identical at 162 mg/dL. Only there you were

dealing with a group that was 100% diabetic and the LDL cholesterols were in

the 90s. So we're looking at a higher-risk group and even in that group the

use of fenofibrate was only associated with benefit when HDL cholesterols

were [very] low and triglycerides were in excess of 200. So again, I think

that HDL is not dead, which was suggested by a journalist in one of the

large newspapers in New York City, and I do not believe that niacin therapy

should be abandoned. I certainly don't believe that patients who are taking

niacin should abandon this medication. Many of them have had to endure

flushing and other side effects in order to get to chronic niacin therapy,

and I think after they've weathered this they should continue to take the

drug. The question comes where the physician should be considering

instituting niacin for people with mixed cardiometabolic risk and I think

the answer is still " yes. "

I think what AIM-HIGH has told us is that perhaps the targets for therapy or

the patients who are targets for therapy should be those with HDLs that are

on the lower side and triglycerides on the higher side. The other thing we

need to recognize is that once LDL cholesterol is below 70 mg/dL, there

really may not be a lot more that we're going to do by modifying other

lipoproteins. And really the majority of the patients that we treat are not

living at the starting levels that the AIM-HIGH patients were. For example,

in the 6% of patients who were not on statins, their LDL was 119, their

triglycerides were 215, their HDL was 32.8, and their non-HDL cholesterol

was 165. These people were certainly great candidates for both statin and

niacin therapy.

I think that we will find out much more information about the patients in

AIM-HIGH; I think we will certainly find out some more about those 515

patients who took ezetimibe in order to get their LDL cholesterols down to

between 40 and 80. This may have been a very interesting modifier of risk,

and of course the post hoc analyses will be very, very useful in identifying

certain patient subgroups who clearly benefited from the use of Niaspan in

addition to simvastatin 40-80 mg/day.

We should remind you that the US Food and Drug Administration has recently

come out with a warning about 80 mg of simvastatin and I think clinicians

should take this to heart because there was an increased risk for myopathy

in both SEARCH[7] and A to Z[8] so really what we're talking about here is

the combination of simvastatin 40 mg with appropriate doses of Niaspan,

which in the AIM-HIGH study was between 1500 and 2000 mg/day. That more or

less sums it up. I'm sure there are many other points that will be discussed

in the coming months, and hopefully I'll get a chance to do it.

I'm Weintraub. I want to thank Medscape very much for offering me the

opportunity to comment on HDL. Have a great day.

References

www.medscape.com

--

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