Microsoft word - j885_transcription_all final.doc

Lipid Summit 2011 Highlights; Transcription

"The Effects on HDL Modulation Therapy on HDL-C and HDL-P"
Q: "What type of HDL modulation therapy in your view will have the greatest impact in treating Acute coronary Syndrome?
H. Bryan Brewer, MD: One of the greatest challenges for the practicing physician, and particularly for the cardiologist, is
a residual risk in the patient with acute coronary syndrome, as many . as 50-60% of the patients continue to have a heart
attack.
There's encouraging new information that we may be able to reduce this by HDL therapy. The patient should have
maximum reduction of their LDL with statins, and two new therapies that are being currently tested are an acute infusion
of HDL -- which would reduce the plaque and decrease the chances of having a heart attack -- and chronic therapy with
CETP inhibitors. These two new approaches may significantly be able to reduce the residual cardiovascular risk in our
patients, targeting HCL therapy both acutely with the infusion of HDL, and chronically with the CETP inhibitors, which both
will be very effective potentially in current tests to reduce cardiovascular risk in these patients.
Q: "What is the effect of the CETP inhibitors on HDL-P?"
H. Bryan Brewer, MD: The CETP inhibitors change HDL cholesterol significantly by raising the level of HDL cholesterol,
but the number of HDL particles actually only goes up a small amount. So, in CETP inhibition, you get HDL that are much
more loaded with cholesterol, but with not a dramatic increase in particle number.
Q: "Is HDL-P a more important target for therapy than HDL-C?"
H. Bryan Brewer, MD: One of the interesting areas in terms of trying to better understand the functionality of HDL, as well
as the role of HDL in . in protecting cardiovascular disease, is whether we can get a better measurement of HDL. And
there have been interesting new studies that are . are currently being, uhh, pursued to see if HDL particle number may
be more effective than HDL cholesterol is accessing cardiovascular risk.
These have clearly suggested that HDL particle number may be advantageous in certain situations to give a better index
of HDL functionality than HDL cholesterol alone.
Q: "What drugs cause HDL-C to increase, but HDL-P remains the same?"
H. Bryan Brewer, MD: Some of the drugs that will increase the HDL cholesterol, but with a minimal increase in HDL
particle, include the CETP inhibitors and niacin. Both significantly increase the amount of cholesterol in the HDL particle,
but with only a minor increase in the number of HDL particles per se.
Q: "Are there any situations in which HDL-C decreases, but HDL-P increases? Is that beneficial?"
H. Bryan Brewer, MD: There are a few situations where the HDL particle number may actually increase, and the HDL
particle is associated with lower levels of HDL cholesterol per particle. This is found in the gemfibrozil drug treatment if
you look at the quantitation of the HDL. The particle number goes up, but they're lipid-poor particles.
And there are several situations where their . the small HDL particle may be beneficial in reducing cardiovascular risk.
The small lipid-poor particles bind very effectively to the ABCA1 transport to remove cholesterol from the cell, and in
addition some of the smaller particles have an effect, uhh, being more aggressive in being able to prevent oxidation of
LDL.
So, if you have increase in the small particles, that may be still beneficial in terms of cardiovascular risk, and this is a very
active area of research, both in the research laboratory as well as in the pharmaceutical industry.
"The Importance of Calculating and Treating Non-HDL-C"
Q: "In your opinion will non-HDL-C be equivalent to LDL-C as a target for therapy in ATP-IV?" Carl E. Orringer, MD, FACC, FNLA: There are some good reasons why non-HDL cholesterol should be
considered as a potential risk factor and also potentially a more important target of treatment. It's been shown in
several studies that non-HDL cholesterol performs at least as well as LDL cholesterol in terms of risk prediction,
and it's also important in that non-HDL cholesterol is especially valuable in patients with the metabolic syndrome.
And we know that the incidence of all of the risk factors in the metabolic syndrome are progressively increasing in
the population.
Consequently, the use of non-HDL cholesterol will be assuming greater performance both for detection of risk and
as a target of treatment as we move forward.

Q: "In your view what is the best therapeutic strategy to reduce non-HDL-C in patients at LDL-C goal - - combination therapy with ER niacin, fenofibrates, omega-3 acid ethyl esters, bile acid sequestrants or increasing statin monotherapy?" Carl E. Orringer, MD, FACC, FNLA: I think it's become very clear that intensification of statin therapy is the most
important and probably the most effective way of reducing cardiovascular risk. There has been no study that has
demonstrated that combination therapy is more efficacious than high-dose statin therapy in reducing
cardiovascular risk, and therefore from my perspective the most important approach and the most efficacious
approach is to increase the dosage of a statin that is being administered.
Q: "If your patient is at LDL-C goal with maximum dose statin but not at non-HDL-C goals what therapy would you Carl E. Orringer, MD, FACC, FNLA: It would depend upon the patient himself or herself when I would make the
decision about what agent to add as a second drug. The decision really depends upon what the patient's
metabolic status is -- Is the patient a diabetic or is the patient non-diabetic? Are there concomitant medical
problems that might lead me in one direction or another?
For example, if a patient were a poorly-controlled diabetic, I would not be inclined to use niacin therapy as a
second agent.
If I were to have obtained lipoprotein testing to demonstrate that the patient has elevated LDL particle
concentration, I might lean more toward an agent such as ezetimibe, which can add in conjunction to statin
therapy the ability to further lower LDL particle concentration.
If a patient were to have concomitant difficulties with triglycerides, a fibrate might be a reasonable second choice.
But in reality, the most important place is that you start with a statin, get the statin to maximal dose, and then
make a decision about the second agent depending upon what the patient's metabolic status is and whether other
medical problems exist.

Q: "Are there any situations in which apo-B and non-HDL-C are discordant?" Carl E. Orringer, MD, FACC, FNLA: While it's important to remember that Apo-B and non-HDL cholesterol are
highly correlated, in most studies there seems to be an excellent relationship between the two -- they tend to
travel together.
However, discordance between the two is more often seen in patients with coronary disease or diabetes or
various forms of dyslipidemia. That is, although population-wise the two tend to run together, you can find
individual patients in whom there is a significant discordance, and under those circumstances you have to then
make other decisions about other therapeutic interventions that you might do.
So, I believe that especially in diabetic populations, patients with coronary disease and patients with concomitant dyslipidemia, it is worthwhile to get a measure of lipoprotein particle concentrations such as apolipoprotein-B or LDL particle concentration to help you make further decisions and try to get to a point where you not only have their LDL cholesterol to goal and their non-HDL cholesterol to goal, but also their LDL particle concentration or their atherogenic particle concentration to goal. Q: "What value do you place on ratios: LDL-C/HDL-C, apo-B/apo-A-1, total cholesterol/HDL-C, Carl E. Orringer, MD, FACC, FNLA: The use of ratios for risk assessment was actually addressed in the
National Cholesterol Education Program Adult Treatment Panel guidelines. They looked at, for example,
considering the importance of the ratio of total/HDL cholesterol, or LDL vs. HDL -- various ratios which look at
atherogenic vs. antiatherogenic lipids or lipoproteins.
And in the end, the adult treatment panel felt that the best way to use this ratio information was for the clinician to
first do Framingham risk scoring, which includes both total cholesterol and HDL cholesterol. That helped to
address the ratio issue. Once you had that information and you were assessing what the patient's absolutely risk
was, you could then make further decisions about how intensively to treat the patient's LDL cholesterol.
So, I think that the use of ratios is interesting and is sometimes somewhat helpful, but in fact the use of
Framingham risk scoring or other means of global risk scoring as the first step then enables you to make
decisions to what to do about your LDL cholesterol and what to do about your non-HDL cholesterol.
Q: "Under what circumstances should physicians measure Lp(a)? Is it worthwhile attempting to lower
Carl E. Orringer, MD, FACC, FNLA: Well, Lp(a), or lipoprotein-A, is an unusual type of LDL particle. It's an LDL-
like particle which has a tail hooked on to the end of a disulfide bridge called "Apo-A." And this particular particle
is proatherogenic and prothrombotic.
It's been shown that in those individuals who have lipoprotein-A levels of 30 mg/dL or above, which represents the
upper tertile of lipoprotein-A measurements, there's an increased risk for coronary heart disease events,
cerebrovascular events, and other manifestations of atherosclerotic vascular disease.
The question then becomes, when you find a patient who has elevated lipoprotein-A concentrations, what should
you do about it? And there has been a prevailing feeling that when this is measured -- and you might measure it,
for example, in patients who have a family history of premature coronary heart disease or patients who have
recurrent coronary events, the first line of treatment is to maximally lower the LDL cholesterol and potentially the
LDL particle concentration.
Once this has been achieved, then the next question is, do you still do something else? There has been some
thought that niacin therapy, which has been shown to lower lipoprotein-A levels, may be of benefit, although there
are no large prospective studies that have demonstrated this alters future coronary events.
In addition, post-menopausal women have been treated with estrogen therapy, and it has been shown that
estrogen therapy does lower lipoprotein-A levels. In addition, post-menopausal women with elevated
lipoprotein-A levels have been shown to have greater benefit from aspirin therapy as compared to those who do
not have elevated lipoprotein-A levels.
So, again, lipoprotein-A values may be helpful in certain specific clinical circumstances, but we have limited data
on whether the administration of drug therapy for elevated lipoprotein-A levels actually makes a difference.
"Dyslipidemia Dilemmas for the Practicing Clinician"
Q: "What does the concept of residual risk mean to the practicing clinician?" Thomas Dayspring, MD, FACP, FNLA: Residual risk is an incredibly important topic, and basically by that we mean,
after you start a therapy in a patient with either a lifestyle or a drug that you think is going to reduce risk, clinical trials have
shown us that a substantial number of people -- even though they're taking an effective therapy -- still go on to have
cardiovascular events. So, it's the risk that's present after you start a treatment.
And of course, that would seem to be a ripe target for additional therapeutic suggestions to perhaps further lower the risk
beyond what your initial therapy did.
Q: "When do you treat a patient with low HDL-C?" Thomas Dayspring, MD, FACP, FNLA: How HDL cholesterol is a powerful independent predictor of risk. We all
know that from multiple epidemiologic studies.
The problem is, although it identifies the patient at risk, we then have to pick a therapeutic regimen to hopefully
lower that risk.
So, I think we have to begin to understand is, what is the risk? Why is risk so high in people who have low HDL
cholesterol? And it's clearly multi-factorial, 'cause low HDL cholesterol is associated with many perturbations that
can cause cardiovascular havoc.
The most important risk factor, though, seen in most people -- especially those who are insulin-resistants with low
HDL cholesterol -- is, they have too many atherogenic particles, almost all of which are LDL particles. So,
paradoxically, even though low HDL cholesterol explains the risk, our treatment is first directed at some
parameter of low-density lipoprotein.
Q: "How do you manage the statin intolerant patient?" Thomas Dayspring, MD, FACP, FNLA: Statin intolerance is a major problem in this world. Although statins are
great proven drugs we use -- they're usually our first choice after lifestyle to achieve goal -- considerably more
patients cannot tolerate statins that have been seen in clinical trials for a variety of reasons.
A lipidologist like myself -- it's one of the #1 referrals I get -- people who can't statins, and what do I do? And
although there's no studies telling us exactly what to do, most of us would try at least 2 or 3 different statins to see
. you often see a patient who can tolerate one but perhaps not the next one, or vice-versa.
Beyond that, if you've tried 2, 3, even 4 statins -- we do have 7 on the market -- I always encourage doctors to
give fluvastatin or pitavastatin a trial. They have different pharmacokinetic pathways of catabolism, and they
seem to be, it's many experts' opinions, that they sometimes can be tolerated better than other statins.
After that, most of us would go off-label and go into intermittent statin use, be it every day, every third day, even
once a week. There are published studies with some of the potent statins using just once a week . although you
might not get to goal, you start to approach goal.
If you really can't take a statin, then we start using the other lipid-modulating drugs that are all out there for us to
try.
Q: "When statins are maximized and further non-HDL-C lowering is needed how does the clinician Thomas Dayspring, MD, FACP, FNLA: Non-HDL cholesterol is an incredibly important, at this time, secondary
goal of therapy in our NCEP guidelines for patients with elevated triglycerides or low HDL cholesterol. In the
future, many believe it should be our primary goal of therapy.
And the important point is this: As good as statins are at lower LDL cholesterol, they are less efficacious at
achieving non-HDL cholesterol goal.
So, in 2001, NCEP ATP-3 told us beyond the statin you could get it to goal by getting more aggressive with
therapeutic lifestyle, or by adding a fibrate or niacin.
Now, since that time, other products have come on the market -- specifically cholesterol absorption blockers like
ezetimibe or high-dose omega-3 fatty acids that can impact on triglycerides. All of them added to the statin would
help you achieve non-HDL-C goal.
However, you must realize non-HDL cholesterol is a poor man's surrogate for too many atherogenic particles,
specifically LDL particles or LDL particle cam LDL particle count. And the scientific evidence right now shows us
after a statin, adding either extended-release niacin or ezetimibe is your best way at achieving that goal.
Third in line would be the bile acid sequestrants like colesevelam. And interestingly, although fibrates and
omega-3 fatty acids can help you with a lot of things, including triglyceride-rich lipoproteins, you get very little
additional Apo-B LDL particle lowering.
So, in my practice, it's pretty much statins, and then you decide whether you want to go down the niacin route or
the ezetimibe brew. HDL cholesterol might persuade you. The presence or absence of diabetes and glycemic
parameters also.
Q:"Do you target HDL-C or HDL-P in your patients?" Thomas Dayspring, MD, FACP, FNLA: Low HDL cholesterol is certainly a major independent risk factor, and
although it's not as widely known, so is laboratory markers of HDL particle count, meaning either HDL-P or some
measure -- Apo-A1, the surface protein on an HDL. They're all independent risk factors.
So, if I'm going to target an HDL parameter, I would prefer to target HDL-P or Apo-A1. But I must emphasize that
you don't even consider doing that until you've normalized atherogenic particles -- LDLs -- whether you're using
LDL cholesterol, non-HDL cholesterol, Apo-B or LDL particle counts.
However, once I have achieve[d] control of those, I do in high- and very high-risk people try to raise the HDL
particle count. So, is the evidence there to support it? It's in its infancy, but it is emerging, and as a lipidologist I
certainly in very high-risk people chase that.

Q: "Under what circumstances would you use a fibrate?" Thomas Dayspring, MD, FACP, FNLA: There is often confusion in picking a fibrate because in the United States
we have available to us gemfibrozil and fenofibrate, or its metabolic byproduct, fenofibric acid.
Now, they're all in the fibrate family, so which should one use? Well, how about outcome data? Well, gemfibrozil
has that. But the only outcome data gemfibrozil has is as monotherapy in very high-risk male patients. Nobody is
using any fibrate as a monotherapy in anybody today who can tolerate a statin.
So, the real use of fibrates nowadays comes in as an add-on therapy to people who are already on statins, but
are not yet at non-HDL cholesterol goal or Apo-B goal.
Interestingly, gemfibrozil is a BID drug, where fenofibrate is QD. Multiple studies have shown going to a BID drug
reduces compliance by almost half.
There are several serious drug-drug interactions with gemfibrozil, specifically with statins. There's only 2 statins you can safety take . although there's always a warning sign, and that would be fluvastatin or pitavastatin. So, that significant limits gemfibrozil use, so I have probably not prescribed that drug in 10 years. I use fenofibrate myself to help get non-HDL cholesterol to goal, and you do that by reducing triglyceride-rich remnant lipoproteins, lowering VLDL cholesterol, a component of non-HDL cholesterol. As far as combining a fibrate with ezetimibe, there are very specific FDA rules. You may do that as long as fenofibrate is the fibrate you combine with ezetimibe. There are drug-drug interactions between gemfibrozil and ezetimibe that you should never go there. And interesting enough, fenofibrate and ezetimibe can reduce non-HDL cholesterol by 20%. Now, I'm a strong advocate that you gotta have a statin on board in these people, but there are many, many people who just cannot tolerate a statin for one reason or another. So, that is a very intriguing secondary therapy in a statin-intolerant patient -- fenofibrate and ezetimibe -- to help you at least take a big step forward to achieving non-HDL cholesterol goals. "The Effects of CETP Inhibition and Potential Benefits: AIM-HIGH Treat Low"
Q: "In your view with CETP inhibition only benefit those patients with LDL-C greater than 100 mg/dL?" Daniel J. Rader, MD: CETP inhibition is a huge experiment in medicine. Will inhibition of CETP reduce cardiovascular
risk and cardiovascular events, and in which types of patients will that happen? In other words, who is mostly likely to
benefit? And no one really knows the answer; I certainly don't. I think a case to be made is that CETP inhibition would
perhaps be more effective in people whose LDLs are higher, who perhaps have less effective clearance of their Apo B-
containing LDL particles. And certainly that's a hypothesis that will be tested by the large clinical trials that are going on.

It's also possible for example, that CETP inhibition would be more effective in people with HDLs, who perhaps
stand more to gain by having their HDLs increased.
But again, we really don't know, and that's why it's appropriate that the studies are being done in a wide range of
people with both LDL and HDL levels to really test rigorously the hypothesis not only that CETP inhibition will
reduce risk, but that perhaps there are subgroups of patients who are more likely to benefit from CETP inhibition.
Q: "What percent of CETP inhibition is required for cardioprotection? Is there a linear relationship?"
Daniel J. Rader, MD: One of the fascinating aspects about the question of CETP inhibition and its relationship to
cardiovascular events is the question of whether the degree of CETP inhibition has a relationship to the reduction
in cardiovascular risk. Certainly, there's a linear relationship between the magnitude of CETP inhibition and the
increase in HDL cholesterol. So, by that logic, one might want to inhibit CETP more to try to raise HDL
cholesterol more. But on the other hand, we're not completely certain that that's the optimal strategy for reducing
cardiovascular risk.
Once again, we have clinical trials going on with compounds that inhibit CETP more or less, and the results of
these clinical trials ultimately will address this very important and interesting question of whether more CETP
inhibition is actually more beneficial with regard with reduction in cardiovascular risk.
Q:"In light of the failure of AIM-HIGH and the disappointing results of ACCORD-LIPID and FIELD in reducing cardiovascular events, are clinicians better off pursuing ATP-III goals for LDL-C using monotherapy with statins and only reach for combination therapy as a last resort
Daniel J. Rader, MD: I think there can be no question that a cornerstone of cardiovascular risk reduction is
aggressive LDL cholesterol reduction -- certainly with high-dose statin monotherapy. But I would argue, in
situations where patients cannot achieve adequate LDL goals with statin monotherapy, that combination therapy
with an additional drug that further lowers LDL on top of the statin makes a great deal of sense, and certainly
that's a way that I practice in my own practice.
I think the question, though, of how to handle the patient whose LDL has been effectively and aggressively
treated, but still has a low HDL, is certainly a big question mark right now. With the failure of AIM-HIGH to show
benefit of niacin, we really don't have right now hard data that adding niacin to a statin reduces cardiovascular
risk.
Of course, we have another large trial going on -- the HPS2-THRIVE trial -- and that trial will shed more light into
this very important question.
I would say for right now the major issue is aggressive LDL reduction waiting for additional data, not only from
HPS2-THRIVE, but from the CETP inhibitor trials that are ongoing as to whether further intervention to raise HDL
also further reduces cardiovascular risk.
Q: "What is your view on how CETP inhibition affects HDL functionality?"
Daniel J. Rader, MD: The question of how CETP inhibition affects HDL function is a very, very important one --
certainly very interesting to the field, and potentially very clinically important with regard to the question of whether
CETP inhibitors are going to reduce cardiovascular risk.
There is data, certainly, that inhibition of CETP promotes increased cholesterol efflux to HDL, so that's at least
encouraging and suggestive, that inhibition of CETP does promote efflux. But frankly, this is another one of these
questions that we really don't know the true answer, and more work is needed -- both in human studies as well as
in preclinical animal models -- to try to look at the impact of CETP inhibition on reverse cholesterol transport.
But ultimately, I would say the real issue is, what is the result of the clinical trials; will CETP inhibition actually
reduce cardiovascular risk; and to what magnitude of CETP inhibition will we see the greatest risk reduction? And
this really is ultimately the most important issue, even beyond the specific effects on HDL function.
Q: "Was the control group in AIM-HIGH significantly compromised by taking crystalline niacin beginning with 50 mg and some even taking more in the uptitration process? Could those doses affect HDL functionality?" Daniel J. Rader, MD: Niacin is a fascinating drug. It's been around for over 50 years, but even to this day we still
don't fully understand what it does.
We don't think that very low-dose niacin raises HDL cholesterol much, if at all, and therefore the low doses of
niacin that were used in the placebo group in AIM-HIGH probably didn't affect the HDL cholesterol levels. But the
impact on HDL function, frankly, is completely unknown. We really don't know what niacin does to HDL function
at all, at any dose, and so that's one big question.
Another question is, there are some data that niacin acts through its receptor on macrophages to actually reduce
inflammation and reduce atherosclerosis. And once again, we don't know what the dose response is there, so it's
at least theoretically possible that the low dose used in the placebo group in AIM-HIGH may have had some
antiinflammatory or antiatherosclerotic effects independent of any effects on HDL.
So, again, these are big questions, important for the interpretation of AIM-HIGH. Fortunately, the other big niacin
trial that's still ongoing does not include giving any niacin to the placebo group, so we'll hopefully have greater
clarity on this very important issue.
Q: "Did the recent safety trials dal-PLAQUE and dal-VESSEL provide assurance that CETP inhibitors Daniel J. Rader, MD: In my opinion, it's fairly clear that the so-called "off-target effects" of torcetrapib contributed
mostly or entirely to the adverse consequences of that drug. It's also quite clear that the newer-generation CETP
inhibitors that are currently under clinical development don't have these off-target effects.
So, I think it's highly likely that these second-generation CETP inhibitors will not have the adverse consequences
that torcetrapib did, and certainly the studies that have been done, such as DEFINE and dal-VESSEL and dal-
PLAQUE, give us even greater confidence that these compounds don't have adverse vascular effects. Clearly,
the large-scale clinical trials looking at cardiovascular events are ultimately going to tell the whole story.
Is HDL a Target for Therapy or Marker of Risk –
Have Recent Trials Changed Our Thinking?
Q: "Is HDL a market of risk or target for therapy?" Michael H. Davidson, MD, FACC, FACP, FNLA: In my opinion, HDL is both a marker of risk and a target of therapy.
There's no debate that it's a marker of therapy. Low HDL confers a greater increased risk for cardiovascular events.
Every 10-point drop in HDL equals about a 60-point increase in LDL cholesterol.

And so, sometimes, for example, you see somebody with an HDL of 30 and LDL of 100, and most doctors would
not necessarily intervene. But if they saw an LDL of 160 and HDL of 40, they likely would intervene.
So, one of the key things that doctors need to recognize is that low HDL is a very important marker of risk; we
should therefore initiate a much more intensive, aggressive non-HDL/LDL cholesterol/Apo-B/LDL particle
reduction.
As far as a target of therapy, that's where it gets a little bit more difficult and complicated. At this time, we don't
have a lot of evidence that raising HDL provides a benefit, but we're looking forward to multiple new therapies that
appear to modify HDL levels, and I believe one of these will ultimately be successful in changing the HDL
cholesterol level in a beneficial way that'll ultimately reduce in the reduction of atherosclerosis, and thereby a
reduction of cardiovascular events.
Q: "Is there an HDL-C level above which further increase does not matter?" Michael H. Davidson, MD, FACC, FACP, FNLA: There appears to be a threshold by which raising HDL further
does not provide additional clinical benefit. And what that threshold might be is unclear. I think most evidence
suggests above 60 mg/dL is not providing any greater benefit.
And there is some concern that individuals that have very high HDL cholesterol levels might have dysfunctional
HDL, which is probably a rare situation. But nevertheless, I think what we know about HDL suggests that getting
it to above 60 is great -- if someone naturally has it above 60, even better -- and that results in a low risk for
cardiovascular events in the vast majority.
But there are certain individuals in which very high HDL levels might not be protected 'cause the HDL itself is
dysfunctional, and not resulting in improved reverse cholesterol transport.
Q: "For at risk patients with an HDL-C below 30 and an LDL-C of 70 mg/dL should we try to raise the HDL-C or lower the LDL-C further?"
Michael H. Davidson, MD, FACC, FACP, FNLA: When someone already has a low LDL, below 70, but also a
low HDL -- for example, 30 mg/dL -- my view actually is to measure LDL particle number, Apo-B, and determine
whether they have achieved yet their LDL particle number target or Apo-B target, less than 1,000 particle number,
or less than 70 for their Apo-B target.
That's my key therapeutic intervention, is to make sure that the actual particle number is below those targets of
therapy.
Once that is achieved, that might require more intensive statin therapy; it might require additional drugs such as
ezetimibe or niacin to reduce those Apo-B LDL particle values. I'm not that aggressive about trying to raise the
HDL as a secondary target of therapy, and I think the AIM-HIGH study, although it has its major flaws, would
support that approach right now. And eventually, if we have better HDL-raising therapies with proven outcome
benefits that will obviously change my opinion about what to do next for these high-risk patients.
Q: "When should clinicians order HDL-P, LDL-P, apo-B and inflammatory markers like hs-CRP and Michael H. Davidson, MD, FACC, FACP, FNLA: Any time you want to consider ordering advanced lipid testing
to include HDL particle number or LDL particle number, or inflammatory markers like Lp-PLA2 or hs-CRP, I think
the key issue is, does that change your therapy for that patient? Does it make a difference as far as what
treatments you might or may not use in that individual patient?
So, in most circumstances, it's an individual that has intermediate risk, where they have risk factors; they have
high triglycerides that are above a certain range, above 100; or HDLs below 40 mg/dL. And the LDL is not that
elevated; it may even be normal. Those are the best patients to consider measuring these advanced lipid tests.
And the same goes for inflammatory markers like hs-CRP or Lp-PLA2.
The other example is someone who has coronary-artery disease, and you're just not certain they've achieved the
maximal risk factor management that you can provide them. You have other options to go to; other drugs to
consider. Measuring these advanced lipid tests or inflammatory markers could be very helpful.
This is especially true for somebody that has a recurrent event on optimal statin therapy. You want to consider
measuring these advanced tests to further define the risk in that individual patient, and then once you find those
risk factors, you can adjust your therapy accordingly to manage those risk factors to their targets of treatment.
Q: "Based on the results of AIM-HIGH and ACCORD-LIPID is there any benefit to adding an HDL increasing drug like a fenofibrate or ER Niacin in patients with type-2 diabetes at LDL-C
Michael H. Davidson, MD, FACC, FACP, FNLA: Both the ACCORD-LIPID and the AIM-HIGH study failed to
achieve their primary endpoint with fenofibrate and niacin, respectively. Both studies had flaws that are important.
In the ACCORD-LIPID trial, overall there was no benefit, but there was a benefit in a subgroup of patients that
had high triglycerides/low HDL. That was statistically significant at p < .03, but there was a lack of significance for
the overall inaction . p was .06, which therefore technically is not significant.
But look at it from the big picture. There were 17% events in that high triglyceride/low HDL subgroup vs. 10%
events in those that did not have high triglycerides or low HDL -- so, a 17% higher event rate in the high
triglyceride/low HDL subgroup in ACCORD-LIPID. And that dropped to 13% approximately when they were put
on fenofibrate, so a 4% absolute benefit, or number to treat of 20, which is quite desirable when it comes to risk
modification.
So, I think there are subsets of patients with diabetes, with high triglycerides/low HDL, that appear that they
benefit from a fenofibrate in the ACCORD-LIPID trial. So, I think we should still keep that in mind as an option for
those patients.
The other individual patient in the AIM-HIGH study is more complicated because they already were treated
aggressively to an LDL about 70 mg/dL. Triglycerides were not that high, and the mean triglycerides about 160.
The HDL was not that low -- it was already about 40, and it went to 44 mg/dL on the niacin. And the triglyceride
reduction was also not that great -- a modest reduction from 160 to 120 mg/dL in the AIM-HIGH trial. So, lipid
differential was not that great in the AIM-HIGH trial for niacin therapy, and those were all aggressively treated with
statins or adding on ezetimibe in the control group to equal the LDL levels about 70 mg/dL or lower between the
two treatment arms.
So, I think the AIM-HIGH study -- although it did not show a benefit for niacin in those already well-treated to their
LDL and even their non-HDL cholesterol goals -- niacin can still be a really good option to consider for someone
that does not yet have their non-HDL cholesterol under control. It's a really good non-HDL cholesterol-lowering
drug.
Example would be someone who comes in to see you, whose LDL's about 80 and their triglycerides are about
200; their HDL is 30. They're not at their goal of 70 mg/dL, for example; they already have coronary disease.
That would still be a good consideration for niacin therapy, because that could further lower his or her non-HDL cholesterol to target, and also improve HDL cholesterol and triglyceride levels. So, that still should be an option on the table for those type of patients that do have high risk in that mixed-paritus lipidemia where niacin can be a very good therapy to maximize lipid management in those patients.

Source: http://www.cardiologytoday.com/pdfs/2011/J885_transcript.pdf