Is Cholesterol just a fancy biomarker?

[npage148]

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So, with the continued failure of of cholesterol lowering meds (recently ACCORD-Lipid) to reduce CV events it really appears thatcholesterol is really just a biomarker of cardiovascular health and what I see new coming out only supports this theory.

What I think is that cardiovascular vascular oxidization stress and endothelial dysfunction is really what we want to lower if we want to see improved outcomes and it just happens that statins do this to some extent.

Is it time to discard the lipid-hypothesis and look for a new root cause of CVD?

 

[Its Z]

hmmm.. interesting..

 

[joetrisman]

Naysayers have been chiming in since JUPITER but everyone wants to bandwagon statins to being the best drug class ever 🙄

 

[owlegrad]

Sorry if my comments are hopelessly clueless, but I figure I might as well chime in and see if we can get some conversation going.


Interesting stuff. Not sure that we need to throw out the lipid hypothesis, but it is obvious there is more to the story that we need to understand.


I made bold the results of the following:

By the end of the study, the mean LDL cholesterol level fell from 100.0 to 81.1 mg per deciliter (2.59 to 2.10 mmol per liter) in the fenofibrate group and from 101.1 to 80.0 mg per deciliter (2.61 to 2.07 mmol per liter) in the placebo group (Figure 1Figure 1Lipid Values., and Section 16 in Supplementary Appendix 1). Mean HDL cholesterol levels increased from 38.0 to 41.2 mg per deciliter (0.98 to 1.07 mmol per liter) in the fenofibrate group and from 38.2 to 40.5 mg per deciliter (0.99 to 1.05 mmol per liter) in the placebo group. Median plasma triglyceride levels decreased from 164 to 122 mg per deciliter (1.85 to 1.38 mmol per liter) in the fenofibrate group and from 160 to 144 mg per deciliter (1.81 to 1.63 mmol per liter) in the placebo group.

It sounds like the fenofibrate was not particularly effective. Mean LDL was actually lower in placebo but not statistically significant (P=.11), HDL was statistically different (P=0.01) but the overall increase from placebo is quite modest, and only triglycerides were lowered statistically significantly (p<.001). But the mean triglyceride levels were only modestly elevated to begin with. I don't see why adding fenofibrate would have been expected to provide a great benefit to this patient population. Isn't fenofibrate typically added for patients with triglycerides above 200 mg/dL or if HDL levels need to be raised?

It seems like not much can be concluded from that. No change in LDL, very modest increase in HDL. Lowering TG from 144 to 122 isn't expected to have much of an impact on coronary outcomes, both levels are considered normal. Is there something I am missing here? Why would we expect this therapy to be beneficial in this patient population?

I don't see how this provides evadence to disregard the lipid hypothesis, considering basically only TG's was effected and that TG's didn't need to be any lower in this group.

 

[spacecowgirl]

So, with the continued failure of of cholesterol lowering meds (recently ACCORD-Lipid) to reduce CV events it really appears thatcholesterol is really just a biomarker of cardiovascular health and what I see new coming out only supports this theory.

What I think is that cardiovascular vascular oxidization stress and endothelial dysfunction is really what we want to lower if we want to see improved outcomes and it just happens that statins do this to some extent.

Is it time to discard the lipid-hypothesis and look for a new root cause of CVD?

I have wondered this for awhile too. Given what happened with ezetimibe, lower LDL doesn't mean lower CV death. But I definitely believe in the pleiotropic effects of statins, which you mentioned. I'm not ready to give statins the heave-ho yet. Right now, it's the best we have.

 

[spacecowgirl]

What's the current literature on hsCRP?

 

[npage148]

I have wondered this for awhile too. Given what happened with ezetimibe, lower LDL doesn't mean lower CV death. But I definitely believe in the pleiotropic effects of statins, which you mentioned. I'm not ready to give statins the heave-ho yet. Right now, it's the best we have.

Looking at Bile Acid Sequestrants, they lower LDL but don't really improve markers of CV inflammation (as far as I know) or outcomes. It's a similar story to ezetimibe. A large part of the problem is that CVD is such a long term disease, it's very difficult to really determine the beneficial effects of these agents outside of using surrogate endpoints

I'm not advocating throwing out statins, they DO have strong benefits on CV outcomes. I just think it's not solely due to their cholesterol lowering effects.

 

[spacecowgirl]

I'm not advocating throwing out statins, they DO have strong benefits on CV outcomes. I just think it's not solely due to their cholesterol lowering effects.

Absolutely, I think the JUPITER trial shows that. I wonder what the new ATP guidelines will suggest in terms of hsCRP monitoring - we measure that sometimes here but we don't really know what to do with it - and if there will be more emphasis on HDL vs just LDL.

 

[Praziquantel86]

Interesting thoughts. With that theory, we're left with an obviously effective class of medications but no obvious reasons for their effects. Short of measuring hard outcomes, such as a long-term mortality study, how can we find what is best?

I think upcoming data from the CETP inhibitors will probably give us the clearest picture yet as to whether cholesterol is the real target, but we'll still be years away from generating any meaningful mortality data with them.

Most of what is done in medicine is treatment of biomarkers, I think it's just a matter of finding the correct one. Looks like we may have some additional work to do on this one.

 

[MatCauthon]

The cholesterol molecules are just a vehicle for transferring various lipids. If the lipids in the cholesterol esters are oxidized it can create a stress reaction in the arteries. Oxidized lipids are extremely common in our world of fried, processed, refined, and packaged foods. We recently battled trans-fatty acids, but i suspect that is only the beginning of the battle. So many of our omega 3 and omega 6 fatty acids are oxidized by the time they reach the consumer that it most likely is a big contributing factor to this whole epidemic.

I have been wanting to do more research on this topic. I suspect there is far more work with fatty acids and fatty acid metabolism that needs to be done. I also suspect this research will prove to be far more effective than statins.

 

[gotdrugs]

Gotta wrap my head around the logic here........

In this thread we have come up with the fact that cholesterol mgt is irrelevant in prevent future cardiac events because:

1) The ACCORD-lipid trial that had no differences between the tx and placebo arms in regards to LDL/HDL effects wound up having no differences in clinical outcomes

2) The Jupiter trial, while everyone seems to buy into A/Z's slant on reducing CRP, it also drastically reduced LDL and had few cardiac outcomes in the rosuva arm.

Yet from all of this from these two trials mentioned we are taking the message that it "proves" LDL doesn't matter?

Sorry, failing to see the logic on this one.

CRP could well play a role. I also believe in the Statin's pleiotropic effects.

Yet the two studies cited in this thread doesn't give enough merit to "trash" the LDL theory.

EDIT: I want to chime in that I don't believe the LDL is the end-all/be-all, I'm just saying IMO there isn't enough "evidence" to ignore trying to reduce LDL as there still seems to be correlation.

 

[VA Hopeful Dr]

Gotta wrap my head around the logic here........

In this thread we have come up with the fact that cholesterol mgt is irrelevant in prevent future cardiac events because:

1) The ACCORD-lipid trial that had no differences between the tx and placebo arms in regards to LDL/HDL effects wound up having no differences in clinical outcomes

2) The Jupiter trial, while everyone seems to buy into A/Z's slant on reducing CRP, it also drastically reduced LDL and had few cardiac outcomes in the rosuva arm.

Yet from all of this from these two trials mentioned we are taking the message that it "proves" LDL doesn't matter?

Sorry, failing to see the logic on this one.

CRP could well play a role. I also believe in the Statin's pleiotropic effects.

Yet the two studies cited in this thread doesn't give enough merit to "trash" the LDL theory.

EDIT: I want to chime in that I don't believe the LDL is the end-all/be-all, I'm just saying IMO there isn't enough "evidence" to ignore trying to reduce LDL as there still seems to be correlation.

I think its also worth adding that there are numerous trials involving other statins that do show morbidity/mortality benefits. Crestor is pretty lacking, but pravachol/zocor/lipitor have some good data behind them.

 

[gotdrugs]

I think its also worth adding that there are numerous trials involving other statins that do show morbidity/mortality benefits. Crestor is pretty lacking, but pravachol/zocor/lipitor have some good data behind them.

Yes, I agree - of course.

But in all of those trials, there were lower LDLs in the tx arms.

I'm a huge fan of the statins.

I'm in critical care and would love to see definitive trial data in sepsis and also my hospital is part of the SAILS trial.

I think the statin effect goes beyond LDL lowering, but I have yet to see "proof" that makes me think we should forget LDL lowering.

 

[karizma098]

Yes, I agree - of course.

But in all of those trials, there were lower LDLs in the tx arms.

I'm a huge fan of the statins.

I'm in critical care and would love to see definitive trial data in sepsis and also my hospital is part of the SAILS trial.

I think the statin effect goes beyond LDL lowering, but I have yet to see "proof" that makes me think we should forget LDL lowering.

Agreed. Statin's work effectively on LDL levels - i've seen it time and time again in the clinic. I don't know about new trials, but LDL is a fairly cheap and specific way to evaluate risk for atherosclerosis/plaque development , which is a huge risk factor for CV events. Obviously , diet/excercise/genetic predisposition play the biggest risk but i don't feel comfortable with the statement that cholesterol isn't an accurate marker; i think it is.

As far as 'endothelial dysfunction' being the true risk factor vs LDL levels, we need to consider the basic pathologic mechanism of how atherosclerosis works - LDL is what gets ingested into the wall of the vessel and forms a 'fatty streak' over time - this serves as a primer for the plaque build up-->ischemia---> M.I. - hence, lower LDL levels --> less fatty streaks / smaller fibrofatty development with endothelial cell injury.

 

[VA Hopeful Dr]

Agreed. Statin's work effectively on LDL levels - i've seen it time and time again in the clinic. I don't know about new trials, but LDL is a fairly cheap and specific way to evaluate risk for atherosclerosis/plaque development , which is a huge risk factor for CV events. Obviously , diet/excercise/genetic predisposition play the biggest risk but i don't feel comfortable with the statement that cholesterol isn't an accurate marker; i think it is.

As far as 'endothelial dysfunction' being the true risk factor vs LDL levels, we need to consider the basic pathologic mechanism of how atherosclerosis works - LDL is what gets ingested into the wall of the vessel and forms a 'fatty streak' over time - this serves as a primer for the plaque build up-->ischemia---> M.I. - hence, lower LDL levels --> less fatty streaks / smaller fibrofatty development with endothelial cell injury.

LDL treatment alone doesn't correlate terrifically well with CV events/outcomes. Zetia, for example, is pretty effective at lowering LDL. There is even u/s evidence that it reduces/stabilizes plaque size, yet it doesn't effect outcomes in a good way. I think that's what our pharmacist colleagues here are getting at. There's something extra about statins that effects outcomes (I think anti-inflammatory properties is the popular theory at the moment).

 

[spacecowgirl]

Sorry, failing to see the logic on this one.

CRP could well play a role. I also believe in the Statin's pleiotropic effects.

Yet the two studies cited in this thread doesn't give enough merit to "trash" the LDL theory.

EDIT: I want to chime in that I don't believe the LDL is the end-all/be-all, I'm just saying IMO there isn't enough "evidence" to ignore trying to reduce LDL as there still seems to be correlation.

I don't quite follow your logic leading to your conclusion about this thread. I don't see where anyone said to get rid of statins 😕 It's a discussion about whether LDL is an endpoint or a surrogate marker for CV death.

Agreed. Statin's work effectively on LDL levels - i've seen it time and time again in the clinic.

No one is debating that! It's questioning the MOA of statins we're talking about.

I don't know about new trials, but LDL is a fairly cheap and specific way to evaluate risk for atherosclerosis/plaque development , which is a huge risk factor for CV events. Obviously , diet/excercise/genetic predisposition play the biggest risk but i don't feel comfortable with the statement that cholesterol isn't an accurate marker; i think it is.

We're saying, do we really know if LDL a causitive agent for CV death or is it a surrogate marker? Am I pushing a statin dose on someone to achieve a certain marker or because a lower LDL actually reduces (and is not just indicitive of) the risk of CV death?

I'm really not sure how specific LDL is anymore, as the ENHANCE trial demonstrated. I don't think LDL monitoring will go away but will be more useful in the context of other measures that we are not routinely checking now - Lp(a), hsCRP, calcium scoring.

As far as 'endothelial dysfunction' being the true risk factor vs LDL levels, we need to consider the basic pathologic mechanism of how atherosclerosis works - LDL is what gets ingested into the wall of the vessel and forms a 'fatty streak' over time - this serves as a primer for the plaque build up-->ischemia---> M.I. - hence, lower LDL levels --> less fatty streaks / smaller fibrofatty development with endothelial cell injury.

Why do omega fatty acids decrease CV death? They can raise LDL-C.

LDL treatment alone doesn't correlate terrifically well with CV events/outcomes. Zetia, for example, is pretty effective at lowering LDL. There is even u/s evidence that it reduces/stabilizes plaque size, yet it doesn't effect outcomes in a good way. I think that's what our pharmacist colleagues here are getting at. There's something extra about statins that effects outcomes (I think anti-inflammatory properties is the popular theory at the moment).

Right.

 

[npage148]

Thanks Spacecowgirl, perfect points to what I'm getting thinking about. You also hit a good point about Omega FA raising LDL but demonstrating effect (due to anti-ox properties?). Also, Praz mentioned it, the failure of Cetp inhibitors (or at least pfizers). You would think the mechanism would be a silver bullet if the lipid hypothesis was what is driving CVD.

I think (based on pure speculation) that we'll see a shift away from the goal of driving cholesterol ALARA with multiple agents, it's AE prone, increasingly expensive and unproven. Maybe a shift towards more correlated endpoints whatever they more be, hs-CRP, TNF-a, ox-LDL or something else. Maybe we'll figure some day that Statins' effect on cholesterol is nothing more than a interesting off target effect and it's affecting outcomes through a different mechanism and we've been chasing cholesterol just by circumstance

 

[Praziquantel86]

Thanks Spacecowgirl, perfect points to what I'm getting thinking about. You also hit a good point about Omega FA raising LDL but demonstrating effect (due to anti-ox properties?). Also, Praz mentioned it, the failure of Cetp inhibitors (or at least pfizers). You would think the mechanism would be a silver bullet if the lipid hypothesis was what is driving CVD.

I don't think we can fairly use torcetrapib as an example due to its non-lipid effects increasing mortality. Anacetrapib seems to be free of those issues, so it will allow us to get to the root of the problem. The addition of anacetrapib to Statins appears to lower LDL to nearly the (proposed) physiologic limit, so mortality data from those will really allow us to see whether it is indeed LDL lowering that confers mortality benefit.

I think (based on pure speculation) that we'll see a shift away from the goal of driving cholesterol ALARA with multiple agents, it's AE prone, increasingly expensive and unproven. Maybe a shift towards more correlated endpoints whatever they more be, hs-CRP, TNF-a, ox-LDL or something else. Maybe we'll figure some day that Statins' effect on cholesterol is nothing more than a interesting off target effect and it's affecting outcomes through a different mechanism and we've been chasing cholesterol just by circumstance

I agree with the additional biomarkers you mentioned as being of interest, with the addition of one less esoteric marker: HDL. I don't think we have any good prospective data indicating what impact HDL might have, which seems to be fairly easily studied.

An addition to this: for statins, at least, LDL appears to be a perfectly appropriate biomarker. CV outcomes are tied to LDL lowering effects of statins, but it doesn't seem to be the same way with the other cholesterol drugs. We may find ourselves in a situation similar to the anticoagulants, where each different class of drugs has a different biomarker that is used to measure apparent efficacy.

 

[gotdrugs]

spacecowgirl - I think you need to 1) re-read my posts and see what I thought the thread was concluding (i.e. LDL being disregarded; not statins) and 2) In fact it does appear the 2nd or 3rd post on the thread does trash statins a bit

Prazi - you last point in your last post sums it up.

 

[gotdrugs]

I'm really not sure how specific LDL is anymore, as the ENHANCE trial demonstrated. I don't think LDL monitoring will go away but will be more useful in the context of other measures that we are not routinely checking now - Lp(a), hsCRP, calcium scoring.


Why do omega fatty acids decrease CV death? They can raise LDL-C.

To be fair, ENHANCE didn't look at clinical outcomes

I agree with the bolded part in that CRP, calcium scoring etc will be included in monitoring over the next 10years

While this iisn't my area of practice, but I thought the jury was kinda out on Omega-3s? Wasn't the "best" study the GISSI-proviencione or something like that and at the time of it's release the theory was actually it was the anti-arrhythmic effects that made had contributed. (which of course would contradict every other theory on anti-arrhythmics)

 

[karizma098]

"Why do omega fatty acids decrease CV death? They can raise LDL-C."



because they decrease non-hdlC which is more important in decreasing atherosclerotic events in relation to CV outcomes. nonhdlc >> than ldlc in terms of atherosclerosis; hence the occasional ldl-c increase is outshadowed by the impact on hdl-c.

again; i haven't taken path for over a year , so this is a bit fuzzy. don't have the time to google this on my phone right now. Doesn't matter. we're not going to stop prescribing and you're not going to stop filling them anytime soon, there are far too many fatties in this country.

 

[spacecowgirl]

spacecowgirl - I think you need to 1) re-read my posts and see what I thought the thread was concluding (i.e. LDL being disregarded; not statins) and 2) In fact it does appear the 2nd or 3rd post on the thread does trash statins a bit

OK 😕

To be fair, ENHANCE didn't look at clinical outcomes

No, it wasn't powered to measure that, but I still think it's interesting that lower LDL didn't impart CIMT benefits. Is the IMPROVE-IT trial still planned?

because they decrease non-hdlC which is more important in decreasing atherosclerotic events in relation to CV outcomes. nonhdlc >> than ldlc in terms of atherosclerosis; hence the occasional ldl-c increase is outshadowed by the impact on hdl-c.

again; i haven't taken path for over a year , so this is a bit fuzzy. don't have the time to google this on my phone right now. Doesn't matter. we're not going to stop prescribing and you're not going to stop filling them anytime soon, there are far too many fatties in this country.

Why do we treat LDL as a primary target in dyslipidemia if it's not as important as non-HDL? Why is non-HDL a secondary target in ATP? Rhetorical question. And why are some posters arguing that the LDL lowering of statins is their primary CV benefit (with other effects being recognized) if LDL isn't as important as non-HDL?

I agree 100% that in a person with CV risk factors or h/o CVD, I think statins should be used, no question. Regardless of what LDL really shows, people die of CVD less often when taking statins. Where it gets iffy for me is for a person who is high risk, on multiple therapies but still has an LDL of, say, 120. Do you put that person on ezetimibe just because the LDL will get to be <100? I don't know that the evidence supports that, however the guidelines would tell you to get that LDL <100 (or 130 or 70, whatever the case).

 

[spacecowgirl]

Also, I wish we had more of these threads on SDN instead of the same old crap that we usually post about. This is at least useful to discuss compared to who should be able to call themselves doctor.

 

[Its Z]

Also, I wish we had more of these threads on SDN instead of the same old crap that we usually post about. This is at least useful to discuss compared to who should be able to call themselves doctor.

yawn... when y'all come to a conclusion on this topic..someone type up an abstract...

 

[spacecowgirl]

Z, always harshing my mellow.

 

[Its Z]

Z, always harshing my mellow.

I know...it's raining and forced me to make changes to my afternoon plans. I hates that.

 

[spacecowgirl]

I know...it's raining and forced me to make changes to my afternoon plans. I hates that.

Jeez, you need more hobbies in your reserve.

 

[Fatpharm]

http://www.fathead-movie.com/index.php/about/

Here is a movie that trashes the lipid theory and the promotion of it by the government. It was made to be the anti-supersize me. Not totally sold, but I thought it was interesting.

 

[Ackj]

http://www.fathead-movie.com/index.php/about/

Here is a movie that trashes the lipid theory and the promotion of it by the government. It was made to be the anti-supersize me. Not totally sold, but I thought it was interesting.

Just from reading the description on the site, it seems to be one of those things that support Paleo diet. "Our ancestors ate raw meat and fat, not rice, grains, sugar, so our bodies are evolved to eat those things that modern science says is unhealthy." I have pretty much the same conclusion as you, interesting, but not really sold on it. However, I will take their advice and eat plenty of meat.

 

[spacecowgirl]

AIM-HIGH trial stopped early due to lack of benefit.

 

[npage148]

So, does anything besides statins have any demonstrable benefit when looking at outcomes?

 

[eventualeventer]

What is the current thinking on the putative link between chronic infection and CAD? I don't know much about it, but I could picture infectious agents as being one of many factors involved.

 

[tablet]

AIM-HIGH was a five-year study of almost 3500 patients, and results were originally expected in September 2012

AIM-HIGH enrolled 3414 participants in the US and Canada with a history of cardiovascular disease, low HDL cholesterol, and high triglycerides, who were all prescribed simvastatin and who were also randomized to either high-dose, extended-release niacin in gradually increasing doses up to 2000 mg per day (n=1718) or placebo (n=1696). Of the participants, 515 were given a second LDL-cholesterol–lowering drug, ezetimibe (Zetia, Merck/Schering-Plough), in order to maintain LDL-cholesterol levels at the target range between 40 and 80 mg/dL.
Participants who took high-dose, extended-release niacin and statin treatment had increased HDL cholesterol and lowered triglyceride levels than participants who took a statin alone. However, the combination treatment did not reduce fatal or nonfatal MI, strokes, hospitalizations for acute coronary syndrome, or revascularization procedures.
During the 32-month follow-up period, there were 28 strokes (1.6%) reported among participants taking high-dose, extended-release niacin vs 12 strokes (0.7%) in the control group. Nine of the 28 strokes in the niacin group occurred in participants who had discontinued the drug at least two months and up to four years before their stroke.

 

[tungsten87]

instead of measuring cholesterol/LDL, it's probably more important to measure the ratio of types of LDL particles in circulation in a particular patient (ie: pattern A vs pattern B). This, like measuring cholesterol/LDL levels are only so good as they provide little information about what is occurring at the blood vessel/endothelial level.

 

[spacecowgirl]

I find the reader comments interesting in this blog post.

"Harlan, What if one patient benefits from a treatment and another does not? Genetic variation and environmental factors that only the attending md can understand. Why should any government group of Oracles get in the way of a physician's choice of therapy based on the patients needs? i don't want people like you or the government involved in that decision, we should work to unfund this boondoggle."

So how do you know if a medication is working for CVD? Moreover, how do you know it's not working before it...doesn't?