Re: Re: Statins & heart disease (was fats & cholesterol)

[Guest guest]

Hi

> There is more but perhaps I should stop here. The conclusions are as

> follows:

It seems from scanning to me that you provided too much information.

I can't possibly look at all of it for participation in a discussion

like this, and it seems that only a few of them concern whether women

or elderly benefit from statins, which I believe was your original

question. Perhaps you could provide one or two studies and/or

meta-analyses showing that statins have failed to reduce CHD in women

and elderly.

> If you have data that indicate otherwise, I'd love to see it.

This is not something I've looked into very deeply, but here is

something that comes up after a quick pubmed search:

============

http://www.ncbi.nlm.nih.gov/pubmed/18172039?ordinalpos=1 & itool=EntrezSystem2.PEn\

trez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

It is well known that statins reduce the risk of cardiovascular

disease. However, the effect of statins in women for the primary

prevention of cardiovascular disease has not been determined. [snip]

The occurrence of cardiovascular events was 26% to 37% lower in the

diet plus pravastatin treatment group than in the diet alone group.

Although these differences did not reach statistical significance, the

overall risk reductions were similar to those in men. Notably, women >

or = 60 years of age treated with diet plus pravastatin had markedly

higher risk reductions for coronary heart disease (45%), coronary

heart disease plus cerebral infarction (50%), and stroke (64%) than

did women treated with diet alone. CONCLUSIONS: Treatment with

pravastatin in women with elevated cholesterol but no history of

cardiovascular disease provides a benefit similar to that seen in men,

and this benefit is more marked in older women.

==============

> The problem this raises for me is that if oxidized LDL was a primary cause

> of CHD and

> CHD mortality, and statins reduce levels of ox-LDL across the board (which

> is not in

> dispute by anyone, it seems), then why aren't statins reducing CHD rates in

> women and

> the eldery?

Even if we were to assume this is true -- and I'm not ready to do that

-- statins do many other things besides lower ox-LDL. And, in fact, I

would not consider a positive effect of statins sufficient evidence to

conclude that ox-LDL is the contributor anyway, since I believe their

biggest benefit is probably from lowering levels of

geranylgeranyl-pyrophosphate, though it is probably impossible to

distinguish one from the other. They also decrease coenzyme Q10

levels at a magnitude similar to the cholesterol reduction, which

would be expected to worsen risk to some degree or another. This and

other confounding effects could produce a lack of net benefit.

However, the biggest thing you have to watch out for is a benefit that

is not statistically significant. Lack of statistical significance

does not mean lack of a real benefit, it just means a lack of

statistical confidence in that benefit.

I think it is very difficult to tease out exactly how important the

contribution of ox-LDL is, but from all the massive mechanistic work

done, it just doesn't make any sense to conclude that ox-LDL is *not*

a contributor, especially based on multi-factorial interventions.

If you have something that lowers ox-LDL and does nothing else, and it

has no effect no matter how much you give and how much you lower

ox-LDL, then that would be compelling negative evidence. But that's

not really what you get in a statin trial.

Chris

[Guest guest]

Hi

> Here is a good summary of the studies on elderly & statins:

>

> http://junkfoodscience.blogspot.com/2008/01/reading-evidence-closely-statins-

> for.html

It cites the PROSPER trial as the largest trial in elderly showing a

24% reduction in CHD deaths. It goes on to say that total mortality

is a more useful figure, but this is only true if you are trying to

determine whether you should take statins or not. It is not true if

you are trying to determine what the cause of atherosclerosis or heart

attacks is.

> See here for info on women and elderly:

>

> - Abramson and contend that statins did not reduce coronary heart

> disease events

> in the almost 11 000 women in pooled trials, nor in men and women older than

> 69

> (n=3239). (http://www.medscape.com/viewarticle/551324)

It looks possible from this article that statins do not offer any

benefit to women, although there are several good contrary points

made. If, as they contend, the CTT has better data and intends to do

their own meta-analysis, and they actually do this, we might see

better data. In primary prevention populations (not clear whether

women are overrerepresented in primary prevention trials or not from

the article), you might not detect a benefit despite it being there

because the number of events is so low.

Perhaps more importantly, they are pooling the data and not discussing

the individual studies. The first article you posted above had this

to say about pooled data:

===========

Already, we're seeing some of the problems with meta-analyses, as has

been previously reviewed. The studies lumped together in a

meta-analysis can vary considerably in quality, measures, populations,

methodologies and statistical analyses. Some studies may show a weak

positive finding, others report none, and others may even report a

negative finding. Meta-analyses can end up giving the same weight to

all the studies (well-conducted and bad) by pooling them together,

trying to create a statistically stronger estimation of an effect or

prove something the studies weren't designed to test. And therein lies

the rub.

===========

The same criticism applies here. I posted an abstract in my last post

showing a large relative risk benefit to women -- was this study

better or worse or somehow more or less informative than other

studies? I don't know the answer to that.

So statins do seem to work in the elderly, and may or may not work in

women. Whether or not the benefit is sufficient to justify taking

them is entirely another story, of course.

Ultimately, however, your question of how statins cannot provide

benefits in certain population if they lower ox-LDL and ox-LDL

contributes to heart disease is similar to asking how they can boost

nitric oxide functioning and provide no benefit in these populations

if nitric oxide is protective, or how they can inhibit platelet

aggregation and smooth muscle cell migration and not provide benefit

in these populations if these factors are known to be part of the

disease process.

We would want to know how effective they were at lowering ox-LDL in

the individual trial, and want to know if it correlated with risk

reduction -- information we don't have. We would want to know, if

there was not reduction in CHD deaths, was there a reduction in or

reversal of the disease process. For example, was there a reduction

in stenosis and intima-media thickness, a reduction in calcification,

etc.

But even still, we have to be aware that statins are multi-factorial

drugs and they have negative effects as well as positive effects.

They are not a single-variable trial, where they only lower ox-LDL or

they only boost NO. So we can't use them as some type of gold

standard trial of the hypothesis that the one contributes to CHD or

the other is protective.

Chris

[Guest guest]

On 2/8/08, chriskjezp <chriskresser@...> wrote:

>

> > Ultimately, however, your question of how statins cannot provide

> > benefits in certain population if they lower ox-LDL and ox-LDL

> > contributes to heart disease is similar to asking how they can boost

> > nitric oxide functioning and provide no benefit in these populations

> > if nitric oxide is protective, or how they can inhibit platelet

> > aggregation and smooth muscle cell migration and not provide benefit

> > in these populations if these factors are known to be part of the

> > disease process.

> > We would want to know how effective they were at lowering ox-LDL in

> > the individual trial, and want to know if it correlated with risk

> > reduction -- information we don't have. We would want to know, if

> > there was not reduction in CHD deaths, was there a reduction in or

> > reversal of the disease process. For example, was there a reduction

> > in stenosis and intima-media thickness, a reduction in calcification,

> > etc.

> Exactly. The deeper I get into the data and analysis of the data, the more

> clear it becomes

> that we just can't be sure of the exact mechanisms of CHD. Nor can we be

> sure exactly

> how statins work.

I think we know quite a bit about the mechanisms, certainly have lots

more to know, and have little idea about the relative importance of

various factors. The fact that it isn't clear which are the most

important factors by which statins work is another question itself.

> However, most people simply aren't interested in the finer points of this

> debate. What

> most people want to know is " what can I do to promote health and well-being

> and improve

> my quality of life as I age " ? " What should I eat? " " Should I take

> statins? " And ultimately,

> as a future health-care professional, those are the questions I'm most

> interested in as

> well.

Me too, but those aren't the questions being addressed in this thread.

This thread is about whether statins (possibly) failing to reduce CHD

in women is evidence against the causal contribution of oxidized LDL.

> From my reading of the data, we can answer those questions with some

> certainty. That's

> why in my mind the total mortality data is so much more important than the

> rates of CHD,

> and even CHD-related deaths. Who cares if a statin reduces CHD events when

> it raises

> mortality from cancer and other diseases at the same time?

Anyone trying to answer the question you originally asked that led to

the establishment of this thread.

> Personally, I'd

> much rather die

> from a massive MI than a long, painful cancer.

I wouldn't want to die from either, but if I was going to die early, I

would want to know before hand.

> What I feel very good about telling the people I work with is this:

> 1) There is absolutely no evidence that eating cholesterol and saturated fat

> in the diet

> raises cholesterol levels in the blood.

This is false. It has long been established that substituting SFA for

PUFA raises levels of cholesterol in the blood in very tightly

controlled metabolic ward studies. Your point about cholesterol is

more true. However, to be more precise, at least with egg

cholesterol, about 70% of people have no response or a very slight but

relatively insignificant increase, and about 30% have substantial

increases in cholesterol levels, but no change in the LDL:HDL ratio

and a general shift from pattern B (bad) LDL to pattern A (good) LDL.

This is dependent on certain genes.

> 2) A diet high in saturated fats and cholesterol is far more healthy for

> your heart (and the

> rest of your body) than a diet high in PUFAs and refined carbohydrates (the

> so-called

> " heart healthy " approach).

I agree.

> 3) The only aspect of your cholesterol levels you should (probably) be aware

> of is the L(p)a

> (as an indicator of the level of oxidization of LDL) and the ratio of

> ApoB100 to LDL (as an

> indicator of the density/size of LDL particles). The way to reduce ox-LDL

> and minimize

> the small, dense LDL particles is to avoid PUFAs and trans fats in the diet

> and eat plenty of

> egg yolks

I agree.

>(see #3 above).

Not sure what you mean -- that was number 3.

> 4) Statins do not reduce total mortality in >95% of the population. They

> have serious and

> significant side effects and risks, many of which are underreported. They

> have been shown

> to cause cancer in every animal study done to date. In the highest risk

> population

> (middle-aged men who already have CHD), a 50-year old man would have to take

> a statin

> for 30 years to extend his lifespan for 2-weeks. Statins do not reduce

> total mortality in

> primary prevention populations or women, and they actually increase total

> mortality in the

> elderly (high cholesterol is protective in this population).

I'm not sure I agree with all of this, but I haven't done enough

research to say for sure. Either way, the benefits are seriously

exaggerated and the number needed to treat is poor and the side

effects and cost are not worth it in my opinion.

> On a practical level, for most people, I think the four points above are

> what it really boils

> down to. The details we are hashing through are only relevant (in my mind)

> to the extent

> that they change the recommendations above in some way. Otherwise, they are

> mostly

> academic. (No judgment there! I enjoy learning about this stuff and

> talking about it. But

> I'm speaking of what I think is relevant to our daily lives.)

I essentially agree with that.

Chris

[Guest guest]

On 2/8/08, chriskjezp <chriskresser@...> wrote:

> I would like to see the data from which you draw this conclusion. Where can

> I find those

> metabolic ward studies?

I don't have the references on hand at the moment because I'm no

longer in possession of Steinberg's book, but they are probably

referenced in Ravnskov's book as well, since in his chapter about it

being a myth that eating saturated fat raises blood cholesterol

levels, he cites them and admits that this is in fact not a myth, but

goes on to give greater weight to observational studies that could not

find any difference in cholesterol levels between different people

eating different amounts of saturated fat and says the metabolic ward

finding is relatively unimportant.

> Because I have seen a lot of studies that indicate the opposite (regarding

> the effect of

> saturated fat consumption on serum cholesterol).

> - " In Framingham, Massachusetts, the more saturated fat one ate, the more

> cholesterol

> one ate, the more calories one ate, the lower people's serum cholesterol...

> we found that

> the people who ate the most cholesterol, ate the most saturated fat, ate the

> most calories

> weighed the least and were the most physically active. " (1992)

Right. This is not a metabolic ward study. It is not an experimental

study. It is not a substitutional study. It doesn't tell you

anything about how your cholesterol levels will change if you choose

to eat more SFA or more PUFA.

> - In a study of 10,000 Israeli civil servants, intake of animal fat ranged

> from ten grams up

> to two hundred grams daily. Yet there was absolutely no relationship

> between intake of

> dietary fat and cholesterol levels. (Kahn HA, and others. Israel Journal of

> the Medical

> Sciences. 1969;5:1117 1127.)

Likewise.

> - A survey of South Carolina adults found no correlation of blood

> cholesterol levels with

> " bad " dietary habits, such as use of red meat, animal fats, fried foods,

> butter, eggs, whole

> milk, bacon, sausage and cheese (Lackland DT, et al. J Nutr, Nov 1990.

> 120:11S:1433-

> 1436)

Likewise.

> - The Masai tribe in Africa subsist largely on whole milk, blood and beef.

> Yet their

> cholesterol is among the lowest ever measured in the world, and about 50% of

> the average

> Americans' (Lapiccirella V., and others. Bulletin of the World Health

> Organization 1962;27:

> 681-697.)

That's true, and it also is lowest when they are eating their

exclusive meat and milk diet in the warrior phase of their life, and

goes up when they eat carbohydrate foods in other phases of their life

(as does their atherosclerosis). However, the metabolic ward studies

were discussing substitution of SFA for PUFA and vice versa, not

substitution of SFA for other macronutrients such as carbohydrate.

> - There is not a single long-term study showing that a high-cholesterol, or

> high

> saturated fat diet, has any impact on blood cholesterol levels in a normal,

> healthy

> population (Farr, M.D., " Why the Cholesterol-Heart Disease is Wrong " ,

> http://www.thincs.org/)

>

> If the above statement by Dr. Farr is incorrect, I would like to see that

> study if you have

> the reference.

All of the controlled experimental studies show that SFA substituted

for PUFA raises blood cholesterol. I don't know whether this changes

long-term, and it's difficult to have a tightly controlled study

long-term. But the authors of these studies claim they are studying

it until they reach a plateau.

There is also some work done on mechanism. It has been suggested

before that the cholesterol is brought into membranes that have higher

levels of PUFA in them, but the bulk of work seems to point to the

higher degree of esterification of cholesterol with linoleic acid.

When LA is high, more cholesterol gets esterified and thus stored in

the liver. Free cholesterol therefore declines, which upregulates the

LDL receptor and causes the liver to take cholesterol out of the blood

and into the liver. SFA have low rates of esterification with

cholesterol. So basically PUFA leads to a transfer of cholesterol

from the blood into the liver, whereas PUFA decreases cholesterol

accumulation in the liver.

It would be interesting to see if, after the initial plateau, the

blood level readjusts again from other factors. For example, it seems

there might be some limit to cholesterol storage in the liver, or if

not, some adverse effect, unless it is somehow disposed of. Also,

PUFA decreases sensitivity to thyroid hormone, which is needed for LDL

receptor function and causes cholesterol to go from the blood into

tissues, which decreases the tissues own synthesis of cholesterol.

However, some of the long-term PUFA substitution studies that Colpo

sites reduced cholesterol levels over a matter of years, which seems

to make this unlikely -- and in a number, increased CHD mortality.

There is a rat study comparing corn oil to coconut oil, called

" metabolic shifting " in the title (should be able to find it on

pubmed), which found corn oil to reduce cholesterol and LDL levels

pretty substantially, and also to reak havoc on the heart through

lipid peroxides, decreased oxidative capacity and glycogen depletion.

Chris

[Guest guest]

Hi

> One more question. Since you advocate eating saturated fat, and since you

> believe ox-

> LDL is a contributor to CHD whereas " normal " (light, fluffy) LDL is not, I'm

> assuming that

> you believe saturated fat increases the " normal " LDL and not ox-LDL.

> (That's a lot of

> assumptions about what you think, so please correct me if I'm wrong!)

Well actually, I'm not sure if SFA increases LDL relative to

carbohydrate, because carbohydrates raise LDL too. I think SFA raises

LDL somewhat relative to PUFA, and yes, I believe that would raise

unoxidized LDL because it is the PUFA that cause LDL to oxidize.

> In the study you reference, did total, HDL, LDL or all three go up after

> eating SFA? How

> much?

I haven't read all of them, but there was a recent one that compared

coconut oil, butter, and safflower oil, and it found that butter and

coconut oil raises LDL in both sexes but HDL only in women. I think

some of the older ones were only looking at total.

> Of what relevance do you believe this finding is, in light of the fact that

> you support eating

> SFAs over PUFAs?

I think it's pretty irrelevant.

Chris

[Guest guest]

Hi Patty,

> I'm just one person BUT last June, I began eating a whole foods, no

> sugar no grain diet. The only fats I use are butter, coconut oil and

> once in a while, a small amount of olive oil. I eat plenty of meat,

> mostly chicken. My total Cholesterol went from around 300 to 150 in

> that amount of time. HDL increased from 30 to 50 and LDL came down a

> little, but still high. So, for me personally, I certainly don't fit

> what was written and from my research, something sounds very wrong with

> that conclusion.

>

> " It has long been established that substituting SFA for PUFA raises

> levels of cholesterol in the blood in very tightly

> controlled metabolic ward studies " .

Since you seem to have replaced carbs with SFA rather than PUFA, it

makes quite a bit of sense and doesn't seem conflicting. Low-carb,

high-SFA diets make cholesterol levels " better " by conventional

standards and also reduce lipid peroxidation and massively reduce

inflammation much more successfully than low-fat diets.

Chris