Statin therapy for healthy people with high cholesterol?

[bohm2]

I thought this was interesting commentary in a fairly recent issue of JAMA arguing for the 2 different viewpoints. To prescrtibe or not to prescribe statins for healthy people with high cholesterol?

No. What is the benefit of statin therapy in healthy men with high cholesterol levels? Data from a meta-analysis of 11 trials including 65 229 persons with 244 000 person-years of follow-up in healthy but high-risk men and women showed no reduction in mortality associated with treatment with statins. A 2011 Cochrane review of treatment with statins among persons without documented coronary disease came to similar conclusions...Do the potential benefits outweigh the potential risks? Based on all current evidence, a healthy man with elevated cholesterol will not live any longer if he takes statins. For every 100 patients with elevated cholesterol levels who take statins for 5 years, a myocardial infarction will be prevented in 1 or 2 patients. Preventing a heart attack is a meaningful outcome. However, by taking statins, 1 or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss.

Healthy Men Should Not Take Statins
http://jama.jamanetwork.com/article.aspx?articleid=1148381

Yes. In the shared decision-making process, the clinician should explicitly inform this patient that a statin is likely to reduce the chance of a first CHD event and reduce the chance of stroke and may offer a survival benefit that is likely to become more evident over a lifetime. Is there a durable benefit to statin therapy, or should statins be prescribed only after a myocardial infarction? There is no apparent logic in waiting for a myocardial infarction or a stroke to occur before starting a risk-reducing therapy. A recent meta-analysis of trials confirms that statins retain their benefit after discontinuation of randomized therapy...Do patients expect medications to prolong survival within 5 years? Most patients do not expect near-term survival benefit from medicine; they are concerned about myocardial infarction, stroke, venous thrombosis, and the resulting chronic disease and disability that may occur. They see their parents, who have vascular dementia and congestive heart failure, and seek safe strategies to reduce their risk. In fact, more than ever, the modern patient is focused on quality of life and not exclusively on longevity.

Statin Therapy for Healthy Men Identified as “Increased Risk”
http://jama.jamanetwork.com/article.aspx?articleid=1148380

 

[mazinse]

I suppose you would also have individualize base on a person's BMI, assuming they don't have any risk factors which the people in the article were.

 

[bohm2]

So are you saying that statins should be recommended even for primary prevention when cholesterol is elevated (but without documented coronary heart disease) but only when BMI is high? But if BMI is not high, one shouldn't recommend statins in such patients?

 

[bohm2]

This recent meta-analysis is interesting because it suggests that statins may not even be effective (at least with respect to increasing longevity) in women with coronary heart disease (e.g. secondary prevention):

Conclusions: Statin therapy is an effective intervention in the secondary prevention of cardiovascular events in both sexes, but there is no benefit on stroke and all-cause mortality in women.

Statin Therapy in the Prevention of Recurrent Cardiovascular Events-A Sex-Based Meta-analysis
http://archinte.jamanetwork.com/article.aspx?articleid=1195535

So basically, if I'm understanding these studies, then:
1. statins aren't likely to prolong life in women with/without a history of coronary heart disease
2. statins are not likely to prolong life in men without coronary heart disease

So, the only group that appears to derive benefits are men with history of coronary heart disease.

 

[Monique]

Isn't it more important to figure out why the healthy individuals are having a high cholesterol and tackle the problem at the root?

 

[bohm2]

Isn't it more important to figure out why the healthy individuals are having a high cholesterol and tackle the problem at the root?

That would be a good approach assuming that cholesterol (or at least the small, dense LDL part acording to some studies) is the problem, particularly for men and it isn't something else correlated/confounding. Kind of like fever and infections. It's the bugs that is the problem, not the fever unless fever gets exceptionally high. Thus, if you get rid of the bugs, you get rid of the problem. Anti-fever meds are not getting at the heart of the problem. Some have suggested that cholesterol may be like that and even questioned the "LDL cholesterol drives atherosclerosis" model but such views are in the minority. For an interesting paper on this critical view see:

The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of coronary artery plaque burden and progression
http://thrivewithdiabetes.com/doc/Medical_hypotheses_cholesterol.pdf

 

[Monique]

Well, I think using statins to lower cholesterol is metaphorically lowering the "fever" thus not tackling the real problem. My question would be: why is the cholesterol high, poor diet or other factors?

I also heard that the "bad" LDL hypothesis has been taken into doubt, how accepted is that position?

 

[bohm2]

Well, I think using statins to lower cholesterol is metaphorically lowering the "fever" thus not tackling the real problem. My question would be: why is the cholesterol high, poor diet or other factors?

I also heard that the "bad" LDL hypothesis has been taken into doubt, how accepted is that position?

Genetics and diet determine cholesterol level. As far as I know every major professional health organization supports the LDL hypothesis and recommends some type of treatment based on reaching certain LDL target but type of therapy varies depending on cardiovascular risk potential.

In high-risk patients, pharmacological therapy should be considered concomitantly with lifestyle changes. In moderate-risk patients, lifestyle changes should be implemented first, followed by medications if the targets are not reached.

For instance, the Canadian guidelines that doctors, pharmacists, etc. use (See p. 575 for the summary):

Canadian Cholesterol Guidelines 2009: Summary of recommendations
http://www.ccs.ca/download/consensus_conference/consensus_conference_archives/2009_Dyslipidemia-Guidelines.pdf

Having said that, there are some health professionals who question some of these guidelines. The most vocal group are the The International Network of Cholesterol Skeptics but again, they are still in the minority. Some have even argued that some of statin's beneficial effects in some patients may be due to anti-inflammatory properties?

 

[SW VandeCarr]

Progression of atherosclerosis (and how such progression is measured) and the correlation of serum LDL cholesterol levels with fatal myocardial infarction (MI or heart attacks) are two different questions. As was mentioned, the anti-inflammatory and anti-thrombotic effects of statins may play a role. Abnormal levels of other lipid fractions as well as high serum triglyceride levels are also considered risk factors for fatal MI. Inflammation associated with the rupture of the coronary arterial (endothelial) lining by the underlying atheroma seems to be the precipitating event in the case of MIs, at least according to some studies. This article summarizes situation as of 2002. This is not a new idea.

http://qjmed.oxfordjournals.org/content/95/6/397.full

 

[bohm2]

This article summarizes the current situation.
http://qjmed.oxfordjournals.org/content/95/6/397.full

The author of that article (Uffe Ravnskov) is or was the spokesman for The International Network of Cholesterol Skeptics (THINCS), I mentioned above. Most experts in the field do not interpret the balance of studies in the same way as that organization; nevertheless, many have questioned the need for using statins in so many individuals especially given the small benefits in all-cause mortality outcomes.

 

[SW VandeCarr]

The author of that article (Uffe Ravnskov) is or was the spokesman for The International Network of Cholesterol Skeptics (THINCS), I mentioned above. Most experts in the field do not interpret the balance of studies in the same way as that organization; nevertheless, many have questioned the need for using statins in so many individuals especially given the small benefits in all-cause mortality outcomes.

There's nothing wrong with a healthy level of skepticism. The fact is, the science, as judged by regulatory agencies, only justifies the use of statins for secondary prevention of fatal MI (that is in MI survivors) afaik. Any other use of statins, such as in primary prevention, would be considered "off label". The effect of statin therapy on serum LDL cholesterol levels or other lipid fractions is not the critical end point.

EDIT: One statin (rosuvastatin) has been approved for the primary prevention of MI, stroke, cardiovascular related death and other outcomes in patients who have have certain risk factors for cardiovascular disease.

http://www.ccmdweb.org/dsl/middle.aspx?Slideid=2738&Catid=1036

 

[mazinse]

the people who have hereditary hyper lipidemia still benefit from statins

 

[feihong47]

I believe that we totally wasting billions on needless cholesterol drugs, and also artificially increasing the already climbing charge for healthcare! If statins can be effective in preventing a myocardial infarction, why while trying to solve a problem, should we trigger many others? Staying away from high-cholesterol foods and adhering to a low cholesterol diet plan will be the most effective approach for healthy people.

Diet and exercise ARE still first line therapy before any statins are recommended in most cases. Only if the individual still maintains a high LDL above the threshold after a certain period of time despite diet and exercise, are then recommended for drug therapy

http://www.uptodate.com/contents/high-cholesterol-treatment-options-beyond-the-basics

 

[ApplePion]

There's nothing wrong with a healthy level of skepticism. The fact is, the science, as judged by regulatory agencies, only justifies the use of statins for secondary prevention of fatal MI (that is in MI survivors) afaik. Any other use of statins, such as in primary prevention, would be considered "off label". The effect of statin therapy on serum LDL cholesterol levels or other lipid fractions is not the critical end point.

By definition of "healthy" there is nothing wrong with a "healthy" dose of skepticism, but empirically it is just about always the case that people who label themselves with that word, as did that cholesterol "skeptic", are wrong and seriously unreasonable. I'd challenge anyone to come up with more than one counter-example to my claim. (I do not want to call my self a skeptic about skeptics, though!)

I also note that after telling us that skepticism can be healthy, you unskeptically post some official guidelines. Guidelines are merely opinions.

The relationship between LDL cholesterol and heart disease is clearly causal. The correlation between LDL and heart disease is very strong. And it is biologically plausible. A correlation between wearing red socks and heart disease is less plausible because red socks are not found lining the coronary arteries. And regardless of the reason for the elevated LDL any group with elevated LDL has increased heart disease risk.

People with Familial Hypercholesterimia (FH) lack a full set cholesterol receptors in their livers leading to very elevated cholesterol lervels, and very high risk of heart attack. People with Apo E2 have lower cholesterol levels than average and people with Apo E4 have higher levels, and the heart attack risk is just about exactly numerically explained by the cholesterol levels. The mechanism for Apo E affecting cholesterol is quite different from FH, yet we see the same cholesterol dependence on heart attack risk. Indeed, the reason why Apo E 2 reduces LDL is because there is a defect in the conversion of triglyceride carriers to LDL. And so despite elevated triglycerides people with Apo E2 have lower heart attack rates. And the relationship is even stronger. People with two Apo E2 genes can sometimes develop a cholesterol abnormality (hyperlipoproteinemia type III ) and those people are then, unlike other people with Apo E2 at increased risk of heart disease. And people with high LDL due to diet are at increased risk of heart disease. If it was not LDL directly causing heart disease you would not see the relationship among groups having increased LDL for so many different reasons.

And just about any method to lower LDL decreases the risk of heart disease--diet, most or all medications, and in the case of people with FH, actually sending their blood through devices to remove cholesterol. Again the diversity argues that the LDL relationship is causal.

 

[SW VandeCarr]

Guidelines are merely opinions.

No. Guidelines for the use of prescription drugs are based on data, or the lack of data, from randomized clinical trials.

The relationship between LDL cholesterol and heart disease is clearly causal.

I challenge you to post a link to a qualified source that says that statistical correlations can establish causality. We can interpret strong associations as possibly causal to some high probability but no responsible scientist would say that a statistical association establishes causality. Do you know what a confounding variable is? Randomization helps control confounding, but most of the data in risk analysis comes from prospective and retrospective observational studies.

People with Familial Hypercholesterolemia (FH) lack a full set cholesterol receptors in their livers leading to very elevated cholesterol lervels, and very high risk of heart attack.

The topic is statin therapy for healthy people with high cholesterol. Do you consider people with FH healthy? No one is questioning the fact that statins lower LDL-C. The question is: Are you treating the patient or the laboratory value? Besides, I've not found any evidence that lowering LDL-C in FH significantly improves survival. Perhaps you could find something?

http://www.nejm.org/doi/full/10.1056/nejmoa0800742

Again the diversity argues that the LDL relationship is causal.

I believe elevated LDL-C is a predisposing factor for MI, but is it a necessary cause? If so, how do you explain MI's in people with normal or low LDL-C? They are not uncommon. Are you aware of the Jupiter trial? You should be if you are making these kinds of arguments in these forums. The rules require that you post links to qualified sources to back up what you say. Just posting your opinions is only allowed in the General Discussion forums.

http://www.diabetesincontrol.com/articles/53-diabetes-news/8950-fda-expands-rosuvastatin-use-to-people-with-normal-ldl

www.nejm.org/doi/pdf/10.1056/NEJMoa0807646

http://jcem.endojournals.org/content/88/6/2445.full

 

[bohm2]

Some might this summary of lipid trials interesting. Note:

1. Primary vs Secondary prevention
2. All-cause mortality when comparing drug vs placebo
3. The # of people and # of years of treatment needed to save 1 life (and it's not clear for how much longer that person may survive?)

And also keep in mind that published studies tend to over-represent positive trials (e.g. publication bias) as pointed out in many reviews. I think one can make a good argument that such funds can be used elsewhere for greater health benefits.

All-cause mortality outcomes from major lipid trials
http://www.midtownclinic.ca/rx7/14-CHT-lipidagents-majortrials.pdf

The source is Rxfiles, a summary used by Canadian doctors and pharmacists to help guide drug therapy decisions.
http://www.rxfiles.ca/rxfiles/modules/druginfoindex/druginfo.aspx

 

[ApplePion]

SW VandeCarr writes the following and then provides us with a link to a study in a prominent medical:

I've not found any evidence that lowering LDL-C in FH significantly improves survival. Perhaps you could find something?

Yes, I can find something--the very article you linked! You very seriously misundersood it. It actually says the opposite of what you thought it said. It did not say that statins were not beneficial in people with FH. It says they are. What it said that confused you was that adding a second drug gave no additional benefits over the benefits statins gave.

I would very strongly urge people interested in this discussion to read the article SW VandeCarr adduced, and see what it actually said. Here it is again:

http://www.nejm.org/doi/full/10.1056/nejmoa0800742

I believe elevated LDL-C is a predisposing factor for [heart attacks], but is it a necessary cause? If so, how do you explain [heart attacks] in people with normal or low LDL-C? ]

.

I would explain the situation as beiong analogous to the situation whereby some people who were not driving drunk die in car crashes. Drunk driving makes one more likely to die in a car crash, and elevated cholesterol makes one more likely to die from a heart attack. In both cases the correlation is causal.

I'm not sure what you mean by "predisposing factor"--I was under the impression that previously you cited approvingly that skeptic group which claimed elevated cholesterol does not increase the risk of heart attacks.

Responding to me saying that guidelines are opinions, SW VandeCarr responds:

No. Guidelines for the use of prescription drugs are based on data, or the lack of data, from randomized clinical trials.

Obviously the guidelineswes have some relationship to the data, but that does not make them not be opinions. They are the opinions of certain people about the data. Indeed, all opinions have some factual motivation (unless they are really unreasonable), but opinions are still opinions.

But what I find puzzling is that you keep using "appeal to authority" while saying how proud you are to be a "skeptic" and while taking a view on cholesterol that respected authorities strongly reject. The group you cite "The International Network of Cholesterol Skeptics" is not considered a mainstrean scientific group, while the American Heart Association, the National Institutes of Health and the Surgeon General, all of which disagree with you, are considered authorities. It is fine for you to have a non-standard view if you can argue it with facts and logic, but it makes no sense to use appeal to authority when you are taking a position at odds with authority.

No. Guidelines for the use of prescription drugs are based on data, or the lack of data, from randomized clinical trials.

Do you know what a confounding variable is?

Indeed I do. And in my vey first post in this thread I, in great detail explained how we know that the correlation is not due to confounding, so perhaps you should ask yourself the question you just asked me. I will summarize it for you.

If there was just one way that high cholesterol was linked to increased risk of heart attack, then confounding should be a concern. So, for example, if studies found that people who ate red meat had higher cholesterol and higher rates of heart attack then we could wonder if maybe, for example, the real culprit was iron in red meat. But there are many disparate unrelated modes of getting cholesterol--diet, genetic deficiency of cholesterol receptors to remove cholesterol from the blood, genetic predisposition to have increased conversion of triglycerides to LDL cholesterol, and all of them lead to increased risk of heart attack. Furthermore, there are many ways to lower cholesterol--diet, statins, blood filtration, and almost all lead to lower rates of heart attack. So it is not some confounding that is going on--the risk is fundamentally from the cholesterol itself.

We can interpret strong associations as possibly causal...

It seems that you might be thinking that a correlation must be strong in order for it to be causal. That is not mathematically correct. While, everything else being equal, a stronger correlation argues more strongly for causation, it is not always necessary.

Suppose one flipped a coin "in a fair way" (i.e. the flipper has set things up correctly, but the coin itself might be defective) and got heads 55 percent of the time. There is only a weak correlation between flipping and getting a head. But it this was over, let's say 10^90 fair coin flips the effect would clearly be causal--we could determine that the coin itself was not fair.

You should be if you are making these kinds of arguments in these forums. The rules require that you post links to qualified sources to back up what you say. Just posting your opinions is only allowed in the General Discussion forums.

I find this very strange from someone who posts stuff from that "International Network of Cholesterol Skeptics" group. I don't know what you want from me--I've posted quite a bit about the science. Do you want me to cite authorities--sometimes you engage in "appeal to authority" but sometimes you tell us you are a skeptic and you post views clearly at odds with mainstream medicine. So what do you want?

But most puzzling is that in a post that was rude, condescending, and now threatening, you claim I am breaking some message board rule. You need to check the rules for yourself.

 

[SW VandeCarr]

SW VandeCarr writes the following and then provides us with a link to a study in a prominent medical:



Yes, I can find something--the very article you linked! You very seriously misundersood it. It actually says the opposite of what you thought it said. It did not say that statins were not beneficial in people with FH. It says they are. What it said that confused you was that adding a second drug gave no additional benefits over the benefits statins gave.

I would very strongly urge people interested in this discussion to read the article SW VandeCarr adduced, and see what it actually said. Here it is again:

http://www.nejm.org/doi/full/10.1056/nejmoa0800742

Where does the article say anything about survival? The end point was intima-media thickness of the coronary arteries; the measurement of which has been challenged by the "cholesterol skeptics". It's in the Ravnsknov Oxford Journals paper I posted earlier. If the second drug (ezetimibe) were effective, it would have supported (not proved) the hypothesis that cholesterol levels alone are causal.

I don't consider myself a "cholesterol skeptic". However, I do think they make some good points. Atherosclerosis and its relationship to various presentations of cardiovascular disease (CVD) is complex. It's not a simple matter of blood levels of LDL-C or even the (total cholesterol)/ (HDL-C) ratio. Some of the papers I linked to clearly make this point. C Reactive Protein (CRP) appears to be an independent risk factor and there may be other independent risk factors.

Your use of the word "causal" is IMO inappropriate. Causality is established by experiments. Our ability to do medical experiments involving human beings is obviously limited by ethical considerations. In a true experiment you can more effectively isolate the variables of interest and manipulate them. The most rigorous medical experiment allowed for these kinds of questions is the randomized double blinded clinical trial. It reduces but does not eliminate confounding and the only variable you can manipulate is the treatment. The results are determined on statistical grounds based on normal theory. I'm not criticizing the methodology. This is how I once earned my living, but I do recognize the limitations.

Causality is usually described in terms of "sufficient cause", "necessary cause", and "necessary and sufficient cause". These terms might be applicable to infectious diseases where the infecting organism or agent is the necessary cause (but usually not a sufficient cause) for the relevant disease. I would again challenge you to find a paper in a reputable refereed journal that uses these terms in reference to the present subject. So far you have not supported your arguments regarding your use of the term "causal" as required in these forums.

EDIT: I also find your characterization that regulatory agencies (specifically the US FDA) operate according to their opinions to be unfounded. Major decisions like product approval and labeling are a very public affair involving experts from the academic community and the pharmaceutical companies. Even if the regulators have opinions, there are sufficient checks on any arbitrary and capricious actions on their part. I know the process very well. I would suggest you don't.

I find this very strange from someone who posts stuff from that "International Network of Cholesterol Skeptics" group. I don't know what you want from me--I've posted quite a bit about the science. Do you want me to cite authorities--sometimes you engage in "appeal to authority" but sometimes you tell us you are a skeptic and you post views clearly at odds with mainstream medicine.

Do you consider the articles I linked in refereed journals to be at odds with mainstream medicine? Science is not (or should not be) dogmatic. As I said, I don't subscribe to the complete skeptical thesis. Cholesterol is a factor in CVD and statins are effective, but possibly not only because they lower LDL-C, but also apparently because they lower CRP (Jupiter Trial) and may also have anti-thrombotic and anti-infammatory effects as suggested in linked articles. This, however, remains to be studied.

Apparently you've translated my "healthy dose of skepticism" into some kind of irrational extreme position. I don't know if that's deliberate or not.

You need to check the rules for yourself.

The rules say you must support your claims in the science forums by referencing valid sources.

In both cases the correlation is causal.

What?

 

[bohm2]

Not sure if this study was mentioned but there's also the ARBITER 6-HALTS trial. In that trial ezetimibe produced greater reductions in LDL cholesterol (so-called “bad” cholesterol) but resulted in no overall improvement in carotid intima-media thickness. In fact, individual results suggested greater thickening with greater LDL reductions. The use of etezimibe was also accompanied by a higher number of heart attacks and deaths:

Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness (R = -0.31, P < 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04 by the chi-square test)...Taken together with a preexisting concern regarding the clinical effectiveness of ezetimibe, our findings challenge the usefulness of LDL cholesterol reduction as a guaranteed surrogate of clinical efficacy, particularly reduction achieved through the use of novel clinical compounds. For ezetimibe, our results indicate a disconnect between reductions in the LDL cholesterol level and increases in the carotid intima–media thickness in patients with dyslipidemia who are receiving statin therapy.

Settings Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness
http://www.ccmconsultants.com/assets/1/7/Extended-Release_Niacin_of_Ezetmibe_and_Carotid_Intima-Media_Thickness.pdf


The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis)http://content.onlinejacc.org/article.aspx?articleid=1142914

 

[SW VandeCarr]

Indeed I do. And in my vey first post in this thread I, in great detail explained how we know that the correlation is not due to confounding, so perhaps you should ask yourself the question you just asked me. I will summarize it for you.

If there was just one way that high cholesterol was linked to increased risk of heart attack, then confounding should be a concern. So, for example, if studies found that people who ate red meat had higher cholesterol and higher rates of heart attack then we could wonder if maybe, for example, the real culprit was iron in red meat. But there are many disparate unrelated modes of getting cholesterol--diet, genetic deficiency of cholesterol receptors to remove cholesterol from the blood, genetic predisposition to have increased conversion of triglycerides to LDL cholesterol, and all of them lead to increased risk of heart attack. Furthermore, there are many ways to lower cholesterol--diet, statins, blood filtration, and almost all lead to lower rates of heart attack. So it is not some confounding that is going on--the risk is fundamentally from the cholesterol itself.

Since you posted 6 in a row without waiting for a response , I'll respond at my leisure to the extent I feel it justifies a response. This post indicates a poor example of scientific reasoning. All the factors you named (and many more), for the sake of this discussion, are considered to be "risk factors" for high serum cholesterol, and in particular LDL-C. Some relationships were discovered in randomized trials were it's presumed that confounding is adequately controlled. However, most of these relationships were discovered in observational studies where potential confounding factors must be identified and controlled. The best of them use very sophisticated multivariate regression models, but for many reasons which I won't list here, they can never justify the confidence one might place in a large well managed randomized trial. Nevertheless, there's little controversy regarding the amount of certain kinds of fats in a diet contribute to high serum cholesterol levels, particularly LDL-D and triglycerides. Other factors such as genetics, and exercise level are considered risk factors for elevated cholesterol (including the total cholesterol-HDL-C ratio.)

To keep things simple, I'll concentrate on just one value, LDL-C. Everything that I talked about above are considered explanatory variables contributing to this one value. This value is considered to be a risk factor for atherosclerosis. Now, we have to make the connection between atherosclerosis and the specific CVD outcomes (heart attack, stroke, etc). Here, we now know that high sensitivity C-reactive protein (hsCRP) is a major independent risk factor for MI (heart attack) through inflammation and clot formation. Your characterization that, say eating red meat causes heart attacks is a misleading and unscientific oversimplification. It may true, but "may be" is not the way you support the claim of strict causality. I will agree that a diet very high in red meat increases your risk for a heart attack if your LDL-C is elevated. I don't agree that we can say this will be the cause of your next heart attack.

Causality is an empirical concept. It's not defined in mathematics or logic. Philosophers have debated about what it really means. I prefer the simple but powerful concepts of "sufficient cause" and "necessary cause". Here the concept of LD(x)50 and LD(x)100 (lethal dose of x for a percent of a population)is useful. At LD(x)100, every individual in the population is dead. In a controlled experiment, we can say that x at D is a sufficient cause of the deaths (ie D(x)=LD(x)100) if all the subjects are dead and all or almost all the controls are alive. Presumably, the subjects in such an experiment are not human beings.

I believe saying x causes y is meaningless unless you state it in terms of a necessary and/or sufficient cause.

 

[Ryan_m_b]

The discussion here is far from civil, may I remind everyone that insults and aggressive behaviour will not be tolerated.

Secondly the discussion is descending into pedantry. When discussing articles please reference and quote specific sections when making your case.

 

[ApplePion]

Since you posted 6 in a row without waiting for a response , I'll respond at my leisure to the extent I feel it justifies a response. This post indicates a poor example of scientific reasoning. All the factors you named (and many more), for the sake of this discussion, are considered to be "risk factors" for high serum cholesterol, and in particular LDL-C. Some relationships were discovered in randomized trials were it's presumed that confounding is adequately controlled.

They actually were adequately controlled. All of these insights you are treating us to are well-understood by the real epidemiologists who work at the American Heart Association, the Surgeon General's Office and at the National Institutes of Health. You are saying things that are obvious, and irrelevant in context.

 

[ApplePion]

.

I believe saying x causes y is meaningless unless you state it in terms of a necessary and/or sufficient cause.

I have no idea what that means.

 

[SW VandeCarr]

They actually were adequately controlled. All of these insights you are treating us to are well-understood by the real epidemiologists who work at the American Heart Association, the Surgeon General's Office and at the National Institutes of Health. You are saying things that are obvious, and irrelevant in context.

What do mean by "real" epidemiogists?

 

[SW VandeCarr]

I have no idea what that means.

If it's not a necessary or sufficient cause, what is it? Some people use the term "partial cause" but what exactly is that? It's usually a factor that is correlated to the outcome which you may believe is causally related. But how do you prove it? You're in physics I believe. Do you believe correlation equals causation? By the way, I worked at NIH for a time.

 

[ApplePion]

What do mean by "real" epidemiogist?

You are the one who is big on authorities.

The sort of problems you are discussing are problems that any serious person, and even many casual people know. While they seem like complex concepts to you, to epidemiologists they are trivial. No one is making the errors you assume are being made.

Why is it that you are always demanding quotes from authorities, while you also assume the authorities cannot get simple stuff right? Do you really think the supposed issues you raised are things only you are aware of? Everyone knows about confounding varuables, and real epidemiologists are not going to just ingnore such. When they say that someything increases the risk of something, it means the risk is increased taking into account confounding variables.

 

[ApplePion]

Do you believe correlation equals causation? By the way, I worked at NIH for a time.

It often does, but not always. What I do believe is that everytime I have seen someone object that causation does not imply correlation, that person was arguing against something where the correlation was clealy causal. (Ironically, that is an interesting correlation.)

We know that the relationship between LDL cholesterol and heart disease is causal because it occurs through all subgroups of people with elevated LDL, and because almost any way of lowering itlowers risk. This is unlike the correlation between coffee and lung cancer--the elevation is found only in one subgroup--smokers--and so we know it is not really coffee that is the cause. In the coffee case, the coffee is not harmful, but rather is correlated with the thing that is really harmful. But it does not work that way with cholesterol--the correlation with heart disease is unrestricted.

 

[SW VandeCarr]

They actually were adequately controlled. All of these insights you are treating us to are well-understood by the real epidemiologists who work at the American Heart Association, the Surgeon General's Office and at the National Institutes of Health. You are saying things that are obvious, and irrelevant in context.

Why did you cut off the quote? The next sentence refers to observational studies where you hope you've controlled for the major confounding factors in the analysis. These comprise the majority of the studies on specific risk factors for elevated cholesterol. I also go on the say that in the aggregate I believe the overall results. Unfortunately, you can't randomize patients to study the effect of diet, and life style differences

 

[ApplePion]

. Unfortunately, you can't randomize patients to study the effect of diet, and life style differences

There are lots of things you cannot randomize. You cannot randomly construct group of people and have them use dirty hypodermic needles, and randomly another group of people and have them not use needles. But even though no randomized trials have been done it still clear that the correlation between getting AIDS and using dirty needles is causal.

Users of illegally injected hypodermic drugs differ from the general population in many ways--higher smoking rates, worse diet, etc., but despite such confounding variables, we still really know that dirty needles is causally related to contracting AIDS.

 

[SW VandeCarr]

You are the one who is big on authorities..

Well, not necessarily. Here in PF we need to post links to authoritative sources. I don't mind this at all as long as it's something that really needs support and has not already been cited in the same thread. But I can look at a paper critically and evaluate it.

I think the central issue in this thread is the recent evidence that cholesterol is not the whole story in CVD (CRP, inflammation, thrombus explanation). This is in the first few paragraphs of the 2002 "cholesterol skeptic" paper that I posted and to which you seem to object to so much. I don't accept their full thesis, but they seem to have gotten that one right. They also claim that the method of measuring arterial wall media-intima thickness is inaccurate. I don't have an opinion on that.

 

[SW VandeCarr]

There are lots of things you cannot randomize.

Of course. You do the best you can, but you may not get the most convincing results.

 

[SW VandeCarr]

It often does, but not always. What I do believe is that everytime I have seen someone object that causation does not imply correlation, that person was arguing against something where the correlation was clealy causal. (Ironically, that is an interesting correlation.)

We know that the relationship between LDL cholesterol and heart disease is causal because it occurs through all subgroups of people with elevated LDL, and because almost any way of lowering itlowers risk. This is unlike the correlation between coffee and lung cancer--the elevation is found only in one subgroup--smokers--and so we know it is not really coffee that is the cause. In the coffee case, the coffee is not harmful, but rather is correlated with the thing that is really harmful. But it does not work that way with cholesterol--the correlation with heart disease is unrestricted.

You can use the word any way you wish, but don't try publish in a medical journal that you've proved your causal hypothesis by means of a correlation. In the case of LDL-C, it is found in plaques, but there's still a lot of research regarding the stability of plaques. Stable plaques can remain asymptomatic for a long time. When they become unstable, there is a high risk of intimal rupture and inflammation leading to a clot. It's not known what causes this destabilization so you can't say cholesterol is involved at this stage for certain.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659534/

 

[Evo]

This is in the first few paragraphs of the 2002 "cholesterol skeptic" paper that I posted and to which you seem to object to so much. I don't accept their full thesis, but they seem to have gotten that one right. They also claim that the method of measuring arterial wall media-intima thickness is inaccurate. I don't have an opinion on that.

Please quote what you are referring to so that we don't have to guess.

Thanks.

 

[SW VandeCarr]

Please quote what you are referring to so that we don't have to guess.

Thanks.

This is the third paper listed at the bottom of post 15. I mistook this one for the 2002 paper by the "cholesterol skeptic", published in the Oxford Journals. This is a 2003 paper which expresses similar points of view regarding the role of cholesterol but uses different arguments and may not be associated with the "cholesterol skeptics".

http://jcem.endojournals.org/content/88/6/2445.full Here's the quote:

"Atherosclerosis is a complex multifactorial disease. Lipids play an important, but not an exclusive, role in its development and progression. In some persons, lipids will be a major factor, and in some, lipids as we currently understand them will play a minor role. Outstanding advances have been made in understanding the biology of the vessel wall and of atherosclerosis, but there is still a long way to go. Our concepts of atherosclerosis and coronary heart disease (CHD) have dramatically changed, and we now know that coronary atherosclerosis is a diffuse multifocal inflammatory vasculopathy (1, 2, 3, 4). Rupture of nonocclusive lesions (<50% of the lumen) are often the most dangerous, abruptly causing sudden death or the acute coronary syndrome (ACS; Ref. 5). The important fact about these nonocclusive or culprit lesions is that there are many of them in the coronary circulation that are as dangerous as the one that causes the ACS. In fact, it is these lesions, and not necessarily the one causing the ACS, that are responsible for recurrent CHD events after myocardial infarction or the development of unstable angina (4). It is for this reason that antiatherosclerotic therapy (including lipid-lowering therapy) should be aggressive in patients with CHD or at high CHD risk. The most dangerous lesions are nonocclusive, asymptomatic, and not necessarily detected by stress testing, with or without imaging, or by coronary arteriography because the lesions may be accompanied by compensatory dilation with little or no encroachment on the lumen (6)."

 

[ApplePion]

I think the central issue in this thread is the recent evidence that cholesterol is not the whole story in CVD (CRP, inflammation, thrombus explanation)

I never claimed that cholesterol is the whole story--smoking, high blood pressure and diabetes are other factors. Indeed, smoking is a much more important factor for heart disease. Nor is the evidence "recent" that cholesterol is not the whole thing. What I claimed was that people with increased cholesterol are at increased risk for heart disease.

Again, consider my driving analogy. Drunk driving is not the whole thing for traffic deaths--there are traffic fatalities that do not involve alcohol. But a drunk driver is nevertheless at increased risk of dying in a traffic accident. And I also point out that there are no randomized studies on this--researchers cannot randomly select people to be told to either drive home drunk or to not drive home drunk.

It is for this reason that antiatherosclerotic therapy (including lipid-lowering therapy) should be aggressive in patients with CHD or at high CHD risk. The most dangerous lesions are nonocclusive, asymptomatic, and not necessarily detected by stress testing, with or without imaging, or by coronary arteriography because the lesions may be accompanied by compensatory dilation with little or no encroachment on the lumen (6)."

Doesn't this contradict your original claim that seemingly healthy people with high cholesterol should not be given medication to lower cholesterol?