20. Oct. 2003
Duane Graveline 
Does anyone have references on studies evaluating the effectiveness of low dose statins on cardiovascular disease risk? We all  know the usual endpoint for judging statin effectiveness is serum  cholesterol or LDL reduction but these do not interest me. My medical intuition tells that if, as many of us think, statins work by some anti-inflammatory role involving platelet inhibition or enhanced thrombolysis this effect might be present at relatively low dosages comparable to what we see with aspirin. As you know the effective dose of aspirin is the so-called "baby aspirin" of 82 mg. Increasing this dose has little or no added benefit. The "super-aspirin" role currently ascribed to statins suggest the possibility  that statins may work at doses now considered as sub-therapeutic since the prevailing focus of most researchers is the cholesterol reduction.
 
There must be studies somewhere involving comparisons of low dose with higher dose statin therapy over a sufficiently long period of time wherein the low dose group--presumably with largely unchanged serum cholesterol levels--might still have shown reduced specific cardiovascular risk, had the experiment been suitably designed.  In most of the studies I know about, the researchers have been so focused on cholesterol and lipoproteins that they could well miss this type of observation.
 
In my mind a priority exists to evaluate this possibility for the benefits might be substantial especially in the reduction of side effects of all types ie cognitive, liver damage, myopathy, neuropathy,cardiomyopathy and even of cancer provocation.
 
Many THINCS members feel that statins have no justification and I must admit there is little research documentation for statin effectiveness on cardiovascular risk reduction. But some studies such as that of Collins do show specific risk reductions in MI's or strokes, which seem to be real and not completely offset by all cause mortality data.

Although I have prescribed more than my share of statins during my last decade of family practice, no longer would use statins for cholesterol or LDL reduction. 

Yet if one of you came to me out of concern for your high MI risk status because your brothers and fathers had departed prematurely I would recommend Kilmer's B vitamins in high dose, Peter's Coenzyme Q10, a supplement of omega 3 along with Joel's magnesium and aspirin in the form of Bufferin BUT I would still add a small dose of a hydrophilic statin, such as Pravachol.
 
I would be most appreciative of any information relevant to the possible effectiveness of low dose statins on cardiovascular risk.

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Malcolm Kendrick
Dear Duane, Your question, in it's current format cannot be answered, because no-one has ever done the trials. It has been assumed, extrapolating backwards from WOSCOPS, that a 1% lowering of LDL results in a 2% reduction in CHD risk. This was based on a 20% LDL reduction and a 40% reduction in relative risk.
 
However, a number of the trials e.g. CARE, demonstrated that there was no connection between the absolute LDL lowering and reduced CHD events. In fact, the correlation was inverse.
 
The HPS study itself did not show any correlation between LDL lowering and reduction in risk. But these studies did not look at statin dose per se.
 
So I share your belief that a small dose of statin may be as effective as a high dose of statin in reducing CHD risk, if statins work in the same sort of way as aspirin. But the pharmaceutical companies manufacturing statins have made billions of dollars on the concept that the more LDL lowering the better. They are never, ever, going to fund a low dose trial - just think what they might find. And no-one else has the money to fund such a trial.
 
Even if they did, I am certain that such a trial would be considered unethical by any ethics committee as the committee members will be convinced that it is absolutely true that the lower the LDL level the better, and so a trial where LDL levels are not lowered to their 'optimal' level in the  control arm would not be allowed.
 
In the area of LDL lowering vs. CHD events, it is already considered an absolute truth that the null hypothesis has been disproven. So I don't know how the hell you could set up a trial to show that a low dose of a statin was just as good as a high dose. Maybe you can think of a way.

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Anders Hernborg
Three large randomized intervention studies are underway adressing the question if "the more the better" is a valid hypothesis.

IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering IDEAL) is planned to investigate the difference in outcome in CHD patients comparing atorvastatin 80 mg to simvastatin 20-40 mg (this control group is treated as the intervention group in the 4S study, giving a higher dose of simvastatin to those not reaching the target level of LDL of 5,0 mmol/L). The study is multicenter, randomized, open label (PROBE-design: Prospective, Randomized Open-label Blinded Endpoint). Primary endpoint is non-lethal AMI and coronary death. 8 888 patients were randomized and the study will end 2004-2005. The study is company-financed and is run in the Nordic countries and the Netherlands. 

TNT The Study Treat New Targets (TNT), which is mainly a US study compares the clinical outcome of atorvastatin 80 mg vs. 10 mg in 10 000 patients with CHD. It is also planned to end 2004-2005. Sponsored by Pfizer. 

SEARCH  This study compares simvastatin 80 mg vs. 20 mg in 12 000 individuals with CHD. Performed by the "Oxford-group" (Clinical trial Servic Unit, Radcliffe Hospital, Oxford) and is company sponsored. "The SEARCH (Study of the Effectiveness of Additional Reductions of Cholesterol and Homocystein) randomised trial aims to demonstrate reliably whether a larger reduction in cholesterol, with a regimen of 80 mg daily simvastatin, produces worthwhile further reductions in CHD compared with a standard 20 mg daily regimen. In addition, using a factorial design, the effects of lowering homocysteine with folic acid will be assessed. Reductions in CHD of 15-20% are plausible, and to be able to detect such effects about 12,000 MI survivors from 90 UK hospitals are to be studied for 5 years (results in 2004/5)." http://www.ctsu.ox.ac.uk/projects/search.shtml

So in 1-2 yrs we will know at least a little more

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Morley Sutter
May I draw your attention to the latest newsletter of the Therapeutics Initiative from UBC that is posted at: http://www.ti.ubc.ca/pages/letter49.htm

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Paul Rosch
There is little doubt that statins may be effective medications, but as I have long maintained, this is not due to any lipid lowering effects and is more likely related to anti-inflammatory activities.  Using CRP levels as a criterion, the effective dosage for achieving such benefits may be much lower than for lowering lipids (see attached).  As indicated in an article in the October issue of Clinical Cardiology sent to Uffe, the effect of simvastatin (20 or 40 mg) on lowering total cholesterol and LDL was clearly dose related after 2 weeks but no such relationship was seen with respect to CRP, which tends to support this view.

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Alena Langsjoen
Dear Duane, Malcolm, Anders and others, I have been meaning to scan and send to all of you a German paper that I recently ran across and Duane's email prompted me to do it today.  It is attached as a pdf file.  The title of the paper is "Statins differ in their ability to block NF-kB activation in human blood monocytes", by Hilgendorff A. et al., International J. of Clinical Pharmacology and Therapeutics, V. 41 - No. 9/2003, 397-401.

What caught my eye was the following:

1. All six tested statins inhibited [the inflammatory response] in a dose-dependent manner
2. The inhibitory effect was due to reduced phosphorylation...and was primarily dependent on the absence of mevalonate
3. There were marked differences in the degree of this inhibition between statins, cerivastatin (Baycol) being the strongest inhibitor

Point 2 is the one of most interest.  Up until we read this, Peter and I thought that the anti-inflammatory effect of statins would hopefully be independent of the degree of HMG-CoA reductase inhibition.  If that was the case, the antiinflammatory effect of statins might be there even at a very low dose.  But if these authors are correct in that this inhibitory effect also follows the degree of inhibition of the cholesterol biosynthetic pathway then tiny doses of statins may not have enough anti-inflammatory effect.

I will end this by paraphrasing what Peter has said somewhere before.  The only legitimate use that statins can possibly have is to treat cholesterol neurotics, created by the whole anti-cholesterol propaganda.

Peter and I would love to hear any of your thoughts on this.

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Anders Hernborg
I do not know anything special about the relation between cholesterol, other steroids and the inflammatory cascade, but I heard a lecture by a person favouring physical exercise and diet to reduce CV risk. He thought that reduction of inflammatory markers like CRP were mainly a secondary effect of lowering LDL. He showed some data on purely diet interventions with considerabel lowering of LDL which was accompanied by lowering of CRP. He thought that the anti-inflammatory effect of statins were not a direct effect but secondary to the LDL-lowering.
Any comments?

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Peter Langsjoen
That's a very interesting thought and he may well be right.  But the description by Fred and Alice Ottoboni (see below) of statins as a "blunt instrument" could not be more accurate.  Who knows, I can't think of too many other drugs that throw such a large monkey wrench into the biochemistry of life.  In a moment of weakness, I gave brief consideration to the thought that statins might have some unique beneficial anti-inflammatory/plaque-stabilizing effect, sort of like a silver lining on a large black cloud.  That moment has since past and I am now back to my solid black view of statins.

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Fred and Alice Ottoboni
The statins appear to act as very blunt instruments and probably impact many biochemical reactions.  Some of these reactions are known and many more are probably yet to be discovered.  Based on all cause mortality studies, the harmful effects appear to offset any beneficial effects, particularly when Q-10 is not a part of the treatment regime. 

The protective effects of low dose statins are described as being similar to those of low-dose aspirin.  The biochemistry that we are aware of is as follows:

The promotion of hypertension, inflammation, and thrombosis as seen in CVD is caused by a group of eicosanoids derived via the Cox-2 metabolic pathway from arachidonic acid.  Arachidonic acid is a 20-carbon omega-6 essential fatty acid.  This pathway after passing through the Cox-2 enzyme, splits into 3 forks.  One of these forks leads to the thromboxanes which are pro-hypertensive, pro-blood clotting, pro-inflammatory, and damaging to the cardiovascular system.  This pathway is inhibited by garlic, onions, alcohol, vitamin E, bromelain, curcumin, eicosapentaenoic acid (EPA), low dose aspirin, and statin drugs. 

The pathway branching from the second fork leads to the PGE-2 series prostaglandins which are pro-bone resorption (osteoporosis), pro-cancer, and pro-inflammatory.  This pathway is inhibited by vitamins E and C, bromelain, and zinc.  Neither aspirin nor statins have been reported to inhibit this pathway. 

The pathway branching from the third fork leads to a group of prostacyclins, all of which are positive, namely anti-inflammatory, anti-hypertensive, anti-clotting, anti-cancer, and cardiovascular protective.  This pathway is stimulated by selenium, zinc, vitamins E and C, and curcumin.  Neither aspirin nor statins are reported to stimulate this pathway. 

Looking at how these pathways are regulated, it is clear, certain vitamins, minerals, and foods act to inhibit harmful end products and stimulate beneficial end products.  It is not wise to use a blunt instrument like the statins on these delicately balanced systems.  Much better to use the vitamins, minerals and foods that are known to act positively with no side effects.

It is also worth considering that the Cox-2 enzyme that is feeding the three branches mentioned above is inhibited by aspirin and ginger, but not by statins.

Additionally, the production of arachidonic acid feeding the cox-2 enzyme is reduced by insulin control, and/or 4-to-1 or lower dietary omega-6 to omega-3 essential fatty acid
ratios.  Controlling this arachidonic acid feed is also associated with control of CVD, pain, inflammation, and many other chronic disease problems.

In short, the statins, and even aspirin, are simply not in the same league as a well-selected and supplemented diet. 

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Malcolm Kendrick
I think that there is a great deal of evidence to support the idea that statins do have anti-inflammatory/plaque stablizing effects. They also have anti-coagulant effects. And these facts have been, basically, proven. After all statins have to reduce the rate of CHD somehow. Unless you believe that every single clinical trial showing a benefit on the rate of CHD with statins was a fake. And I don't.

Whether or not they have any effect on overall mortality is a different question. In primary prevention trials, any benefit on CHD reduction is wiped out by an increase in other causes of death. To quote from the University of Columbia therapeutics newsletter.

'Therefore, statins have not been shown to provide an overall health benefit in primary prevention trials.'

However, in secondary prevention trials, statins seem to have a greater anti-CHD effect. So they may actually save lives.

This does not mean I am particularly pro-statin, and I accept that these drugs have some pretty unpleasant side-effects - including death. But just because I don't believe that lowering LDL provides any benefit, does not mean that I automatically attack statins. 

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Morley Sutter
Dear All, As usual, Malcolm has summed up the situation in a succinct, rational and eloquent way.  There is a genuine scientific and medical controversy regarding the role of cholesterol in producing and in the role of statins in treating coronary artery disease and atherosclerosis.  There are several distorting issues including enthusiasts for pet aspects of causality as well as commercial considerations of big Pharma and also pedlars of various remedies.  Should we not admit our ignorance of causality and best treatment of atherosclerosis/coronary artery disease and move toward solving both these puzzles?
I am getting off my soap-box now.

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Anders Hernborg
I am not reading all on this list, when I do I am a lot sceptic even to what many sceptics write. I am just now working with "academic detailing" as a GP working like an educational physician going around to the surgeries discussing the new official Swedish guidelines with my collegues in small groups. What we try to stress is:

Do not use Crestor until proven to reduce  CV events, not just LDL –

Use cheap simvastatin, today generic simvastatin  costs just equivalent of 0,30 $ (2,20 Swedish kronor) per tablet of 40 mg, if statins are indicated. The indication is high CV risk, mainly as    secondary prevention   

In primary prevention do use statins rarely  especially among women and in the elderly.

Indicated in high risk type 2 diabetes patients and in familial hypercholesterolemia with a  lot of young persons suffering CV events among relatives. (around 1 in 500 persons) Otherwise only if CHD-risk is over 20-30% within 10 yrs (not applicabel to older persons) –

Give a fixed dose simvastatin, 20-40 mg if  statins indicated (4S and HPS doses)

No target LDL values for the therapy. Do not measure lipids on therapy, possibly one or  two times so you know if the patient takes the pills or not (25-50 % don´t!)  

Cancer induced or stimulated by statin I think is still a concern, but not that strong that I do not use statins in high risk patients.

A lot of therapy used today to reduce CV events is less cost effective than statin therapy. In the HPS-study among the 10 000 patients in the simvastatin group around 300 individuals escaped a coronary event (MI or coronary death) and 157 patients escaped a stroke because of the statin therapy. The difference could have been even bigger as in the last year of the study 20 % in the statin group had stopped taken the active drug and in the placebo group a third of the patients took statins outside the protocol (which was permitted)

In patients who fulfilled inclusion criteria in HPS you can expect at least a total mortality reduction of 12 per cent. May I remind you that all vascular events were reduced by 17 % relatively, around 5 % in absolute terms (NNT around 20 for 5 yrs to save one serious event) and ALL OTHER NON-VASCULAR DEATHS were ALSO reduced in the statin group 537 vs 560 in the placebo group (probaly by chance, non statistically significant of course)

So I am not amongst those totally throwing away this therapy because it does not fit with my theory. I am 56 yrs old. If I had a MI myself I would probably take 40 mg of simvastatin for many years to come considering the pros and cons.

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Duane Graveline
Several of you forwarded very helpful comments to my query re low dose  statins. To Paul, Fred and Alice, Malcolm, Anders and Peter and Alena I  am particularly grateful. Anders forward of the IDEAL, TNT and SEARCH  studies were very relevant, especially the TNT study comparing the  clinical outcomes of atorvastatin 80mg vs 10mg in a 10,000 patient  study, sponsored by Pfizer. Fred and Alice's comments on the  anti-inflammatory and anti-thrombotic action of statins via the  arachidonic/cox-2/thromboxane pathway were specially relevant after  Peter and Alena called my attention to Hilgendorff's paper on Nuclear  Factor kappa B in Clin. Pharm and Ther.  This paper, titled "Statins differ in their ability to block  NF-kappaB activation in human blood monocytes" proved quite remarkable.  First it led me to Shovman's review paper, "Anti-inflammatory and  immunomodulatory properties of statins"; then Delhase's "1 kappa B  Kinase and NF-kappaB - key elements of proinflammatory signaling"; next,  to Ritchie's "NF kappaB is selectively and markedly activated in humans  with unstable angina pectoris" and finally back to Hilgendorff's paper.  I strongly recommend these papers to anyone interested in what is  probably the major pathway for statin effectiveness in cardiovascular  disease. All of this seems completely independent of any cholesterol or  LDL effect.

In both inflammatory and coagulative processes the vast majority of cellular events require NF-kappaB transcriptional activity, leading to gene activation for cell adhesion, inflammation, coagulation and cell growth responses. Monocyte NF-kappa B is a persistent finding in  atherosclerotic plaque and is particularly evident in patients with unstable angina. Hilgendorff reported wide variation from statin to statin in their ability of to inhibit this activity. Although all  statins inhibit NF-kappaB activation, Baycol seemed to have been in a class by itself with 100 fold greater effectiveness on NF-kappaB  inhibition than the others. 

What caught my attention, however, was his graph comparing Mevacor,  Pravachol, Lipitor and Zocor. All had comparable 15%- 25% reduction in  NF-kappaB activation at statin concentration of 10 to the -7 moles/L but  for Mevacor, Zocor and Pravachol this effect was unchanged or less with  a hundred fold increase in concentration (10 to the -5 rather than 10 to  the -7). But with Lipitor the effect was dosage dependent  and 20% at 10  to the -7, became 40% at 10 to the -5.

All of these reactions were abolished by the addition of mevalonate to the solution reflecting the role of diminished mevalonate in the reaction. Fred and Alice, you know better than I how this fits with  arachidonic/Cox-2/thromboxane biochemistry but it seems likely the NF-kappaB transcription event is what makes the chemistry happen.

The bottom line is that whatever effectiveness statins have on cardiovascular disease is likely mediated by this pathway and the results of this study hint that low doses of statins may offer some protection.     

I am not an advocate of statins for cholesterol control but this proven anti-infammatory action is intriguing for atherosclerosis is an inflammatory process.

I have summarized all too briefly these several papers. They make  fascinating reading:
 
1.Shovman O. Anti-inflammatory and immunomodulatory properties of  statins.
www.rheuma21st.com/archives/cutting_report_shoenfeld_antiinfl_statins.html
2.Ritchie M. Nucler Factor- kappa B is selectiely and markedly actvated  in humans with unstable angina pectoris. Circulation, 98, 1707=1713, 1998.
3.Delhase K. The 1 kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signaling. Semin immunol, 12(1), 85-98, 2000.
4.Hilgendorff a. Statins differ in their abiity to block NF-kappaB activation in human blood monocytes. J of Clin Pharm and Thera, 41(9)  397-491, 2003

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Fred and Alice Ottoboni
Duane:  Regarding your question:  "Fred and Alice, you lnow better than I how this  fits with  arachidonic/Cox-2/thromboxane biochemistry but it seems likely the  NF-kappaB transcription event is what makes the chemistry happen."
 
Our view is that the arachidonic/Cox-2/thromboxane biochemistry comes first  and enables the the NF-KappaB and other inflammatory processes.
 
The biochemistry starts with the two essential fatty acids and their eicosanoid end products, some of which are inflammatory.  These inflammatory  eicosanoids are all derived from arachidonic acid (an omega-6 fatty acid)  via the cox-2 enzyme and the lipoxygenase enzyme (working in parallel, not  in series).
 
 A surplus of arachidonic acid leads to these inflammatory eicosanoids which  are formed when the dietary ratio of omega-6 to omega-3 is too high and/or  when insulin levels are high as in the case of high sugar/starch diets.
 
Inhibition of the metabolic pathways to the eicosanoids may occur at the cox-2 and/or the lipoxygenase enzymes.  For example, NSAIDS inhibit cox-2.  Ginger inhibits both cox-2 and lipoxygenase.  Inhibition may also occur in the pathways below these two enzymes.  For example the pathway from cox-2 to the thromboxanes is inhibited by garlic, onions, alcohol, bromelain,  curcumin, and eicosapentaenoic acid (from fish oil).  Statin drugs and aspirin also inhibit this pathway.
 
Studies indicate that diet, namely balanced essential fatty acids and  insulin control will prevent common inflammatory processes in which NF-KappaB plays an important role.
 
Thank you for your very insightful email.  You have looked at some areas  that we were not aware of.

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Uffe Ravnskov
Little has been said about what concerns me most, the risk of cancer. I think that we all agree that treatment of healthy people with high cholesterol is out of the question. Also, the results from PROSPER, where the number who died from cancer outweighed the number who should have died from a cardiovascular disease, argues against treating old people. But where is the age limit? You may argue that the risk of cancer in young people may be very small. But young people, in particular children, are supposed to be treated for a longer time than old people and thus exposed to possible carcinogenic factors for longer periods also. As mentioned before, you will not get lung cancer after having smoked for 5-6 years. Chemical carcinogenesis in human beings demands decades.

Another question is whether we can rely on the trial directors’ reporting of side effects? The reason for that question is that only three of the trials reported the number of skin cancer. This type of cancer is very common in people above age 60. In HPS  a total of 445 cases were seen, 243 in the simvastatin group and 202 in the control group. In 4S 19 cases were seen, 13 in the simvastatin group, 6 in the control group, in AFCAPS 493 cases, 250 in the pravastatin group, 243 in the control group. None of the other trials reported any, see this table: 

Obviously, many cases of skin cancer must have occurred in the five trials that did not present any such figures. Either the trial directors haven´t recorded these cancers, which I consider highly unlikely, or there were more skin cancers in the treatment groups. A non-melanoma skin cancer is relatively innocent because,  being detected at an early stage it can be treated effectively. Therefore, the authors may have considered an increase unimportant (which it isn´t, of course, being the first indication that the treatment is carcinogenic). That there were fewer skin cancers in the statin groups is unlikely because if so the authors would with all certainty have given these figures as an argument that statin treatment prevents cancer. 

By the way, is there any biochemical explanation to the finding that simvastatin seems to promote skin cancer, but not pravastatin?

A comment to Anders´ letters. The guidelines Anders has sent are mainly identical with the ones that have been presented recently to Swedish doctors. Even if I still disagree with some of them, it is most satisfactory to note that they are much more cautious than the American ones. For the first time the Swedish experts have deviated from the American guidelines; previously they have just translated them uncritically to Swedish.

Anders, wasn´t you a member of the expert panel? Have you anything interesting to tell about the negociations? According to the Swedish medical press there were major disagreements among the participants.

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Anders Hernborg
Yes, it’s correct that I participated in the national workshop (Sweden + Norway actually) in late 2002 leading up to the official recommandations published in June 2003. I participated more as a representative of GPs than as an "expert".  

The two sides in the discussions could a little simplified be grouped into one side seeing
LDL-cholesterol lowering as the only mecanism by which statins work and in favor of therapeutic target values for blood cholesterol levels (LDL and total-chol). The other group with less bindings to earlier theories were more prone to see the positive effects of statins in high CV-risk group as something coming from a fixed dose of statin (like 40 mg simvastatin in HPS). The low and high responders (in lowering LDL) in the prerandomisation phase of HPS had the same relative risk reduction. We (I belonged to that group) did not see any strong evidence for the lower the better.

I think the different ways of looking upon the dosing strategy is well described in the latest Therapeutic Letter from Univ of Br Columbia, Canada: “Fixed dose” strategy, “LDL target” strategy or “Average cholesterol reduction” strategy, see http://www.ti.ubc.ca/pages/letter49.htm . They come out with good Letters every 3 months and have written about lipid lowering before in a balanced way I think: Statins in primary prevention: http://www.ti.ubc.ca/pages/letter48.htm  and in 2001: http://www.ti.ubc.ca/pages/letter42.htm   

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Eddie Vos
Statins lower squalene [anti cancer], CoQ10 [anti cancer] and may promote angiogenesis [pro cancer if one has "dormant or incipient" cancers just waiting for blood supply to grow]. The former theory was the theory Kilmer and I proposed in response to PROSPER and that we put on BMJ here: http://bmj.bmjjournals.com/cgi/eletters/321/7267/983#29001  The latter was the theory proposed by T Stefanec in Lancet letters V361: 427 (Feb. 1, 2003).

Stefanec proposed that in elderly with such incipient cancers, statin might wake them up and make them grow. Younger people would not have so much cancer nodules in their bodies [AND produce more CoQ10 and probably squalene] so that statins may not be as cancer promoting in the younger.

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Herbert Nehrlich
As far as I am concerned I would not consent to the use of statins regardless of the mechanism of action.   What little evidence there is of statins being able to 'save lives'  cannot be called impressive.  Statins are, as Alice and Fred Ottoboni so succinctly put it,  "blunt instruments"   and I agree that they are out of place in the delicate machinery of the human biochemistry.   The 'war on cancer' that Richard Nixon announced in 1973 is not being won, we add new cancer-causing chemical concoctions to the food chain and the environment every day, so do we really need to introduce another potent medicine which is apparently capable of humonguous deeds?  I agree with you that the  potential to act as carcinogens should seal the fate for statin therapy.   Statins work by creating damage to the liver if you look at it in a practical way. If there is or ever will be a role for the statins in the treatment of human beings I would suggest to apply the same amount of extreme caution that SHOULD be used in the introduction of genetically modified foods.   Do the homework first, prove your point and remember the   "Above all - do no harm"   and perhaps a disease will be found that can be treated with statins. 

Read also letter to The Lancet by Uffe Ravnskov (rejected by the editor)

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