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.
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
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.
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
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.
Three large randomized intervention studies are underway adressing
the question if "the more the better" is a valid hypothesis.
(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
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.
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
in 1-2 yrs we will know at least a little more
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
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.
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:
All six tested statins inhibited [the inflammatory response] in a
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
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
Peter and I would love to hear any of your thoughts on this.
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.
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.
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.
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.
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.
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.
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.
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.
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.
short, the statins, and even aspirin, are simply not in the same
league as a well-selected and supplemented diet.
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.
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
I am getting off my soap-box now.
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 –
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
primary prevention do use statins rarely especially among women
and in the elderly.
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) –
a fixed dose simvastatin, 20-40 mg if
statins indicated (4S and HPS doses)
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!)
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.
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
activation in human blood monocytes" proved quite remarkable.
First it led me to Shovman's review paper, "Anti-inflammatory
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.
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
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.
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
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
am not an advocate of statins for cholesterol control but this
proven anti-infammatory action is intriguing for
atherosclerosis is an inflammatory
have summarized all too briefly these several papers. They make
1.Shovman O. Anti-inflammatory and immunomodulatory properties of
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
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)
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
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
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.
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.
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:
Non-melanoma skin cancer;
Non-melanoma skin cancer;
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.
the way, is there any biochemical explanation to the finding that
simvastatin seems to promote skin cancer, but not pravastatin?
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.
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
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".
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
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
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
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.
also letter to The Lancet by Uffe Ravnskov (rejected by the editor)