On Statins / Jupiter Study

On Statins / Jupiter Study

After all the Vitamin D3 / Covid-19 discussion (When the second wave cometh) — why am I into statin "research" now? And write about a 12 year old study?

Because there we there find an equal pattern like in our D-research and I will show that the most valued RCT intervention study ("Jupiter" study on Rosuvastatin) quite obviously was misinterpreted - by the critiques as well as the "statin community" (i.e. most cardiologists, the pharma industry etc.). B/c even in 2020 the grand narrative on cardiovascular diseases still lingers on, that says that statins will protect you and you should take them even if you had no heartattack yet, if you have a cholestrol-level above 200 mg/L or LDL above 130 mg/L. And JUPITER was one of the most important studies to hammer home this message and it still stands.

If you are not familiar with this common cholesterol / CVD (cardiovascular disease) narrative, try this first:  http://www.ravnskov.nu/cholesterol/

Do not mind a seemingly angry tone, popping up here and there, Uffe Ravnskov has got the facts right, and as he fights against cholesterol misinformation for so many years now, of course he is a bit angry - as many of the mostly rational D-apologists are as well and for the very same reason.

For a first intro into the Jupiter study, you might read this critique (originally in German):

Rosuvastatin, a typical “me-too preparation” for lowering cholesterol, is approved in Austria - in contrast to Germany - and is heavily advertised (Crestor®, AstraZeneca). The JUPITER study recently published in the New England Journal of Medicine (NEJM) comes in very handy for the manufacturer and sponsor (1). A study population of 17802 subjects with normal cholesterol values (initial LDL cholesterol <130 mg / dl or <3.4 mmol / l) and increased hs (high-sensitivity) -CRP (> 2 mg / l ) it was shown that taking rosuvastatin 20 mg / d reduces the relative risk by 44% with respect to the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, arterial revascularization or hospital treatment for unstable angina pectoris). But what does this study really say when you take a closer look at the methodology and figures? ....
So should we really determine the hs-CRP in all patients and treat elevated values with rosuvastatin as in the JUPITER study? Hardly: Epidemiological studies have shown a connection between increased hs-CRP and mortality from coronary diseases, but the classic risk factors already explain more than 90% of cardiovascular morbidity, so that the gain in information is insignificant compared to the exclusive determination of the classic risk factors (2).

There ist two interesting tables in the study (this one taken from the "critique"):

Any statician can tell you that if heart attacks ("Myokardinfarkt") as well as strokes ("Schlaganfall") both occur almost twice as often in the placebo group or - the other way round - are halved in the verum group, the chance, that this doesn't has to do with the intervention is miniscule. Together with unspecified death from CVD ("kardiovask. Tod") it sums up to the 0.45% deaths p.a. in the verum group versus 0.85% in the placebo group and thus is absolutely significant - pro verum. If you don't like that interpretation, please wait and read on.

Of course lethality as a whole cannot be statistically significant when the real difference, like shown above, is much smaller than in the "death by CVD" subgroup. There might be adversal effects of the verum, which count for this "unexplained" difference. Like this: 40 participants of the verum group, but 75 in the placebo group died due to CVD, both out of 8.901 in each group. Other causes of death then caused 48 in the verum, but "only" 36 in the placebo group. Thus lethality of non-CVD deaths was higher in the verum group, not only relatively, but absolutly. You now may say that with Placebo the higher number of CVD deaths minimized deaths for other reasons, sort of covered them. Well, we will never know for sure.

Now, having said this, I don't want to be misunterstood: I said: it is significant and obvious that the intervention with the verum in this specially recruited group of patients caused lower lethality overall as well as due to CVD. It also caused a reduced occurence of non fatal CVD events. But I didn't say that this supports the theory that lowering the LDL cholesterol level - which is the well known main effect of statins - is responsible for it.

What else could it be? Statins do have a side effect, as we know - they are antioxidants and do have an anti-inflammatory effect. Also we know, that building up cholesterin plaque follows a silent and/or chronic inflammation of the walls of blood vessels. These "wounds" then are plastered, are "band aided" with cholesterol and it is oxidised cholesterol (very bad ;-) building up there - that's the plaque which will block up the blood vessels more and more, leading to heart attacks and strokes.

Now the real interesting part of the JUPITER Study is that the participants were healthy wrt their LDL cholesterol levels:

We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter

We'll keep that in mind, ok?

Also, the authors of the critique state, that the maker of Rosuvastatin does also have a patent on hs-CRP measurement:

Finally, it should be mentioned that the JUPITER study [...] was funded by AstraZeneca. AstraZenaca not only produces rosuvastatin, but also holds the patent license for the determination of hs-CRP.

Why did they mention that? B/c the JUPITER authors wrote:

We randomly assigned .... and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to ....

In fact no one needs hs-CRP for values above 0.5 mg/L - which the authors of the critique should know. But on the other hand mentioning AstraZenecas patended hs-CRP in the study then is superficial, normal CRP lab measure would have been sufficient. In fact, there is a note  at the end of the study we today would call a solid "conflict of interest":

Dr. Ridker reports receiving grant support from AstraZeneca, Novartis, Merck, Abbott, Roche, and Sanofi-Aventis; consulting fees or lecture fees or both from AstraZeneca, Novartis, Merck, Merck–Schering-Plough, Sanofi-Aventis, Isis, Dade Behring, and Vascular Biogenics; and is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease, including the use of high-sensitivity C-reactive protein in the evaluation of patients' risk of cardiovascular disease.

As a side note: compare this real conflict of interest to the "Letter of concern" PlosOne published wrt MF Holicks latest study on Vitamin D:

However, publicly available information indicates that corresponding author MFH may have potential competing interests that include non-financial interests based on his vitamin D research and other activities focused on vitamin D; contributions to an app that tracks vitamin D; and interests that include consultancies, funding support, and authorship of books related to vitamin D usage.

Back to statins and explaining CRP: c-reactive protein is a biomarker for ongoing infections / inflammations in the body. The family doctor will call any value below 5 mg/L being "normal", 5-15 then a chronic inflammation and above that an acute infection. In case of Covid-19 CRP values of 20-80 are seen often according to the RKI, but it can reach values way beyond:

In severe cases, values up to> 200 mg / l are observed [15]. In particular the CRP increase in COVID-19 correlates with acute alveolar damage [17]. In a study on inflammation markers and COVID-19, CRP values> 41.8mg / L were predictive for a severe course [18]. A retrospective analysis showed that patients, who contracted COVID-19 and had not survived, had median CRP values of 125.0 mg / L [19].


The JUPITER study states

 We randomly assigned .... and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher ....

As said, you only need hs-CRP if you would like to measure below 0.5 mg/L, but in the Jupiter study the starting point was 4.2 mg/L on the average(!), a value that I myself e.g. have never reached.

Anecdotic: My CRP varied between <0.5 and 0.9 over the past 7 years. Only once my CRP showed 3.6, which I couldn't believe. Next day just by chance I saw my dentist. He told me that I had a purulent gum pocket, a completely "silent" infection, no pain, nothing. Got rid of the one bad tooth, with it the infection vanished and CRP again sank to 0.7 mg/L. Every value below 1.0 mg/L should be quite ok, more than 1.2 mg/L and you might start to look out for a hidden source of infection. hs-CRP seems mostly superficial, as you'll find not many people with values less then 0.5mg/L at all, and certainly not any people being ill then.

So again: the Jupiter-participants seemed to be healthy, but in fact were chronically inflammated with a CRP of 4.2/4.3 mg/L in both groups:

Now looking at the table after 12 and more months:

Two things happened in the intervention group: LDL was lowered to half of the starting level and CRP sank in both groups, but was reduced really significantly in the verum group by 57% (4,2=>1.8 mg/L) vs. the placebo group with only 23% (4.3=>3.3 mg/L). Of course the question, why it also sank in the placebo group is open, but ... well later.

Now Uffe Ravnskov is stating:

One of the most surprising facts about cholesterol is that there is no relationship between the blood cholesterol level and the degree of atherosclerosis in the vessels. If a high cholesterol really did promote atherosclerosis, then people with a high cholesterol should evidently be more atherosclerotic than people with a low. But it isn t so.

The pathologist Dr. Kurt Landé and the biochemist Dr. Warren Sperry at the Department of Forensic Medicine of New York University were the first to study that question. The year was 1936. To their surprise, they found absolutely no correlation between the amount of cholesterol in the blood and the degree of atherosclerosis in the arteries of a large number of individuals who had died violently.

[...]  by Dr. J. C. Paterson from London, Canada and his team. For many years they followed about 800 war veterans. Over the years, Dr. Paterson and his coworkers regularly analyzed blood samples from these veterans. Because they restricted their study to veterans who had died between the ages of sixty and seventy, the scientists were informed about the cholesterol level over a large part of the time when atherosclerosis normally develops.Dr. Paterson and his colleagues did not find any connection either between the degree of atherosclerosis and the blood cholesterol level; those who had had a low cholesterol were just as atherosclerotic when they died as those who had had a high cholesterol. Similar studies have been performed in India, Poland, Guatemala, and in the USA, all with the same result: no correlation between the level of cholesterol in the blood stream and the amount of atherosclerosis in the vessels.

and he links to his paper: High cholesterol may protect against infections and atherosclerosis

It actually reflects the findings of swedish researchers, that elderly people live longer with each additional mg/dl cholesterol.

So it is highly unlikely, that lowering LDL did the trick, i.e. saved people from heartattack and strokes, and although this conclusion:

In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681. opens in new tab.)

is right, and:

Currrent treatment algorithms for the prevention of myocardial infarction, stroke, and death from cardiovascular causes recommend statin therapy for patients

indeed is the case, the reason given is absolutly not logic, when on the other hand, Ravnskov showed that there is no correlation between cholesterol level and  atherosclerosis, whereas a higher level even correlates with a longer life.

And you can hear the authors of JUPITER grind their teeth, when stating:

However, half of all myocardial infarctions and strokes occur among apparently healthy men and women with levels of low-density lipoprotein (LDL) cholesterol that are below currently recommended thresholds for treatment.

Apparently healthy - but with a high CRP? The main function of Rovustatin here can very well be counted on its anti-inflammatory "side effect". That CRP sank in the Placebo group also would then reduce the (positive) statistical outcome.

The primary objective of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was to investigate whether treatment with rosuvastatin, 20 mg daily, as compared with placebo, would decrease the rate of first major cardiovascular events.

Which it did, but all in all rather poorly and with other side effects, which again are stated to be not "statistically significant", like: death of cancer: V: 35 / P: 58, but new Diabetes II: V: 270 / P: 216.

There is no known mechanism, why and how a lower LDL-level should cause less cancer, but it is well known, that many cancers are the result of a chronic infection / inflammation through malevolent agents like the HPV-virus or bovine plasmides (BMMF => colon cancer) etc. Also it is known, that anti-inflammatory therapy like with ASS would lower the incidence of i.e. colon cancer, but the negative side effects by treating the whole populace with ASS would be way over the positive effects wrt avoiding colon cancer.

So if a lower CRP shows, that the therapy lowered the overall inflammation index, that might explain lesser CVDs as well as lesser cancer. The higher rates of Diabetes II on the other hand is a well known fact for statins:

Increases in glucose and glycated hemoglobin levels, the incidence of newly diagnosed diabetes, and worsening glycemic control have been reported in previous trials of pravastatin, simvastatin, and atorvastati

All in all explaining the Rovustatin effect with indirectly lowering the CRP level seems to be free of contradictions, whereas lowering the LDL and thus avoiding the growth of the plaque does contradict many findings that Ravnskov has cited. Mother Nature isn't as stupid as not to regulate one of the most essential substances in our body herself, and to downregulate cholesterol may have many adverse effects in our body chemistry. If you are not familiar with why Cholesterol is absoutly essential, read this page, which was linked before:   http://www.ravnskov.nu/cholesterol/

Last-not-least: As long as there is any cholesterol and also inflammation, there will be plaque - which neatly explains, that the natural level of cholestrol in people does not  correlate to atherosclerosis at all. I prophecy that instead of LDL the CRP level would correlate highly with atherosclerosis.  It has to be the antiinflammatory effect of statins, that caused the positive effects in JUPITER, counteracted by negative effect of lowering cholesterol, as a "tertium non datur". And we might find much better ways to fight chronic inflammation than statins.

This of course came to Ridkers mind also, and 9 years after JUPITER Ridker is cited like this:

Meanwhile, at the cardiology congress in Barcelona in August 2017, the results of the Cantos study caused a stir: "We have shown for the first time that an anti-inflammatory drug reduces the number of heart attacks," notes Paul Ridker, director of the Center for Cardiovascular Disease Prevention in Boston....
Auf dem Kardiologenkongress im August 2017 in Barcelona sorgten unterdessen die Ergebnisse der Cantos-Studie für Aufregung: "Wir haben erstmals gezeigt, dass ein antientzündliches Medikament die Anzahl von Herzinfarkten vermindert", bemerkt Paul Ridker, Direktor des Center for Cardiovascular Disease Prevention in Boston...

Unfortunately, this effect was not positive in the end, as this notion shows:

The protective effect, however, was relatively low and its clinical relevance was called into question by a number of fatal infections or sepsis diseases.
Die Schutzwirkung war allerdings verhältnismäßig gering und ihre klinische Relevanz wurde durch eine Reihe von tödlichen Infektionen oder Sepsis-Erkrankungen infrage gestellt.

What happened?

As anti-inflammatory substance they used Canakinumab. It originally was invented for  people with a geneticly dependent overproduction of Interleukin-1 beta.

IL-1β is secreted as part of an inflammatory response and is involved in important processes such as cell proliferation, cell differentiation and apoptosis. The most important functions include

Induction of fever (already a few nanograms)
Induction of Acute Phase Proteins
Recruitment of neutrophils
Platelet recruitment
It also induces the production of cyclooxygenase 2 (also COX2 or prostaglandin endoperoxide synthase 2, PGES2) in the central nervous system, which contributes to the neuronal mediation of pain, hypersensitivity and the development of hyperalgesia.

Of course one should imagine that people with higher CRP levels, which indicate an eventually chronic infection, do also have a higher level of IL-1 beta, as this is a natural reaction of our body to fight infections (why else should IL-1beta otherwise induce fever ;-)

Down regulating IL-1beta in people which do not overproduce it genetically does not seem to be a rational decision, as you do not fight the "infection", which causes the inflammation, but you only suppress the normal reaction of our body. And it is quite likely that doing so, you worsen things when an acute infection adds to the chronic one, like noted above: "... by a number of fatal infections or sepsis diseases."

We should look at that multifactorial chemistry plant we call our body from the point of death risk first, as survival is the one and only goal of evolution. The highest risk to survival, not only in absolute figures, but even more when measured in life years lost, ever has been and even nowadays still is - hunger. After seven decades of not being underfed, but rather overfed we inhabitants of developped countries may have forgotten, that 50.000 years ago ischaemic heart disease was certainly not the first problem evolution had to solve. And you only have to go back 75 years to post WW2 hungry Germany to find that people were mostly lean and CVD then - compared to today - was of no big significance. So periods of sparse food had been the biggest problem, infections second to that.

Well, I left out one great danger to human life, and that had been animal predators. But there is no natural herb or evolutionary body chemistry trick to solve that problem - mankind reacted to that threat by retreating into regions where food throughout the year was not opulent and became scarce in the dry season, but also predators were rare. By analyzing teeth of Australopithecus africanus prehistoric humans researchers found that those prehistoric humans stayed in that region even throughout the dry season and "did not migrate like wildebeest, zebras and other mammals". (WELT)

It is true that in the rainy season the adults were able to feed themselves a fat pad for the coming months with a very limited supply of food. The offspring, however, put the excess energy into growing and therefore had to do without the winter supply of pork belly to a large extent.

Nevertheless, the pre-human children apparently got through the dry season quite well: the women continued to feed their children with breast milk years after weaning, report Renaud Joannes-Boyau from Southern Cross University in Lismore in the Australian state of New South Wales and his colleagues in the journal "Nature".

writes Roland Knauer in the WELT. The pattern, being shown by Barium "year rings" in the teeth, says, breastfeeding stopped after 9 months just like today, but was taken up for some months each year until the age of 4 or 5 - obiously for the reason given above: dry season - low food:

The researchers also find a comparable periodic pattern in the enamel of orangutans [...]. The precipitation in these forests changes in regular cycles. If there is little rain, the orangutans find much less to eat. It is true that the great ape mothers wean their little ones after a few months, but breastfeed them again in dry periods. These cycles even last up to the ninth year of the offspring,

So here we see, why nature first packs each beer and each candy bar right on our hips: saving energy for hunger times - which of course do not come, but Diabetes II instead.

If saving energy does have the highest priority, any energy consuming process in the body will be checked for efficiency. For example muscles which are not used will decompose within four to six weeks to half their size - anyone suffering from an Achilles tendon tear knows, that when the Orthosis finally comes off, the calf muscle is reduced to a thin sausage compared to the other healthy side. In C-19 patients with week long intubation even the muscles for moving the lungs evidently weaken so much that they have to be trained and rebuilt for months.

What does that mean for our immune system? As being one of the energy consuming systems of the body, which must be upheld even over times where it is not acutely needed, evolution will have sought to find a level to weather most of the threatening storms, i.e. infections, but on the other hand not to consume to much energy, which would diminish the survival packs on the hips.

High level immune systems which can cope with worser virusses and bacteriae than ours, are known e.g. from hyaenas. They can afford it, b/c especially bad times for other animals do serve food in abundance, if the immune system is able to handle day old carvasses full of infetcious material. This is a very special ecological niche, but to settle for it is successful - evolution found many ways to secure survival.

Our own immune system is a mixture of external and internal composites, between them vitamins as well as anti-oxidants and anti-inflammatory substances. It is interesting that we pick up composites externally if possible thus saving energy not having to synthesize them ourselves. But if we do the synthesis ourselves it has to balance the loss of life saving hip fat packages.

There should be studies with the above setup, but comparing a statin with other anti-inflammatory therapies, like daily doses of Vitamin D and C and/or anti-inflammatory substances like glucosinolates etc., showing that it is the anti-inflammatory effect of the statins, which reduces the CVD risks, but does have adversal effects not seen with D+C, glucosinolates etc.

A well known driver of inflammation is a high Body Mass Index, indicating usually also a lot of visceral fat which is known to produce inflammatory substances. In a study upon the question if Vitamin D levels are influencing the CRP levels (Vitamin D deficiency and C-reactive protein) the authors did find a correlation between D3 and CRP, significant, but rather weak: a D-Level of 25 nmol/L and less corresponded with a CRP of 1.64, a 3-times higher level of 75 nmol/L and more with a lower CRP of 1.21 mg/L. We then may look at the BMI in the table: less than 18.5 finds only 0.59 mg/L CRP, whereas a BMI of 30 and more produces 2.57 mg/L. Also interesting: that's even a wider range than the comparison between non-smokers (1.27 mg/L) and heavy smokers witrh 15 or more cigarettes a day and a CRP of 2.56 mg/L. Last-not-least alcohol: Non-drinkers: 1.69 mg/ml, 1-3 times a month: 1.62, 1-2 times a week 1.38, 3 or 4 times/week 1.23, daily or almost daily 1.27 mg/L. Non drinkers worse than moderate users? Well yes, that's what's the result. The best CRP is that of the group consuming alcohol 3-4 times a week, followed by daily intake. That does seem to prove, that moderate alcohol consumption goes along with a lower CRP, and if it's the CRP being responsible for plaque and CVD it might underline the public narrative, that one or two glasses of wine per day may save you from heartattacks.

So keeping a low BMI certainly comes first in avoiding CVD caused by high CRP, not really surprising, as usually it's not the lean people suffering from CVD. But as shown by Rovustatin, there's other subtsances than just alcohol to bring down the CRP by fighting inflammations. Glucosinolates are contained especially in broccoli (as Sulforaphane), horseradish and nasturtium (Kapuzinerkresse), which all are available as nutrition supplements, dito antioxidants like vitamin C, E, Astaxanthin as well as polyphenols, contained in tea, coffee, red wine and some vegetables also will provide inflammation protection. But of course a good and natural level of Vitamin D3 (not 75, but 125 nmol/L or 50 ng/ml, read here) as well as a sufficient intake of Vitamin C (rather 1-3 g/d, not just 100-300 mg) will also help to keep CRP low. Not to forget a better balance of Omega3 vs. Omega 6 fat seems helpful: Our nutrition unfortunately is full of inflammation driving Omega 6 (especially sunflower oil). The latest study (DO HEALTH) on D3 (2.000 IU/d, O3 (1 g/d) and light exercise, all tested against placebo and in all combinations showed that each of the components did reduce new cancers by 20-30%, where all of them combined reduced cancer by 60-75% of the 70+ aged sample.

A healthy lifestyle with a little exercise, low or normal BMI, some additional intake of Omega-3 and some inflammation "fire exinguishers" as named above might save you from plaque, heartattaks and strokes as efficient as statins or even better - without all those adverse effects that are known to come with statins.