How statin drugs really lower cholesterol & kill you one cell at a time
Written by Zoë on October 25, 2013 - 37 Comments
Categories: Conflict, Dieting, Exercise
Introduction
This is a review of a book written by James & Hannah Yoseph entitled How statin drugs really lower cholesterol: and kill you one cell at a time (and many thanks to Eric who posted a comment to say that there is a ‘made easier’ version of this here.)
I won’t reiterate the importance of cholesterol – you can read this on this post. Suffice to say your body makes cholesterol because it is so utterly vital, the body cannot leave it to chance that you would consume it. You would die instantly without cholesterol – it is a fundamental part of every cell in your body.
This book should be read by every person BEFORE they either prescribe or take statins. I would be interested to know if any person could prescribe or take statins AFTER reading it…
There is an interview with the Yosephs here.
The three key contributions of the Yoseph book
There are three key contributions of this book:
1) The explanation of precisely how statins work in the human body (and in animals where they have been used for drug testing).
2) The documentation of medical journal articles proving that the precise mechanism as to how statins work has been known by their proponents throughout.
3) The detailing of the conflict of interest endemic in the pharmaceutical industry and approval processes, which have monumentally failed the human race. The book takes one drug company, Merck, and the American Food & Drug Administration (FDA) and a number of other related bodies (e.g. the National Cholesterol Education Programme NCEP) and a handful of individuals and traces in incredible detail the role that each played in this scandal. And it is a scandal.
Let us look at the three main findings that the Yosephs have given us:
1) How statin drugs really lower cholesterol
Every cell needs sustenance. The cell says “I’m hungry” and makes a protein called “reductase.” Reductase activates something called the mevalonate pathway. Mevalonate is cell food just as glucose is brain food. Mevalonate is utterly vital for the life of every cell in the human body.
The Yoseph’s put it this way: “Mevalonate is the essence of cell renewal. In all cells, mevalonate travels down the mevalonate pathway to make cholesterol and isoprenoids (five-carbon molecules). Both stimulate the cell to grow, replicate its DNA and divide into two cells. This is the ‘cell cycle’. This is life.”
Cell renewal is continuous throughout the body – cells lining the gut are turned over every 10 hours to 5 days; skin cells are recycled every two weeks; liver cells are replaced every 300-500 days and bone cells last a decade.
Without the cholesterol and isoprenoids made by the mevalonate pathway, none of this cell rejuvenation happens. Isoprenoids make our cells replicate and renew. Without mevalonate and without isoprenoids, cells age and die. They cannot be replaced.
CoQ10 is an isoprenoid. CoQ10 is vital for cell energy. Heme-A is an isoprenoid. Heme-A is vital for cell energy and drug metabolism. Isopentenyl adenine is an isoprenoid. Don’t worry about the names in all of this – just remember that Isopentenyl adenine is vital for DNA replication. DNA is the blueprint of every cell. Before a cell divides, it replicates its DNA and the new cell can be formed from the same blueprint. There are other vital isoprenoids – all are stopped from functioning by the disruption of the mevalonate pathway.
In the simplified flow chart above, showing the cholesterol production pathway in the body, we can see why statins are called HMG-CoA Reductase inhibitors – this is the part of the pathway that they disrupt. Statins disable reductase. Without reductase, the mevalonate pathway cannot function properly. Without the mevalonate pathway, cells cannot rejuvenate properly. It follows that the life of every cell in the human body is catastrophically impaired by statins.
How long does it take cells to be affected? That depends on the life cycle of the cell – 300-500 days for liver cells and up to 5 days for the cells lining the gut.
In chapter four of the Yoseph’s book there is one of the most incredible explanations about what statins actually do, which I have not seen elsewhere. The Yosephs describe the fact that statins are not just HMG-CoA reductase inhibitors, they are also reductase stimulators…
Life preserving responses are hard wired at the cell level – our body will do whatever it takes to keep us alive; every cell will do its bit to keep us alive. Because reductase is the ‘food’ for cell reproduction, taking something that impairs this process (statins) triggers the body to try to overcome the damage that is being done. Reductase production increases to try to reopen the mevalonate pathway. It’s a terrific attempt by the body to fight back. However, the Yosephs sadly note: “So far, they have not figured out how to save statin-fed dying cells except by adding back mevalonate.”
The book describes that there are two ways in which every cell of the body can get the cholesterol it so vitally needs: 1) it can make cholesterol and 2) it can take cholesterol from the blood stream.
When someone takes statins, the cells are impaired from making cholesterol so they try to take the cholesterol from the blood stream. The LDL receptors on each cell go into overdrive and try to ‘receive’ more LDL from the blood stream to compensate for the fact that the cell can’t currently make as much itself. This lowers the cholesterol in the blood stream. (Please remember that LDL stands for Low Density Lipoprotein – it is not cholesterol, let alone bad cholesterol. Similarly HDL stands for High Density Lipoprotein – it is not cholesterol, let alone good cholesterol).
That’s how statins lower cholesterol and that’s how statins kill us one cell at a time.
Familial Hypercholesterolemia (FH)
It is time to mention Familial Hypercholesterolemia (FH) here. FH is a genetic condition caused by a gene defect on chromosome 19. The defect makes the body unable to remove LDL from the bloodstream, resulting in consistently high levels of LDL. Bearing in mind that FH is rare to start with – one in 500 people – in some cases of FH the LDL receptors work to an extent (just not very well); in other cases the LDL receptors work barely at all.
My logical consideration of FH suggests to me that the problem is that the LDL receptors don’t work properly and therefore the LDL (lipoproteins) cannot get into the body’s cells in the way that they are supposed to. This means that cells don’t get the vital LDL, carrying the vital protein, lipids and cholesterol needed for the cell’s health. LDL in the blood stream is high because the LDL has stayed in the bloodstream and has not been able to get into the cells – where it is supposed to go. Hence high LDL blood levels are the sign that someone has FH. The high LDL levels are, however, a symptom and not a cause or a problem per se. The problem is that the health of every cell is compromised by LDL not getting to the cell. This includes heart, brain and muscle cells – all cells. An FH sufferer can therefore have heart problems – because of too little LDL reaching the heart cells – not because of too much LDL! How differently things can be seen when one is not blinded by thinking that cholesterol or lipoproteins are bad.
This also explains why high HDL would be seen as good. HDL is the lipoprotein that carries used lipids and cholesterol back to the liver for recycling. If the LDL were not able to get to the cells to do its job then there is little for HDL to carry back to recycle. Hence HDL would be low and this would be seen as bad with impaired understanding as to why.
Ironically, the most serious form of Familial Hypercholesterolemia would receive no benefit from statins anyway. As the extreme form of FH is characterised by LDL receptors working barely at all, even the body going into crisis mode, and trying to take LDL from the blood stream with increased LDL receptor activity, will not work if the LDL receptors are not working well enough in the first place. Hence the LDL will stay in the blood stream with an extreme sufferer of FH and yet the statin has reduced what little chance the FH sufferer’s body had of making cholesterol within the cell. The FH sufferer should ideally be given medication (if anything existed) to stimulate cholesterol production within the cell, so that the cell would at least get the vital cholesterol it needs, even when it couldn’t get it from the blood stream.
2) What was known by whom and when as statins were pushed through to approval?
We need to introduce some key players here:
- Brown & Goldstein were awarded a Nobel Prize for their work with lipoproteins. We will see what they knew along the way and their involvement with statin approval.
- Akira Endo was a Japanese biochemist who graduated from Tohoku University in 1957 and joined Sankyo Pharmaceuticals in Tokyo. Endo is the guy who discovered the poison that statins are made of. In 1971 he began his search for a fungal mycotoxin that would lower cholesterol. (Definition: “Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals”). (A metabolite is a small molecule produced during metabolism.)
In 1976 Endo managed to extract something called citrinin, a disease-causing mycotoxin from Penicillium Citrinum. He discovered that citrinin lowered blood cholesterol and published a report on this. In the same year he abandoned his work with citrinin because it was too toxic. He extracted another mycotoxin from Penicillium Citrinum called “ML-236B”, which was less toxic but still lowered cholesterol. ML-236B became Endo’s first experimental statin. (There’s a great story in the book about how Sankyo, with Japanese cultural traits of trust and honour, approached the American drug company Merck to develop the statin together. Merck shafted Sankyo and Endo was wrongly seen as the betrayer and was ostracised by Sankyo). Endo was then ‘out on his own’ and he approached Brown & Goldstein, seeing the work that they were doing with lipoproteins, and this is how these guys got together.
(Also – if you are thinking that Penicillium Citrinum sounds like an antibiotic, you’d be right. The book states “Statins – secondary fungal metabolites – are anti-life or anti-bios. Statins are antibiotics. Because antibiotics are anti-bios and kill ‘good’ vitamin-producing bacteria in the gut, most are prescribed for as short a term as possible. Statins, on the other hand, are often prescribed for life. Most antibiotics also have specific action on specific microbes. Not so with statins. Statins indiscriminately kill any cell including human cells.” (Their emphasis). This could explain the warnings about gut health on statin patient leaflets.)
In 1953 Watson and Crick discovered the structure of DNA. In 1979 Marvin Siperstein discovered that DNA replication (cell rejuvenation) required isoprenoids from mevalonate (specifically the isoprenoid called isopentenyl adenine). (p10 in the book) (I won’t dwell on Marvin Siperstein, but he’s one of the good guys in the Yoseph book – writing his important discoveries and highlighting serious issues in medical journals. These articles were sadly ignored.)
In 1976, Beecham Labs in the UK (what became SmtihKline Beecham and then Glaxo SmithKline) had discovered a statin named “compactin”. Sankyo Pharmaceuticals had discovered the same compound in parallel in Japan. They called it Mevastatin. “Stat” in statin means to stop and mevastatin means “to stop mevalonate”. So they knew exactly what they were stopping when they named this drug. Within an hour of adding compactin to cholesterol-rich cells, the cell reproduction cycle was completely stopped. Within minutes of adding back a small amount of mevalonate, DNA replication and cell cycles were completely restored.
This bit is key – because the cells were given ample cholesterol before the experiment (they were “cholesterol-rich cells”), it was clear that the problem was not cholesterol deprivation but isopentenyl adenine deprivation (that isoprenoid that enables DNA replication). The absence of this isoprenoid prevented DNA replication and the entire cell cycle.
As the Yosephs state “Cells are poisoned by statins because statins block the making of isoprenoids from mevalonate. If cells cannot replicate, they inevitably die.”
In 1977 (p37 of the Yoseph book), Endo, Brown and Goldstein published a paper documenting that statins caused an increase in reductase. It was therefore known back this far that statins should not necessarily be called reductase inhibitors, but reductase stimulators. They didn’t detect the increase in LDL receptor activity at this time.
In 1978 Merck developed their own statin.
In 1979 Endo patented another statin and sold it to Sankyo to try to restore his honour.
On p143 of the book, The Yosephs present an image of a paper written by Brown and Goldstein in The Journal of Biological Chemistry (1979). This incredible quotation from their paper is extracted: “Mevalonate, the product of HMG-CoA reductase, also supported growth, confirming that compactin was exerting its killing effect by a specific inhibition of HMG-CoA reductase.” So Brown and Goldstein admitted that the first statin, compactin, had a killing effect and this was a result of inhibiting reductase. They went on to develop further statins, which also inhibited reductase and also had a killing effect.
In 1980, Brown and Goldstein wrote the following in The Journal of Lipid Research (we’ll see who’s behind this journal shortly): “When the regulator of reductase is identified, it may be possible to administer this compound to animals and perhaps to patients, preventing the compensatory rise in reductase…” Hence Brown and Goldstein knew by 1980 that statins both inhibited and stimulated reductase. They also knew that the “compensatory rise in reductase” was something to be prevented.
In 1980, Brown and Goldstein co-authored a paper in The Journal of Biological Chemistry stating: “CoA reductase is inhibited by compactin, mevalonate formation is blocked and cultured cells die.” (p14)
In 1980, Brown and Goldstein co-authored a paper in The Journal of Lipid Research stating: “Incubation of cultured cells with compactin blocks mevalonate production and converts the cells into mevalonate auxotrophs.” (p172) An auxotroph is something that has lost the ability to synthesise certain substances needed for its growth and metabolism.
In 1980, Endo co-authored a paper in The Journal of Biological Chemistry entitled “Isolation and characterisation of cells resistant to ML236B (compactin) with increased levels of HMG-CoA reductase”. The extract (p146 of the Yoseph book) states: “…cholesterol alone is ineffective in preventing cell death…Addition of other mevalonate-derived metabolites to the culture medium along with cholesterol including ubiquinone [That’s CoQ10 remember], dolichol and isopentanyl adenine [that’s the isoprenoid vital for DNA replication] did not prevent the toxic effect of ML236B.” i.e. nothing we could add back to the cell, to compensate for the damage we had done, could prevent the toxic effect.
Also in 1980, Sankyo cancelled clinical trials of their statin on humans after half their laboratory dogs died of cancer. Merck called Sankyo to try to learn from this and Sankyo told them to sod off – quite right! Merck stopped statin development (sadly, only temporarily).
In 1982 Brown and Goldstein wrote in The Proceedings of the National Academy of Sciences: “If reducatase cannot increase sufficiently to overcome the inhibition by compactin, the cells die.” (p144)
Incredibly, given all of this going on, in 1982 Merck was allowed to give Lovastatin to humans in the first human trial. At this time:
- It was known that statins were toxins.
- It was known that statins blocked the mevalonate pathway.
- It was known that blocking the mevalonate pathway caused cell death.
- It was known that nothing could be added back to the body (not cholesterol, not isoprenoids, nothing) to prevent cell death and the toxic effect of statins.
- It was known that statins not only inhibited reductase, but they stimulated it too. It was known that inhibition of reductase “had a killing effect”. The consequences of stimulating reductase were not precisely known, but caused enough concern for the 1980 Brown and Goldstein article in The Journal of Lipid Research to discuss what might be administered to “prevent(ing) the compensatory rise in reductase…”
In 1984 lovastatin was approved by the FDA in record time.
In 1985 Brown and Goldstein were awarded the Nobel Prize!
3) The conflicts of interest:
We need to introduce some more players at this stage:
Daniel Steinberg
Daniel Steinberg is the overall ringmaster. If you do an internet search you will find remarkably little about him personally and this seems to be deliberate. The Yosephs should be commended for what they have managed to piece together about this orchestrator. (You will find his “Cholesterol Wars”, where he writes that “after much controversy, cholesterol and lipoproteins were implicated, indicted and ultimately found guilty.”)
Steinberg was the founder and first editor in chief of The Journal of Lipid Research (a vehicle for Endo, Brown and Goldstein and lipid theory supporters to use).
Steinberg was Chairman of the Council on Arteriosclerosis of the American Heart Association and used his position to recommend treating high cholesterol as early as 1969. (Introducing the theory that this life vital substance, made by the body, should be treated rather than revered).
Steinberg was co-chair of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). This trial was led by the National Institutes of Health (NIH), costing the taxpayer $150 million over 13 years. In January 1984 the results were published and claimed that the long sought evidence was now available – absolute differentials were less than 2% in different groups observed.
Steinberg was Merck’s scientific advisor when lovastatin was approved in record time in 1984.
Steinberg was the first speaker at the FDA advisory committee meeting on statins, held at the NIH, in February 1987.
In 2006, writing in his own Journal of Lipid Research, Steinberg reported that “the Goldstein/Brown laboratory showed that this huge over production of reductase, representing an attempt by the cell to overcome statin inhibition, is accompanied by a huge buildup of endoplasmic reticulum, the organelle [place] in which the reductase resides. As a result the cells look “abnormal” but of course they are not cancer cells.” Steinberg admits that the cell tries to overcome what the statin is doing, he uses the unscientific word “huge” twice – neither time in his favour – and he is apparently able to single-handedly declare that abnormal cells are “of course not cancer cells”.
The same article “The discovery of statins and the end of the controversy” (how arrogant is that?!) declared: “…there was no hard evidence that compactin would be toxic in humans, only rumors about toxicity in dogs…” Rumors? Merck contacted Sankyo to understand why half their dogs had developed cancer.
Steinberg chaired the NIH consensus panel, which in December 1984 declared that LDL cholesterol was the cause of Coronary Vascular Disease (CVD) and recommended that a National Cholesterol Education Programme (NCEP) be adopted. Since this time the NCEP has set continually lower cholesterol targets. Their recommended age for statin use is now nine!
The members of the NCEP
The 2004 NCEP financial disclosure report reveals that all members of the 2004 guideline participants had received payments and/or grant funds from the following organisations:
Dr Scott Grundy: Abbott, Astra Zeneca, Bayer, Bristol-Myers Squibb, Glaxo SmithKline, Kos, Merck, Pfizer, Sankyo.
Dr Bairey: Astra Zeneca, Bayer, Bristol-Myers Squibb, Kos, Merck, Novartis, Pfizer, Procter & Gamble, Wyeth.
Dr Brewer: Astra Zeneca, Esperion, Fournier, Lipid Sciences, Merck, Novartis, Pfizer, Sankyo, Tularik.
Dr Clark: Abbot, Astra Zeneca, Bristol-Myers Squibb, Merck, Pfizer.
Dr Hunninghake: Astra Zeneca, Bristol-Myers Squibb, Kos, Merck, Novartis, Pfizer.
Dr Pasternak: Astra Zeneca, BMS-Sanofi, Pfizer, Johnson & Johnson, Kos, Merck, Novartis, Takeda.
Dr Smith: Merck.
Dr Stone: Abbot, Astra Zeneca, Bristol-Myers Squibb, Kos, Merck, Novartis, Pfizer, Reliant, Sankyo.
The members of the 1987 FDA Panel
On February 19th 1987 the FDA held an advisory committee meeting to review the NIH clinical guidelines for altering cholesterol with Merck’s new statin, lovastatin. The NIH hosted the event. This would be like the NHS hosting the approval meeting for a drug in the UK; implicit support. Incredibly a Merck consultant, Fred Singer, was in the Chair.
Steinberg and the Nobel prize winners Brown and Goldstein were present in support of Merck. The FDA advisory committee comprised 4 FDA employees, 8 FDA advisors (2 were Merck consultants) and 11 Merck speakers and guests. That put the vote 13-10 in Merck’s favour from the outset.
The Yoseph book fully documents the actual comments made in the meeting and by whom – the record was sequestered through a Freedom of Information request. A Merck toxicologist (MacDonald) admitted that rabbits on lovastatin died rapidly. He attributed this to “elevated blood levels” and got away with no one asking him elevated blood levels of what? MacDonald glossed over the fact that statins failed to lower cholesterol in rats, mice and hamsters. This was because rodents are able to reopen the mevalonate pathway – this is why they live. The rabbits couldn’t do this. This is why they died. Dogs were somewhere in between. MacDonald had to admit to liver cell damage in dogs but, again, got away with “We clearly do not understand the mechanism”. It was denied that cataracts had been observed in rats (a few cases in dogs were skimmed over).
A pharmaceutical consultant called Dr Richard Cenedella said: “I have consulted for many drug companies over the years. All of the hyper-lipidemic drugs induce cataracts in mice; it’s an early observation that holds up.” Cenedella wrote to the Journal of the American Medical Association in 1987 “…to caution against the possible complication of cataract development that might result from long-term use of this agent” [statins]
Jonathan Tobert was Merck’s Clinical Director for all trials. In March 1988 he stated that to date there had been no cataracts seen in humans taking lovastatin. The year before he co-authored a paper documenting an increase in lens opacities (i.e. cataracts) in 101 lovastatin consumers. The Yosephs pull no punches in the book. This is just one of a catalogue of examples where they are able to prove contradictory statements made by Tobert. On p121 they say “You can tell when Tobert is lying. He is either writing or his lips are moving.” And I thought I was bold!
Interestingly cataracts are back in the news as I publish this, but I have not seen any reduction in statin prescription or usage since the headlines that emanated from this JAMA research.
In April 2009 an extraordinary letter was written to President Obama by FDA scientists to say that “The FDA is fundamentally broken” and detailing examples of suppression of truth, distortion and the “FDA failing to fulfil its mission.” Nothing has happened as a result of this letter.
Conclusion
The remarkable Yoseph book has brought us the most precise understanding of how statins lower cholesterol. It has shown that the dangers were known all along – by those pushing through the launch and approval of statins. It has shown how a few key players – Steinberg, Endo, Brown and Goldstein could work with Merck and how Merck and other drug companies could infiltrate the FDA, influence the NIH and even see the establishment of a National Cholesterol Education Programme comprised of drug company funded representatives.
The scandal has been brilliant, meticulously planned and success guaranteed. Billions and billions of dollars have been generated from first demonising cholesterol and secondly discovering a poison (Definition: “Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals”) that could stop the body making cholesterol. Or, as we now know more accurately – a poison that could drive cells to remove cholesterol from the blood stream, as those cells fight to avoid death.
The mevalonate pathway should never be blocked in a living creature. A rat may get away with it, a human won’t. If only humans died as quickly as rabbits, maybe statins would have never have been approved. The fact that they are killing us one cell at a time, but just more slowly, is little consolation.
The Executive Summary:
Cholesterol is utterly life vital. We die instantly without it. We need it for every single cell of the body, the muscles, the brain, hormones, bile production, fat digestion, reproduction – it simply cannot be emphasised enough how vital cholesterol is.
It is so vital that the body makes it – the body cannot afford to leave it to chance that we would need to get cholesterol from our diet. This makes cholesterol even more vital to the body than essential fats and protein – as we need to eat these.
Statins stop the body from making the cholesterol that it was designed to make (not entirely, or they would have an immediate 100% death rate).
Statins block something called “the mevalonate pathway”. This is catastrophic. Blocking the mevalonate pathway means that cells cannot replicate or repair themselves properly. Blocking the mevalonate pathway means that every cell in the body dies. The only thing that varies is how long each cell takes to die – some take more time than others.
Nothing can compensate for blocking the mevalonate pathway. Nothing except adding mevalonate back in to the body and we don’t do this. (We don’t even know if we can do this in humans. We shouldn’t block this pathway in the first place.) Adding cholesterol makes no difference, adding CoQ10 makes no difference. Blocking the mevalonate pathway is so flipping serious that anyone who does it should be shot. (I really think using the ‘F’ word here is quite appropriate).
The body tries to respond to the crisis that it detects. As cells realise that their ability to make cholesterol has been impaired, they try to take the cholesterol they need from the blood stream. This lowers blood cholesterol levels and ignorant doctors are happy. They know not what they have done.
There is a second way in which the body tries to save itself – it tries to increase the production of reductase, hoping that this may unblock the mevalonate pathway. It can’t. Hence reductase is both stimulated and inhibited at the same time. Who knows how the body responds to this mechanism being totally confused.
LDL receptor activity and reductase activity increase in parallel. The LDL receptors (the ‘doors’ on each cell responsible for letting LDL in to the cell, with the cholesterol and other good stuff that it is carrying) work harder to try to get LDL from the blood stream into the cells. The reductase production increases to try to reboot the mevalonate pathway, so that cells can make cholesterol as they are designed to do.
The inventors of statins knew what statins were really doing throughout the development of this drug (mevastatin literally means to stop mevalonate – they knew exactly what mevastatin would do). They knew that statins blocked the mevalonate pathway. They knew that this caused cell death. They knew that nothing could compensate for this other than putting the vital mevalonate back. They knew that CoQ10 was affected and this was serious. They patented adding CoQ10 to their statins but then never bothered to add it.
Statins were only originally intended for the 1 in 500 people with Familial Hypercholesterolemia. This would not have enabled drug companies to reach the profit potential of their dreams. Hence cholesterol has been demonised and targets have continually been reset by conflicted bodies so that the norm is no longer the norm and everyone can be told that they need statins.
Ironically, the most serious form of Familial Hypercholesterolemia would receive no benefit from statins anyway. As the extreme form is characterised by LDL receptors working barely at all, even the body going into crisis mode, and trying to take LDL from the blood stream with increased LDL receptor activity, will not work if the LDL receptors are not working sufficiently. Hence the LDL will stay in the blood stream with an extreme sufferer of FH and yet the statin has reduced what little chance the FH sufferer’s body had of making cholesterol within the cell.
There’s a great message on p304 of the book where the Yosephs suggest a notice that should be put up in washrooms:
Employees must wash hands before returning to work.
And do not touch the mevalonate pathway!
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发表于 2014-1-8 17:17:13