Big Pharma has gone bonkers! That is the only way I can explain the most recent developments in the quest to destroy cholesterol synthesis in the body. The recent FDA mandate to label every statin prescription with warnings of increased risk to diabetes and cognitive impairment has not phased them in the least! With their extraordinary marketing schemes, the industry has managed to convince the doctors, the media, and the general public that there is no number below which LDL becomes pathologically low; no number above which HDL becomes pathologically high. If you happen to fall outside of a strict range, you have no doubt that you are sick – you need to take at least one drug for the rest of your life to whip those numbers into shape. Never mind that you feel just fine. Never mind that you are a child with a maturing brain or a young woman about to start a family. In fact, some are now suggesting that anyone over 50 years old should be automatically put on a statin, without even bothering to check their cholesterol levels .
The industry has now decided that it is not enough to offer an HMG coenzyme A reductase inhibitor (statin) that interferes with the mevalonate pathway at its root – a pathway that is essential to the survival of the cell. Now they are scheming with two new drug classes, one of which promises to knock your LDL cholesterol down by 75%, and the other of which promises to drive your HDL sky high, to levels never seen in nature. Can they be serious? Can they have any credibility left after the fiasco that will surely develop once these new toxins are widely disseminated?
It turns out that, if you take a statin drug, your body tries desperately to get around the toxic effect of the statin by greatly increasing the synthesis of the enzyme, HMG Coenzyme A reductase, that the statin drug inhibits. This alone ought to tell us that the body needs this enzyme! But furthermore, your body will also increase its synthesis of an extraordinarily powerful high level controlling element, called NARC-1 (also known as PCSK9), one of only a handful of so-called protein convertases, which are still today poorly understood, but which surely have far reaching implications for the homeostasis of the body. NARC-1 is unusual among the protein convertases in that, unlike all the others, it does not require calcium uptake to be activated . Furthermore, it is sulfated at two highly conserved tyrosine residues as it leaves the ER ready for prime time. I find both of these observations highly significant in light of the research I have been conducting on the importance of sulfate and the pathology associated with calcium uptake.
One of the known effects of NARC-1 is to decrease the reuptake of LDL by the liver, which is a good idea in order to allow the LDL (now in scarce supply) to linger longer in the blood so that it can deliver its goods (triglycerides, antioxidants, fat-soluble vitamins, and cholesterol) to the tissues. The industry, in all its wisdom, has now come up with a new injectable drug which interferes with the synthesis of NARC-1 , and the hope is that people who are not happy with their LDL numbers even after statin therapy can use this drug to drive their LDL down to as close to zero as possible. The two people who won the Nobel prize for their research on cholesterol back in the 1980’s are now working for one of the companies that is marketing a version of this new drug. These agents apparently can get your LDL down to levels you won’t see even if you’re taking the highest dosage of a statin drug [4, 5].
What NARC-1 stands for is “neural apoptosis-regulated convertase 1,” which is, to say the least, a confusing name, but with the word “neural” in there you ought to be worried about the concept of an inhibitor of this protein. Studies on zebrafish have shown that NARC-1 is expressed in neurons in the cerbral cortex and in the cerebellum in association with neurogenesis. Suffice it to say that, if you render NARC-1 inactive in a zebrafish embryo, the embryo dies after just 3 to 4 days of development with its midbrain and hindbrain blended together in a confusing array of disorganized neurons . This is not a protein that I would care to mess with! Yet the industry is currently getting its rocks off thinking about the kachink of the cash register if it can successfully market this drug, as a way to further reduce your LDL number beyond the already too-low values achievable through statin therapy.
CETP InhibitorsThe other new drug, Torcetrapib, that had everybody excited  until the phase III trial results came in, is in a class called “CETP” (cholesterol ester transferase) inhibitors, and it works by inhibiting a protein that allows all the various lipoproteins (HDL, LDL, IDL, VLDL) to equilibrate their supplies of cholesterol and fatty acids by making trades. A quote from a recently published article on a phase III trial involving 15,000 people sums up the current situation: “Hopes have been running high that treatments aimed at raising HDL levels would soon help to reduce the large burden of cardiovascular disease that remains in patients at high risk of CHD who are now treated with statins. The unexpected and premature termination of the ILLUMINATE study has dashed those hopes.”  p. 257.
After 82 people died in the treatment group, as against only 51 in the placebo group, they called an early halt to the trial, and scrambled to regroup. As well as a substantially increased death rate, increases were observed in the treatment group in heart failure, angina, and revascularization procedures .
Why they could possibly think this drug was a good idea is beyond me! CETP is critically important for getting the fatty acids from the factory to the table. In diabetes, the skeletal muscles are insulin resistant, which means that they don’t like glucose as a fuel. The fat cells have assumed an awesome responsibility in maintaining fat stores that can be delivered to the muscles to keep them well fed. The delivery mechanism is interesting – kind of like the truck taking the goods to the dock where they’re piled into a containiner that’s loaded onto the cargo ship for long-distance transport. The HDL particle is the truck, and the VLDL particle is the ship. HDL takes up the fatty acids from the fat cell, and, as a consequence of now having a cargo load, it picks up an apo signature called “apo-CIII” which tells the liver not to recycle this particular particle (because it still has valuable goods to deliver). What it’s supposed to do next is to hand over its goods to a VLDL particle, along with the apo-CIII sign, and to pick up more cholesterol in return, so that it can now support a new load of fatty acids (the fatty acids need adequate cholesterol to wrap them and protect them from oxidative damage during transport). But with a CETP inhibitor at work, this exchange of goods can’t take place, so the HDL particle is stuck with a load it can’t deliver. The muscle cells don’t get fed, and the HDL particle is essentially converted into an LDL particle that can never be recycled. Your HDL numbers are high, but you should be thinking of them as LDL numbers! HDL containing apo-A1 is the healthy kind of HDL, but these fat-laden HDL particles can no longer reconvert themselves into apo-A1 versions, due to the fact that CETP isn’t working. In an in vitro study, it was shown that apo-CIII is handed over along with fatty acids when the exchange takes place. And HDL particles containing apo-CIII, i.e., burdened with fatty acids, are even worse than LDL containing an apo-CIII signature in terms of cytotoxicity to cells .
People with metabolic syndrome or diabetes tend to have an excess of free triglycerides in their blood, which have been released by fat cells to supply fatty acids to skeletal muscle cells for fuel. So their HDL particles are often overloaded in fatty acids relative to their cholesterol content, particularly in the context of a statin drug which has assured that cholesterol is in short supply. The CETP inhibitor prevents them from trading their excess triglycerides for some cholesterol with a VLDL particle, and therefore they are stuck with a situation where they can’t protect the fats they’re carrying from attack by oxidizing agents, and they can’t unload them. So, when you take this drug, you end up with a wonderfully high number of HDL particles in your blood, laden with dangerous undeliverable goods, because these oxidized fatty acids will launch a reaction cascade to create further damage to any biologically important molecules that intersect their path.
Now I want to reexamine the effects of statin drugs on muscle cells, in the light of some new information I have recently uncovered from the literature. It appears to me that statins offer the possibility of a nasty reaction cascade that would lead to an escalating pile of toxic cell debris accumulating in the skeletal muscles. This would go a long ways towards explaining all the muscle pain and weakness associated with statin therapy. As I’ve said before, statins interfere with the mevalonate pathway at its root. What I have come to realize lately is that, despite the fact that cholesterol is vitally important to the cell’s well-being, it may be the effect that statins have on another branch of the mevalonate pathway that is even more significant. This is because this other branch, involving G-proteins, is critical to the ability of the cell to communicate with other cells , something that is particularly important when the cell is distressed. Such communication turns out to be essential in order for the cell to die graciously. Why might the cell be distressed? Well, with insufficient cholesterol in its membrane, it’s going to be subjected to excess ion leaks, as I’ve discussed before. To solve this problem, it will switch from potassium to calcium (a bigger molecule) as a positively charged electrolyte to help it maintain its ion buffering and its charge balance. Having switched to calcium, it also has to switch its eNOS molecules from producing sulfate to producing nitric oxide. If the cell is a muscle cell, it depends on calcium transport between cellular compartments to generate the contractions that will support mobility. However, excess calcium in the cytoplasm provides background noise that weakens the signal and therefore the contraction strength. Furthermore, nitric oxide nitrosylates a critical protein that pumps calcium back into the sarcoplasmic reticulum to restore initial conditions after the contraction has completed . So the cell becomes less and less able to perform its function, and at some point the best option is to die.
In such a situation, ordinarily a cell would send out a signal using G-proteins and this would draw the attention of a nearby neutrophil, which would arrive on the scene, ready and waiting to clean up the debris left behind after the cell dies with dignity. The neutrophil actually sends a reply signal that initiates a programmed cell death process called apoptosis, such that the cell can die in an orderly fashion, much like initiating a controlled computer “shutdown” rather than just pressing the power button [12, 13]. The SOS signal is called ”Fas” and the neutrophil’s response signal is called “Fasl.” The complex response initiated in the cell is aptly named a “death-inducing signaling complex” (DISC).
But with statins suppressing the mevalonate pathway, both the cell in trouble and the neutrophil are depleted in G-proteins  and are thus impaired in their ability to initiate the Fas-Fasl signaling that would allow the cell to shut down gracefully. Neither one can carry out its half of the signaling handshake, so instead the cell dies a messy unorchestrated death by necrosis, spilling its guts out into the intercellular space. One of the really toxic substances that shows up as debris when a cell dies an “unnatural” death is D-ribose, a glycating agent that is much worse than fructose, which in turn is much worse than glucose. So now we have a reaction cascade taking place where neighboring cells also die untimely deaths as a consequence of the toxicity of D-ribose, and a necrotic pile of cell debris accumulates. I would imagine that an accumulation of necrotic cell debris would also show up in the atherosclerotic plaque, because neutrophils are unable to respond to SOS signals sent out by distressed cells in the plaque. Indeed, what you typically see in statin therapy is a decrease in the overall number of heart attacks (and I think this may also be attributable to the shutdown of cell-cell communication channels), but an increase in the number and size of big heart attacks that are much more likely to kill you.
But the bigger problem, in my view, with these necrotic deaths, is that it has the effect of globally increasing the body’s cells’ exposure to advanced glycation end products (AGEs). Some have argued that AGEs should be equated with aging: that aging can best be defined as the accumulation over time of more and more AGE products. These AGEs are the biggest health problem associated with diabetes. They cause impaired function for all cells and blood proteins that come in contact with them. This accumulation of D-ribose from debris from dead cells is, in fact, I think, the key reason why statin drugs accelerate the rate at which you grow old. And I think that is the best way to characterize statin drugs.
An Exciting New Book
Finally, I want to shamelessly promote a book that has just been released called, “How Statin Drugs Really Lower Cholesterol and Kill You One Cell at a Time.” I just got a copy of this book , and I have been devouring it! The technique the authors use of showing snippets from papers written by the major players in the early promotion of statin drugs is stunning. If you do nothing else this summer, read this book! It will change forever your view of the medical establishment and the FDA.
Here, I just want to talk about one key paper referenced in the book . This paper, written in 1980, discusses the core problem with statins addressed by the book, namely, that they interfere with the cell cycle and therefore prevent cells from being able to replicate their DNA. It’s another branch of the mevalonate pathway besides the cholesterol branch that leads to the key enzyme that is necessary for cell replication, and this is why statins interfere with the cell’s ability to multiply. Many cell types depend upon such cloning to maintain healthy tissues, such as in the skin, and most certainly a fetus, which probably explains why they’re labelled class X for pregnancy. But the really disturbing thing, to me, that this paper points out is that tumor cells exhibit a near universal pathology which is uncontrolled, unregulated, synthesis of mevalonate, the precursor to the reaction that is blocked by statin drugs. Since stressors induce tumorigenesis, and since the mevalonate pathway is highly stressed when a cell is bathed in statin drugs, I would expect that statins would be highly tumorigenic. But the key reason why they don’t actually lead to tumor growth is that statins interfere with the new tumor cell’s ability to clone itself. My prediction is that, when people who have been taking a statin for a long time go off of it (which they will surely do in droves if they read this book!), they will be primed for runaway cancer, because the statins are probably causing many cells to become malignant, but these cells have been trapped in a limbo state because of the suppression of DNA replication by statins.
 R. Smith, “All over 50s should be taking statins,“ The Telegraph, May 17, 2012. Accessed May 17, 2012.
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 M. Bennett, K. Macdonald, S.-W. Chan, J.P. Luzio, R.Simari and P. Weissberg, “Cell Surface Trafficking of Fas: A Rapid Mechanism of p53-Mediated Apoptosis,” Science 282(5387):290-293, Oct. 9, 1998.
 L.M. Blanco-Colio, B. Muñoz-García, J.L. Martín-Ventura, C. Lorz, C. Díaz, G. Hernández and J. Egido, “3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Decrease Fas Ligand Expression and Cytotoxicity in Activated Human T Lymphocytes,” Circulation 108:1506-1513, 2003.
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 V.Q. Huneeus, M. H. Wiley, and M.D. Siperstein, “Isopentenyladenine as a mediator of mevalonate-regulated DNA replication,” Proc. Natl. Acad. Sci. 77(10) 5842-5846,Oct. 1980.