Thursday, December 15, 2011

Cholesterol and Statins: Who’s the Hero? Who’s the Villain?

The statin drugs, known more technically as HMG Coenzyme A reductase inhibitors, are the biggest blockbuster drug class of all times. Now that Lipitor, the number one selling drug in history, has gone off patent, we can expect the price to drop precipitously, and even more people will be able to afford this wonder drug that promises to keep heart attacks at bay.

Statins’ claim to fame is that they reduce serum levels of cholesterol, that villainous moleclule that clogs up our arteries and leads to an early death. Statins work remarkably well – most people who adopt statin therapy quickly see their measures of serum LDL drop dramatically.

Beyond their ability to delay heart attacks, statins have also been credited with a large and growing number of “off-label” benefits – you can find articles on the Web claiming that they protect form Alzheimer’s disease, osteoporosis, multiple sclerosis, cancer, and infection, among others. Some are even advocating, not necessarily tongue in cheek, that statins should be added to the drinking water.

A good example is the article that just appeared on the Web on the subject of statins and influenza. The headline claims that statins may improve your chances of surviving the flu, but a couple of points in the article lead me to suspect that instead statins are increasing the risk of healthy people catching the flu. As will become clear later in this article, cholesterol is an important weapon against infection and statin drugs disturb the immune response in ways that would be expected to increase susceptibility to infection. This idea is borne out by the fact pointed out in the article that a greater percentage of the statin users had gotten a flu vaccine, but nonetheless acquired the infection. Furthermore, fully one third of the infected people were on statins, a number that is surely significantly larger than the frequency of statin use in the general population; i.e., statin use is associated with increased risk of infection. Finally, the statin users had an increased incidence of chronic lung disease, something that I have argued previously would be promoted by long-term statin therapy, and something that would likely increase the risk of infection from exposure to influenza. If the serum cholesterol levels of the people who died had been measured, it would probably have been found that their levels were low and falling, as has been shown to be the case for people with sepsis who fail to recover [24]. In fact, these authors wrote: “In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. ... New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis.” A paper published in 1997 revealed an inverse association between cholesterol levels and pneumonia hospitalization [20], suggesting that high cholesterol is protective against pneumonia as well.

Curiously, despite aggressive campaigns to get people vaccinated against the flu, morbidity and mortality from flu has steadily gotten worse in recent years. Besides the ineffectiveness of vaccines, I suspect this increased mortality is due in large part to the ever increasing use of statin therapy. My personal belief is that it will eventually be shown that not only susceptibility to infection, but every one of the claimed off-label benefits of statins is actually a benefit derived from cholesterol, and that statins are actually eroding that benefit by steadily depleting the supply of cholesterol to the tissues. Furthermore, I predict that it will eventually be shown that the depletion of cholesterol supply to the plaque caused by statin drugs leads to heart failure down the road, due directly to the cholesterol deficiency brought on by the statin drug.

How can my bold claim possibly be true? Below, I will examine several of these alleged off-label benefits, and show how statin drugs have been able to systematically play a devious game that results in stealing credit from cholesterol and falsely giving it to themselves.

Cancer

It is not easily shown that statins increase risk to cancer, because it takes considerable time for cholesterol to become depleted in the tissues as the supply line to replenish worn out cholesterol is reduced, and then more time for this depletion to lead to cancer due to genetic mutations. However, low cholesterol is a risk marker for cancer [15], and, despite the fact that statin trials are usually too short to reveal the trend towards increased cancer risk, several statin trials have resulted in observable differences between treatment and control groups, with treatment groups faring worse. In the first two trials on simvastatin, non-melanoma skin cancer was more prevalent in the treatment group, a result that becomes statistically significant if the data from the two trials are combined. In the CARE trial, which involved exclusively women, 12 women in the treatment group developed breast cancer, as against only one in the control group, a result that was highly significant (p = 0.002). Two other trials, both PROSPER and SEAS, also showed statistically significant increases in cancer incidence in the treatment group compared to the control group.

The story, in my view, for how statins increase your risk to cancer, involves a number of players and some complexity regarding mechanism. But it’s a very logical step-by-step progression, taking place steadily over an extended period of time. To understand the story, you first have to know something about vitamin B12 (cobalamin), a key player in the story. Vitamin B12 catalyzes a great number of reactions that require methionine, an essential sulfur-containing amino acid, as substrate, extracting the methyl group from methionine and adding it to some other molecule. One of the key molecules that benefits from such reactions is DNA. Methylation of DNA protects it from damage due to exposure to carcinogens or oxidation or radiation.

Methionine can also be degraded via a different pathway, and it’s an either-or situation here. This alternative fate results in the production of homocysteine, which later becomes substrate for the synthesis of sulfate. So, logically, if sulfate is in short supply, then methionine would get side-tracked down the homocysteine pathway, and less of the DNA would get methylated. Eventually, this would manifest as an increased risk to cancer.

Why might sulfate supply be deficient? This is something I have already discussed in previous blog posts, and one way it could happen is if the cells in the epidermis didn’t have enough cholesterol. This is because they need cholesterol in order to produce cholesterol sulfate, upon exposure to sunlight. The cholesterol sulfate is then shipped out via the blood stream to all the tissues, which eagerly take it up to resupply themselves with both cholesterol and sulfate.

The cells in the skin can synthesize their own cholesterol, but statin therapy would interfere with this process. As a result, they would not be able to spare cholesterol to ship out. What happens first is that, due to cholesterol deficiency in their membranes, they start leaking potassium at an excess rate, and an energy burn they can’t afford ensues, to pump the potassium back in. This becomes untenable, so calcium is brought in to replace some of the potassium as a positively charged electrolyte. Being a much bigger molecule, calcium doesn’t leak out nearly so easily. Its presence has a dramatic effect, however, on the eNOS molecules that had been responsible for synthesizing sulfate. They detach from the cell membrane and start making nitric oxide (−→ nitrate) instead. Unfortunately, this also results in some nasty side products like peroxynitrite and superoxide, which are potent oxidizing agents.

One of the first molecules that gets oxidized is cobalamin [1]. This drives the cobalt atom in cobalamin to a +3 charge, which inactivates the molecule, meaning that it will no longer support the methylation of the vulnerable DNA, thus increasing the risk to cancer. This is interesting from a biological standpoint, because it means that the methionine will naturally shift towards producing sulfate, a good idea since the skin is no longer going to be able to keep up with the supply.

One of the other molecules whose synthesis is catalyzed by cobalalmin is coenzyme Q10, probably the most important antioxidant in the mitochondria. The mitochondria are the chambers where sugars and fats are oxidized to produce ATP, the energy currency of the cell. Mitochondria are the organelles in the cell that suffer the greatest exposure to oxidizing agents, because oxidative metabolism takes place there. They contain their own separate mitochondrial DNA, now highly vunerable to attack.

To add insult onto injury, statins also interfere with the synthesis of coenzyme Q10, so this potent antioxidant is now in very short supply in the mitochondria of any cell in the skin that has been hit hard by a statin drug. The cells in the skin are now poised to develop cancer: they’ve got an extra burden of oxidizing agents, an increased vulnerability in their DNA to susceptibility to damage due to the demethylation process, and a decrease in the agents that would mop up extra free radicals. It’s not at all surprising that skin cancer is where the increased risk to cancer with statin therapy was first noted.

Another cancer which I suspect is increasing in incidence directly due to statin therapy is prostate cancer, which is the most common cancer by far in men. A very interesting recently noted observation is that prostate cancer tumors actually are producers of cholesterol sulfate! [3]. It has been suggested that this feature might be useful as a more reliable indicator of prostate cancer than the PSA test. I suspect in fact that this is a positive role they play, to try to correct a severe deficiency in this vital molecule, as cholesterol sulfate plays an essential role in fertilization [6]. Unlike women, men normally remain fertile throughout life, but not if cholesterol sulfate is insufficient. I would predict that surgery to remove a prostate tumor, beyond rendering a man infertile, will lead to an increase in various medical problems related to cholesterol sulfate deficiency.

Infection

Population-based observational studies have suggested that statins may reduce the risk to infection and improve recovery following infection. I find this idea astonishing, because there are numerous ways in which cholesterol protects from infection, so the reverse should actually be true. Very recently, articles have begun to appear that have questioned this benefit. A meta study looking at the results of several placebo-controlled studies relating statins to infection showed no benefit [22]. So, once again, the benefit goes away when the study is done properly.

Beatrice Golomb, a professor at UC San Diego, argues that the idea that statins protect from infection is likely to be completely spurious, being mainly attributable to what has been called the “healthy user” effect – people who take statins are also more conscientious about their health, by exercising, losing weight, eating healthier foods, and quitting smoking [5]. More than this, Golomb also argues for publication bias, where studies that come out favorably towards statins get published, and the ones that don’t don’t. For example, only 11 of 632 statin trials were included in the meta analysis that showed no benefit for statins in infection [22]. Tellingly, none of the other trials provided data on infection, which could well be because those data would show statins in a bad light. I think another important factor is that people who take statins have had high serum cholesterol for a long time prior to taking the statins, and therefore their tissues are, ironically, better supplied with cholesterol, at least in the short term. Of course the statins are steadily eroding this benefit.

A study trying to determine how statins might protect against infection discovered a remarkable effect of statins on macrophages and on phagocytes [2]. Phagocytes are the immune cells that are supposed to engulf bacteria and subsequently kill them, a process referred to as phagocytosis. Statins had a bizarre effect on both macrophages and phagocytes, which was to turn them into suicide bombers: instead of ingesting bacteria, they intentionally kill themselves (apoptosis), simultaneously releasing a potent toxin called “extracellular trap,” intended to do harm to the bacteria. Contrary to the idea that statins might increase the activity of the standard immune reaction, it was found that statins reduced both oxidative burst and phagocytosis. All of these effects were found to be due directly to statins’ ability to reduce the bioavailability of cholesterol.

Due to their interference with an early step in the mevalonate pathway, statins wreck a great number of pathways in the cell. One of the affected signaling pathways is the activation of NF-kβ, normally happening in macrophages (immune response white blood cells) in response to exposure to toxins from pathogenic bacteria. As a consequence of the production of NF-kβ, macrophages synthesize inducible nitric oxide synthase (iNOS), resulting in the production of a burst of nitric oxide, which is toxic to the invading bacteria. Experiments have demonstrated conclusively that statins weaken this immune response of macrophages to endotoxin [11], and this effect is explained as being due to their inhibition of the synthesis of farnesyl pyrophosphate, a mevalonate metabolite that plays a critical role in cell signaling.

Now I would like to take a look at the science behind how cholesterol protects from infection, and what effect that might have. Let’s start with the skin, an important interface with the world where bacteria might gain entry. A case-control study has shown that statin users are more susceptible to bacterial infection through the skin [7]. A key protein in the skin that keeps bacteria out is filaggrin, which maintains a healthy epithelial barrier [14]. The synthesis of its precursor, profilaggrin, is catalyzed by cholesterol sulfate [8]. Since statins interfere with cholesterol production in the skin, they would deplete the cholesterol sulfate supply, which would then interfere with the maintenance of filaggrin, and bacteria would more readily gain entry.

Once bacteria have managed to gain entry into the blood stream, they need to break through an individual cell’s defenses in order to actually infect the cell. Here, the presence of sulfate anions in the extracellular matrix proteins of the cell affords an invisible shield, due to the negative charge field that now surrounds the cell. The bacteria have a similar negative charge field, and so the two negatively charged “particles” will repel one another. If the cell becomes depleted in sulfate, it will become easier for bacteria to gain entry. Since the major supplier of the sulfate is cholesterol sulfate, produce by cells in the skin, by red blood cells and platelets, and by endothelial cells lining the artery walls, suppressed cholesterol synthesis induced by statin therapy will render the cells more susceptible to infection by the bacteria that gained entry due to the imapired skin barrier, also attributed to cholesterol deficiency.

Finally, LDL, the lipid particle whose serum concentration dramatically drops with statin therapy, is a powerful antibacterial agent. LDL has been shown to bind to the endotoxin (lipopolysaccharide) produced by pathogenic microbes and literally deliver it to the macrophages, so that they can properly dispose of it. Mice that have been engineered to have low levels of apoB, the signature apolipoprotein of LDL, are more susceptible to infection by Staph aureus, the microbe responsible for the MRSA epidemics now taking place in hospitals throughout the Western world [12]. In fact, it has been suggested that increased statin use may be a factor in the rapid increase in meth resistant Staph infections [4, 17].

Alzheimer’s Disease

The way the numbers game has been played in Alzheimer’s disease is a great example of how the truth can be hidden from view without actually falsifying the data. Luckily, one group not beholden to the statin industry decided to look at the numbers in a slightly different way, and that is how it becomes clear what is really going on.

Several studies have shown that, if you look at people currently taking statins and those not currently taking statins, the ones taking statins have a slightly reduced incidence of Alzheimer’s disease. Such observational studies were the basis for exalted claims that statins might protect from Alzheimer’s, such as this 2003 Newsweek article.

At face value, this result seems compelling, but you have to remember that people taking statins have enjoyed elevated cholesterol levels for much of their life, and this may be the true source of their reduced Alzheimer’s risk. Much has been made of a study that showed that elevated cholesterol levels in midlife lead to increased Alzheimer’s risk three decades later [19], but this study explicitly stated that they did not have access to information on whether their subjects were taking statins in the intervening years. You can be sure that if it had shown statins in a favorable light, they would have been granted access to those data. In fact, what has become clear is that it’s a drop in cholesterol levels that increases risk, to Alzheimer’s disease, and I think that drop is likely due to statin therapy.

In the study I alluded to earlier that looked at the data in a slightly different way, the researchers first showed, as have others, that that there were proportionately fewer cases of Alzheimer’s among people currently tkaing statins, compared to those who were not [16]. But then they took the group who were not, and asked them the simple question: “Have you ever taken a statin drug?” Turns out that the ones who answered “yes” to this question were two and a half times as likely to have Alzheimer’s, compared to those who said “No.” The easy answer is that the doctor takes you off the statin when you first complain of memory problems, a known side effect of statin drugs. This puts you on the other side of the fence. It’s not that statins protect from Alzheimer’s, but rather that Alzheimer’s protects from statins.

There’s a consistent pattern with these claims that statins protect from some condition – early observational studies seem to show that statins help, and this idea is widely publicized, but then later placebo cotrolled studies get a contradicting result, and this result is buried. The placebo controlled studies are the only ones that count, because people are chosen randomly to receive drug or placebo, and you don’t run up against biases due to other factors such as the “healthy user” effect that distinguish the two populations being observed. A randomized placebo-controlled study funded by Pfizer [18] showed not only that statins did not slow the decline of Alzheimer’s patients, but that the patients on statins actually showed more mental decline than the ones not on statins. The results were not statistically significant, but, on the other hand, any patients whose caretaker decided to take them out of the trial prematurely were left out of the data. These people were likely declining even faster than the ones who stayed in the trial.

In a study comparing cholesterol levels among patients with Alzheimer’s disease (AD) and healthy controls, the authors wrote [13], p. 117: “Serum cholesterol, LDL-C , and HDL-C levels were significantly lower in all patients with AD than in healthy subjects... Patients in the late stage of disease had significantly lower cholesterol, HDL-C, LDL-C and TG levels than healthy controls and significantly lower cholesterol and LDL-C levels than patients in the middle stage of disease.” In other words, healthy people had more cholesterol than Alzheimer’s patients, and late-stage Alzheimer’s patients had lower cholesterol than early stage patients. This observation flies in the face of the argument that lowering cholesterol with statin drugs would improve your odds against developing Alzheimer’s disease.

References

[1] M Brouwer, W Chamulitrat, G Ferruzzi, DL Sauls and JB Weinberg “Nitric oxide interactions with cobalamins: biochemical and functional consequences,” Blood 88: 1857-1864, 1996.

[2] O.A. Chow, M. von Köckritz-Blickwede, A.T. Bright, M.E. Hensler, A.S. Zinkernagel, A.L. Cogen, R.L. Gallo, M. Monestier, Y. Wang, C.K. Glass and V. Nizet, “Statins Enhance Formation of Phagocyte Extracellular Traps,” Cell Host and Microbe 8:445454, Nov. 18, 2010.

[3] L.S. Eberlin, A.L. Dill, A.B. Costa, D.R. Ifa, L. Cheng, T. Masterson, M. Koch, T.L. Ratliff and R.G. Cooks, “Cholesterol Sulfate Imaging in Human Prostate Cancer Tissue by Desorption Electrospray Ionization Mass Spectrometry,” Anal Chem. 82:9, 34303434. May 1, 2010.

[4] M.R. Goldstein, L. Mascitelli and F. Pezzetta, “Methicillin-resistant Staphylococcus aureus: A link to statin therapy?” Cleveland Clinic Journal of Medicine 75:5 Letter to the Editor, May 2008.

[5] B.A. Golomb, “Do statins reduce the risk of infection? Observational evidence of a benefit is now refuted by randomised trials,” BMJ, Nov. 29, 2011.

[6] C. Iribarren, D.R. Jacobs, Jr, S. Sidney, A.J. Claxton Gross, M. Sadler and H. Blackburn, “Serum total cholesterol and risk of hospitalization, and death from respiratory disease.” Int J Epidemiol 26:11911202, 1997.

[7] J.Langlais, M. Zollinger, L. Plante, A. Chapdelaine, G. Bleau and K.D. Roberts, Biochemistry 78:12, 7266-7270, Dec. 1981 Localization of cholesteryl sulfate in human spermatozoa in support of a hypothesis for the mechanism of capacitation

[8] A.P. Liappis, V.L. Kan, C.G. Rochester and G.L. Simon, “The effect of statins on mortality in patients with bacteremia,” Clin Infect Dis 33:13521357, 2001.

[9] H. Nakae, O. Hanyu, H. Fuda and C.A. Strott, “Novel role of cholesterol sulfate in gene regulation during skin development,” The FASEB Journal 22:782.2, March, 2008.

[10] T. Neale, Senior Staff Writer, “Statins May Protect Against Flu-Related Death,” MedPage Today, Dec. 14, 2011; http://www.medpagetoday.com/InfectiousDisease/URItheFlu/30214

[11] D. Noonan, “You Want Statins With That?” Newsweek, Jul 27, 2003; http://www.thedailybeast.com/newsweek/2003/07/27/you-want-statins-with-that.html

[12] K. Pahan, F.G. Sheikh, A.M.S. Namboodiri, and I. Singh, “Lovastatin and Phenylacetate Inhibit the Induction of Nitric Oxide Synthase and Cytokines in Rat Primary Astrocytes, Microglia, and Macrophages,” J. Clin. Invest. 100:11, 26712679, Dec. 1997.

[13] M. M. Peterson, J.L. Mack and P.R. Hall, A.A. Alsup, S.M. Alexander, E.K. Sully, Y. S. Sawires, A.L. Cheung, M. Otto, and H.D. Gresham, “Apolipoprotein B is an Innate Barrier Against Invasive Staphylococcus aureus Infection” Cell Host Microbe.4(6): 555566, Dec. 11 2008.

[14] P. Presecki, D. Mück-Seler, N. Mimica, N. Pivac, M. Mustapic, T. Stipcevic and V. Folnegovic Smalc, “Serum Lipid Levels in Patients with Alzheimers Disease,” Coll. Antropol. 35 (2011) Suppl. 1: 115120

[15] R.B. Presland, “Function of Filaggrin and Caspase-14 in Formation and Maintenance of the Epithelial Barrier,” Dermatol Sinica, 1-14, 2009.

[16] U. Ravnskov, K.S. McCully and P.J. Rosch, “The statin-low cholesterol-cancer conundrum,” QJMed, Advance Access published December 8, 2011.

[17] T.D. Rea, J.C. Breitner, B.M. Psaty, A.L. Fitzpatrick, O.L. Lopez, A.B. Newman, W.R. Hazzard, P.P. Zandi, G.L. Burke, C.G. Lyketsos, C. Bernick and L.H. Kuller, “Statin Use and the Risk of Incident Dementia: The Cardiovascular Health Study,” Arch Neurol 62:1047-1051. Jul 2005.

[18] S.J. Rehm, “Staphylococcus aureus: the new adventures of a legendary pathogen,” Cleve Clin J Med 2008; 75:177192.

[19] M. Sano, K.L. Bell, D. Galasko, J.E. Galvin, R.G. Thomas, C.H. van Dyck, et al. “A randomised, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease,” Neurology 77:55663, 2011.

[20] A. Solomon, M. Kivipelto, B. Wolozin, J. Zhou, and R.A. Whitmer, “Midlife Serum Cholesterol and Increased Risk of Alzheimer’s and Vascular Dementia Three Decades Later,”Dementia and Geriatric Cognitive Disorders 28, 75-80, 2009.

[21] C.S. Valente Barbas and L.B. Kawano-Dourado, “What is the real role of statins in community-acquired pneumonia and sepsis?” Crit Care Med 2011 39: 8, 1998-1999.

[22] H.L. van den Hoek, W.J. W. Bos, A. de Boer and E.M.W. van de Garde, “Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials,” BMJ, Nov. 29, 2011.

[23] M.L. Vandermeer, A.R. Thomas, L. Kamimoto, A. Reingold, K. gershman et al., “Association Between Use of Statins and Mortality Among Patients Hospitalized With Laboratory-Confirmed Influenza Virus Infections: A Multistate Study,” J Infect Dis. 2011.

[24] R.F. Wilson, J.F. Barletta and J.G. Tyburski, “Hypocholesterolemia in Sepsis and Critically Ill or Injured Patients,” Critical Care 7:413-414, 2003.

[25] S. Yende, E.B. Milbrandt, J.A. Kellum, L. Kong, R.L. Delude, L.A. Weissfeld and D.C. Angus, “Understanding the potential role of statins in pneumonia and sepsis,” Crit Care Med 2011 39:8, 1871-1878.

9 comments:

  1. Fantastic essay. Now I'll have something to reference if I ever discuss with someone the ungodly nature of statins. Off the subject of statins specifically though, I find it interesting you brought up buried research...it seems as though once someone in a position of authority comes up with a hypothesis, they will use the slightest shreds of evidence to support it, but then they bury or just completely ignore evidence to the contrary. Such it is with the low-fat dogma.

    Anyway, I am using your essay on low-fat diets and vitamin D as my subject for a rhetorical analysis essay for my argumentation class. It's a great piece of work!

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