The statins (or HMG-CoA reductase inhibitors) along with other drugs, such as cholestyramine (Questran), comprise the class of hypolipidemic drugs. Hypolipidemic drugs are prescribed - sometimes aggressively so - to lower cholesterol levels in people with or at risk of cardiovascular disease and certain inflammatory diseases such as sarcoidosis. Statins are prescribed even though their full mechanisms of action remain unclear. One strong possibility is that statins exert their effects via the body's nuclear receptors, which are intricately connected to innate immune function.
The statins have a range of documented negative effects, some of which may be immunopathological. Because statins may interfere with the Marshall Protocol, these drugs are contraindicated.
Statins interfere with the actions of Olmesartan, as they are a very similar molecule, and compete with Olmesartan for many of Olmesartan's molecular binding sites. The actions of statins on the Nuclear Receptors are therefore competitive with Olmesartan, as they reduce or negate Olmesartan's therapeutic activities.
As the 2008 ENHANCE trial illustrates, while high cholesterol is correlated with increased incidence of diseases, lowering cholesterol does not appear to improve human health.1) Indeed, there is some evidence this type of intervention does the opposite.2)
The following is a list of common cholesterol-lowering drugs known as statins:
The following is a list of common non-statin cholesterol-lowering drugs:
Large numbers of patients at risk for cardiovascular disease or stroke are prescribed statins – drugs that are marketed as improving health by lowering cholesterol. There’s no question that statins can effectively lower cholesterol. But, does lowering cholesterol actually benefit patients with coronary artery disease, and more importantly, are the effects of statins on patients with heart disease even related to their ability to lower cholesterol?
The fact that statin treatment lowers both total and cardiovascular mortality in high-risk individuals is taken as evidence that cholesterol lowering is effective. However, statins are just as effective whether cholesterol is lowered by a small amount (as in the unsuccessful non-statin trials) or by more than 40%. In addition, statin treatment is effective whether the initial LDL-C is high or low.3) 4) If high LDL-C were causal, the greatest effect should have been seen in patients with the highest LDL-C, and in patients whose LDL-C was lowered the most, but this is not the case. Lack of dose-response cannot be attributed to the knowledge that the statins have other effects on plaque stabilization, as this would not have masked the effect of cholesterol-lowering, considering the pronounced lowering that was achieved.
U. Ravnskov 5)
Ravnskov compares two separate trials of a single statin, simvastatin: a 2002 trial (nicknamed HPS)6) and a 1994 study (nicknamed 4S)7). The 4S research team reported a three times greater risk of coronary death in the HPS trial, even though patients' total cholesterol in the 4S trial was decreased to a much lower extent.8)
A seminal study called the ENHANCE trial was published in 2008. The trial tested the effects of a new cholesterol-lowering medication called Zetia (which, as opposed to the statins, works by decreasing cholesterol absorption in the intestine) on patients with cardiovascular disease. It found that Vytorin, a combination pill containing both Zetia and the statin Zocor (simvastatin), proved better than the statin alone at reducing levels of cholesterol. However, ENHANCE collaborators reported that Vytorin resulted in growth of plaque.9)
All together, this evidence suggests statins' ability to (slightly) improve health outcomes is independent of their ability to lower cholesterol.10)
Statins are now known to alter nuclear receptor activity, and it may be the effects which result from these mechanisms that account for in health outcomes of patients taking the drugs. (Note: Zetia, which is not a statin, does not seem to have this property.)
Statins have been demonstrated to increase CYP3A expression in vitro, most likely because they are ligands to nuclear receptors (pregnane X receptor and constitutive androsterone receptor) that form heterodimers with retinoid X receptors and bind to responsive elements in the CYP3A4 and CYP3A5 promoter regions.
M.A. Willrich 11)
Because each of the statins has such different affinities for the receptors they bind, each works in different ways and influences the transcription of different genes. Some may activate the nuclear receptors while others might slow their activity. Indeed, this may explain the variability in side effects between one statin and the next.
Simvastatin, rosuvastatin and atorvastatin work in vastly different ways. They may each benefit people under different conditions but we have no way of knowing exactly how at this point.
Trevor Marshall, PhD
According to the reports from the statin trials, all of which have been sponsored by the drug companies, side effects are mild and rare, but underreporting is prevalent. According to drug companies, muscular symptoms occur in less than one percent of patients taking statins, however researchers independent of drug companies have found the frequency to be 64%12) and 75%.13) In the IDEAL trial, almost 90% of participants in both groups had side effects, and in almost half of them they were recorded as serious.14) The following adverse effects for statins have been noted in the medical literature:
As discussed in the previous section, it may be that their effect on nuclear receptors explain how some statins increase patients' disease symptoms. Indeed, a 2009 Pathology paper described antimicrobial activity of atorvastatin and rosuvastatin.24) Some of the observed side effects of statins may be immunopathological in nature. One study reports both bactericidal and inflammatory response changes in macrophage activity from simvastatin. 25) It is possible that statins have similar immune-activating properties to the main drug for the Marshall Protocol, olmesartan, which causes an increase in disease symptoms following bacterial death.
In any case, researchers tend not to study or discuss what may be statins' primary mechanism of action: its effect on immune function. Nor, is their an earnest exploration of how modulating immune activity against chronic microbes29) affects the course of human disease.
In particular, the following drugs seem to make the statins more likely to cause problems:
For adults aged between 30 and 80 years old who already have occlusive vascular disease, statins confer a total and cardiovascular mortality benefit and are not controversial. However, 75% of patients who take statins are not in this category.30)
For patients who are healthy, there is marginal evidence that statins prevent heart attacks or strokes.31) One meta-analysis (which was itself compromised almost entirely of industry-funded studies) showed that in healthy patients, there was only a 0.6% reduction in mortality. In other words, physicians would need to treat between 100 and 450 patients with a statin for more than four years to prevent one death.32)
Certainly, one of the motivations to demonstrate statins' value as a preventative therapy is financial. The best-selling drug in the world is Lipitor (atorvastatin), which is manufactured by Pfizer.
The guidelines that create the clinical imperative for physicians are done by experts who have financial ties to drug companies that make the drugs being considered in the process. Fifty-nine percent of the experts who formulate the guidelines have financial ties. In a meta-analysis of statins in Lancet, 13 out of 14 studies were commercially sponsored. The one that was not commercially sponsored showed distinctly less benefit from statins.
John Abramson, M.D., Harvard Medical School
A 2012 randomized, placebo-controlled trial gave 120 adults with levels of 25-D below 20 ng/mL and elevated risk for cardiovascular disease either 50,000 IU of vitamin D3 weekly for 8 weeks or placebo. The study found a significant and undesired increase in LDL cholesterol.33)
In March of 1999, I was prescribed a statin drug (provachol) for cholesterol lowering. I took one 20 mg. tablet in the evening upon retiring. I awoke 8 hours later in the throes of what I now know was Lofgren's syndrome. I took one tablet each night for the next 2 nights with a total of 3 tablets. For the next 6 months I suffered from terrible myositis (pain used to cause me to scream out loud), swollen legs, erethyma nodosum, terrible fatigue, joint pain, etc. No health care provider recognized sarcoidosis in its acute form.
At the end of that 6 month period, I quit on the doctors. I had no idea what was wrong with me and was sick of searching for help in my rural area where there aren't a lot of doctors who can think out of the box. In the next 6 months, those symptoms resolved but I had terrible headaches, constipation, vision problems.
J Leukoc Biol. 2010 Mar;87(3):433-42. Epub 2009 Nov 5. Opposite effects of simvastatin on the bactericidal and inflammatory response of macrophages to opsonized S. aureus. Benati D, Ferro M, Savino MT, Ulivieri C, Schiavo E, Nuccitelli A, Pasini FL, Baldari CT. Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Abstract Besides lowering circulating cholesterol, statins act as immunomodulators. Although the effects of statins on lymphocyte activation and differentiation have been clearly defined, there is no consensus as to effects of these drugs on phagocytes. We have addressed the outcome of simvastatin treatment on the activation and effector function of human macrophages in the pathophysiologically relevant context of challenge with an opportunistic pathogen. We provide evidence that: simvastatin blocks the biological effects rapidly triggered by IgG-opsonized bacteria (phagocytosis and oxidative burst) while enhancing the delayed effects elicited by FcgammaR stimulation (production of proinflammatory mediators); these opposite effects of simvastatin result from enhancement of the JNK pathway and concomitant impairment of other signaling modules activated by FcgammaR engagement; and these activities are dependent on the capacity of simvastatin to block protein prenylation. The results provide novel mechanistic insight into the activities of statins on phagocytes and are of relevance to the assessment of potential side-effects in patients undergoing long-term hypocholesterolemic therapy. PMID: 19892847
Cell Host Microbe. 2010 Nov 18;8(5):445-54.
Statins enhance formation of phagocyte extracellular traps.
Chow OA, von Köckritz-Blickwede M, Bright AT, Hensler ME, Zinkernagel AS, Cogen AL, Gallo RL, Monestier M, Wang Y, Glass CK, Nizet V. Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA. Abstract Statins are inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent clinico-epidemiologic studies correlate patients receiving statin therapy with having reduced mortality associated with severe bacterial infection. Investigating the effect of statins on the innate immune capacity of phagocytic cells against the human pathogen Staphylococcus aureus, we uncovered a beneficial effect of statins on bacterial clearance by phagocytes, although, paradoxically, both phagocytosis and oxidative burst were inhibited. Probing instead for an extracellular mechanism of killing, we found that statins boosted the production of antibacterial DNA-based extracellular traps (ETs) by human and murine neutrophils and also monocytes/macrophages. The effect of statins to induce phagocyte ETs was linked to sterol pathway inhibition. We conclude that a drug therapy taken chronically by millions alters the functional behavior of phagocytic cells, which could have ramifications for susceptibility and response to bacterial infections in these patients. Copyright © 2010 Elsevier Inc. All rights reserved.
People on a high-dose regimen of the cholesterol drug Lipitor may have a slightly increased risk of developing type 2 diabetes – particularly if they have several of the classic diabetes risk factors, a study published Monday finds. A number of studies have linked Lipitor (known generically as atorvastatin) and other cholesterol-lowering statin drugs to a small increase in users' risk of diabetes.
This latest study, based on data from three large clinical trials, strengthens evidence of a connection.
Atorvastatin may be immunsuppressing: J Gastroenterol Hepatol. 2012 Aug;27(8):1353-61. doi: 10.1111/j.1440-1746.2012.07123.x. Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. Ajamieh H, Farrell G, Wong HJ, Yu J, Chu E, Chen J, Teoh N. Source Gastroenterology and Hepatology Unit, Australian National University Medical School, the Canberra Hospital, Australian Capital Territory, Canberra, Australia Institute of Digestive Disease and Department of Medicine and Therapeutics, Li KaShing Institute of Health Sciences, Hong Kong, China. Abstract Background and Aim: Steatosis accentuates the severity of hepatic ischemia-reperfusion injury (IRI). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (“statins”) protect the heart and brain against post-ischemic injury, without necessarily lowering serum cholesterol. We tested whether 10-day or 1-day atorvastatin administration protects livers with fatty change or non-alcoholic steatohepatitis (NASH) against IRI. Methods: Mice with dietary or genetic simple steatosis (SS) or NASH were subjected to 60 min of partial hepatic ischemia/24-h reperfusion, with/without atorvastatin administered with food (5 mg/kg body weight) for 10 days, or injected intravenously (5 mg/kg) 24 h before ischemia. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, endothelial nitric oxide synthase (eNOS), activation and thromboxane B2 production were determined. Results: Atorvastatin conferred 70-90% hepatic protection against IRI in obese animals with SS or NASH, in which IRI was accentuated twofold to fivefold. IRI markedly upregulated TLR4 and activated nuclear factor-κB (NF-κB); atorvastatin abrogated these effects, as well as activating eNOS. Atorvastatin dampened the post-ischemic induction of thromboxane B2, macrophage inflammatory protein-1a, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin (IL)-12 p40, γ-interferon, IL-6, and adhesion molecules (vascular cell adhesion molecule-1, E-selectin, vascular endothelial-cadherin), and reduced macrophage and neutrophil recruitment. There was no reduction in serum cholesterol that could explain these effects, and hepatic cholesterol was normal in these mice. A single 24-h injection of atorvastatin conferred equivalent hepatoprotection. Conclusion: Statins exert major hepatoprotection against IRI in lean, fatty, and NASH livers that is not due to cholesterol removal. Rather, statins downregulate TLR4 to prevent NF-κB activation, with resultant suppression of adhesion molecules, chemokines/cytokines, and thromboxane B2 production. Short-term statin treatment is an effective, readily-available preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd. PMID: 22432744