Statins and other anti-cholesterol drugs

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 receptorsIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affect transcription., 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:

• cholestyramine (Questran) – Part of another treatment protocol, cholestyramine is touted to relieve symptoms supposedly caused by the release of toxins as the Lyme spirochete is killed. However, cholestyramine is known to interfere with the action of tetracycline, an antibiotic in the same class – the tetracycline family of antibiotics – used by many of the MP antibiotics.
• gemfibrozil (Lopid, Gemcor)
• Omacor
• pantethine
• red yeast rice (monascus purpureus)

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 receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. 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 vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory., 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:

• increased incidence of lupus and pneumonia¹⁵⁾ – Note the similarity between “statin-induced lupus” and “minocycline-induced lupus.”¹⁶⁾
• dyspnea (pain while breathing) – Those with pulmonary involvement such as sarcoidosis patients sometimes confuse their disease symptoms with the side effects of statins.
• muscle pain^{17) 18)}
• renal dysfunction — Statins appear to be able to cause proteinuria through tubular inhibition of active transport of small molecular weight proteins.^{19) 20)}
• tendon complications²¹⁾
• cognitive dysfunctionThe loss of intellectual functions such as reasoning; memory loss; and other neurological abilities that is severe enough to interfere with daily functioning. – A 2008 survey of statin patients found that 75% experienced cognitive dysfunction determined to be probably or definitely related to statin therapy. Of 143 patients who reported stopping statin therapy, 90% reported improvement in cognitive problems, sometimes within days of statin discontinuation with a median time to recovery of 2.5 weeks. In some patients, a diagnosis of dementia or Alzheimer's disease reportedly was reversed. Severity of cognitive problems were clearly related to statin potency.²²⁾
• fatigue – Almost half of participants in a 2012 study reported a significant increase in fatigue while taking statins.²³⁾

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.

However, olmesartan has several advantages over the statins including a superior safety profile,²⁶⁾ demonstrated ability to decrease plaque formation,²⁷⁾ and renoprotective properties.²⁸⁾

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:

• prenisolone (Prednisone) and steroid inhalers
• Methotrexate and Imuran
• antimalarials such as Cloroquin and Plaquenil
• thyroid preparations

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-DThe vitamin D metabolite widely (and erroneously) considered best indicator of vitamin D "deficiency." Inactivates the Vitamin D Nuclear Receptor. Produced by hydroxylation of vitamin D3 in the liver. below 20 ng/mL and elevated risk for cardiovascular disease either 50,000 IU of vitamin D3Form of vitamin D made in the skin when exposed to light. Also available in fish and meat. This secosteroid is sometimes converted into 25-D. Also known as cholecalciferol and activated 7-dehydrocholesterol. 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.

Kaitlyn, MarshallProtocol.com

• Bad News For Statins Is Good News – blog post explaining how evidence does not support the use of statins in patients without cardiovascular disease
• Jeff Cable:Adverse Events of Statins