The Questionability of the Use of Statins to Lower Cholesterol Marian Laderoute, PhD Medical Sciences- IMMUNOLOGY Lab Director – Immune System Management.

The Questionability of the Use of Statins to Lower Cholesterol

Marian Laderoute, PhD Medical Sciences-IMMUNOLOGY

Lab Director – Immune System Management

Clinic & Lab – Ottawa

November 4, 2014

Outline1. Introduction

2. The origins of the high cholesterol hypothesis

3. What are statins?

4. What are arguments against the notion that high cholesterol causes atherosclerosis in humans?

5. What are the medical and naturopathic views on the use of statins?

6. What are the side-effects of statins?

7. A role of foamy macrophages in atherosclerosis.

8. What causes foamy macrophages in humans and how does this relate to atherosclerosis?

9. The Cortisol/DHEA index and how it affects health as you age.

10. Statins and Cancer Risks including Lymphomas

11. Summary

It remains a common misconception that high cholesterol causes atherosclerosis as shown

here from the Heart and Stroke Foundation.

Heart & Stroke Foundation Website 2014

Opinion Statement (MPL):Elevated blood cholesterol might be a marker of stress, chronic inflammation (chronic infections) and/or insufficient flavonoids (and/or other nutrients in the diet), and is not necessarily a direct cause of atherosclerosis in humans.

Statins do lower cholesterol but the benefits for prevention of cardiovascular events appear to relate moreso to the anti-inflammatory effects of statins.

The longer term adverse effects of using a strongly immunosuppressive statin for 5-10 years or more on all cause mortality have not been adequately addressed. Trials or epidemiological studies under 5 years are insufficient to address the true safety of immunosuppressive agents.

http://www.spokesman.com/stories/2010/sep/28/japan-study-high-ldl-has-lower-death-rate-than/

Dr. Tomohito Hamazaki, a professor at Toyama University’s Institute of Natural Medicine, who compiled the new cholesterol level guidelines for the Japan Society for Lipid Nutrition said “When examining all causes of death, such as cancer, pneumonia and heart disease, the number of deaths attributable to LDL cholesterol levels exceeding 140 mg/dl is less than people with lower LDL cholesterol levels.”

Where did the notion that high LDL cholesterol causes atherosclerosis

come from?

The Lipid Hypothesis of Rudolph Virchow

1856

“Father of modern pathology” Rudolph Virchow

In autopsies noted the fatty streaks in arteries of persons who died from heart attacks and that there were lipid-laden “foam cells”. Postulated high fat/cholesterol diets promote heart attacks by closing off arteries.

… but he did not have access to Electron Microscopy (1939 was the commercial launch of EM).

Seven Countries Study: 1963Showed correlation of increased fat intake and heart disease by country.

… but apparently he had data from 22 countries and “cherry-picked” those 7 countries with the best correlations. … but we know that 80 to 90 % of the serum cholesterol is made in the liver and that oral intake does not significantly affect levels.

Ancel Keys

1984: National Institute of Health held a consensus conference.

“It has been established beyond a reasonable doubt that lowering elevated blood cholesterol levels (specifically, blood levels of low-density lipoprotein (LDL) cholesterol) will reduce the risk of heart attacks caused by coronary heart disease...”

[However, how does this impact longevity or all cause mortality? And how did these studies distinguish the lipid lowering effects of statins

from their anti-inflammatory properties?]

Animal Models have shown LDL and oxLDL to Increase Atherosclerosis Risks

[ But why might this not be translated to the human situation?]

So what are statins?

Statins inhibit HMG-CoA reductase

http://en.wikipedia.org/wiki/Statin

An early enzyme in the cholesterol pathway in the liver needed to make cholesterolAnd are used to lower

cholesterol levels (LCL-C)

These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), pitavastatin (Livalo), and simvastatin (Zocor).

Red yeast rice extract, one of the fungal sources from which the statins were discovered, contains several naturally occurring cholesterol-lowering molecules known as monacolins. The most active of these is monacolin K, or lovastatin (previously sold under the trade name Mevacor, and now available as generic lovastatin).

http://en.wikipedia.org/wiki/HMG-CoA_reductase

Arguments against high cholesterol causing atherosclerosis

1. Statins (which reduce LDL-C cholesterol) do not reduce blood pressure Sacks, FM et al, NEJM 2001, 344:3-10

2. Statins do not change all cause mortality rates in hospitalized patients with acute coronary syndrome Vale N et al, Cochrane Review: Statins for Acute Coronary Syndrome. 2011 http: summaries.cochrane.org

3. According to a 2011 Cochrane Review (but interestingly changed in an updated review in 2013), statins do not reduce the cardiovascular risks of patients without cardiovascular risk factors.

4. 75 % of people suffering heart attacks do not have high (LDL) cholesterol Sacheva A et al, American Heart Journal 2009, 157:111-117.

Arguments against high cholesterol causing atherosclerosis

(cont’d)5. People with genetic high cholesterol (heterozygotes) do not

suffer heart attacks throughout their entire lives.

6. There is clearly an age component in the cause of atherosclerosis.

7. Why do heart attacks peak with flu season (ie. February) but cholesterol levels are not seasonal? See http://www.aminomics.com/professionals/HERVK.htm, “Why is February Heart Month?”

8. Statins and anti-platelet drugs only prevent 30-40 % of major cardiovascular events. (Maranhao RC and Leite AC, 2014)

9. Other cholesterol-lowering medications do not block heart attacks, only statins do (Fuch FD et al, 2012).

10. Jupiter trial for the prevention of CVD was based on statins blocking inflammation and not the reduction of high LDL-c levels.

(Ridker PM et al, NEJM 2008.)

A major role of inflammation in atherosclerosis is now widely accepted.

Inflammation drives atherosclerosis.

Libby, Peter, Arterioscler Thromb Vasc Biol 2012, 32:2045-2051. [Harvard Medical School, Division of Cardiovascular Medicine.]

Two Camps of Medical Opinion in Canadafor Reduction of Cardio-Vascular Risks (CVR)

[7.5 millon Canadians have HBP]

Pro-statin Anti-Statin Test blood pressure properly

and frequently

Reduce high blood pressure through natural means such as stop smoking, loose weight, avoid or minimize stress, keep sugar balanced, avoid toxins, etc.

When unsuccessful, try drugs to lower blood pressure

• Canadian Heart and Stroke Foundation

• Canadian Cardiovascular Society

• American College of Cardiology

• American Heart Association

• Hypertension Canada (non-profit, all volunteers)

• Public Health Agency of Canada

Various lay books on the Statin Controversy have been published

Side effects of Statinsmuscle and nerve damage, increased diabetes risks, immunosuppression, etc.

The nerve damaging effects of statins are also well documented. Memory and cognitive loss, neuropathy, anemia, cataracts, sexual dysfunction, liver dysfunction, fatigue, immune system weaknesses and mental depression side effects have often been reported. If you suffer from cancer and use statins, it’s time to rethink that statin prescription. - See more at: http://vitalitymagazine.com/article/challenging-the-statin-drug-dogma/#sthash.XTQMstVw.dpuf

All statins work primarily by blocking an enzyme (HMG CoA reductase) in the liver that helps manufacture cholesterol. Unfortunately, this is the same enzyme the body uses to manufacture coenzyme Q10, the most important antioxidant for the cardiovascular system. Consequently, coenzyme Q10 tissue levels are lowered by statins and numerous side effects occur. - See more at: http://vitalitymagazine.com/article/challenging-the-statin-drug-dogma/#sthash.XTQMstVw.dpuf

Nor was it known that statins are powerful anti-inflammatory agents*, the fundamental reason for their benefit in cardiovascular risk.

* STRONG IMMUNOSUPPRESSANTS

What do we know about the cause of high blood pressure and cardiovascular disease risks?

What is known, is that atherosclerosis (hardening of arteries)

initiates with foamy macrophages

From: Lo J & Plutzky J. J Inf Diseases 2012; 205:S368-74.

Foamy Macrophage (FM)

…does high cholesterol turn monocytes into foamy macrophages?

From: AstraZeneca 2007 Video on:

“How your cholesterol clogs your arteries. “

LDL-C

Induces foamy macrophages?

And if this was true, people with genetically high cholesterol would have foamy macrophages all the time, which they don’t.

… there is NO evidence that cholesterol can induce foamy macrophages in humans (in vitro attempts have failed,Hughes DA et al, 1992).

Human Macrophages Undergo Spontaneous Foam Cell Formation Without the Need for Lipid or TLR Signaling

In murine systems and as tested in human monocytic leukemic cell lines, foam cell formation requires oxLDL and/or Toll Like Receptor (TLR) signaling,

but in humans oxLDL is not needed to stimulate foamy macrophage formation.

Keyel PA et al, Coordinate stimulation of macrophages by microparticles and TLR ligands induces foam cell formation. J. Immunol, 2012 189:4621.

And foamy macrophages are also associated with tumors and viral infections where a role of high

cholesterol seems less obvious

Foamy Macrophages in Lymph Nodes Adjacent to Tumor

Foamy Macrophages in Brain with Re-activated John Cunningham Virus (JCV)

From: Vaklavas C et al, Virol J 2010, 7:256.

So what causes foamy macrophages in humans?

Electron Microscopy of Foamy Virus Particles in Foamy Macrophages in CB later identified as HERV-K102 * Laderoute M et al, AIDS, 2007.

We* discovered that a cause of foamy macrophage in humans appears to be the induction of endogenous foamy retrovirus particles identified as HERV-K102.

Culture of CB in IMDM Media instead of RPMI

Human Endogenous Retrovirus – K102

HERV-K102 Is unique to humans and not found in any other animal species including closely related monkeys (ie. is not found in chimpanzees or great apes).

This is why animal modeling fails to address or predict outcomes for therapeutics of major chronic diseases of humans, such as cardiovascular diseases.

HERV-K102 particle production appears to be a potent host protection mechanism in humans, against viruses, other intracellular pathogens and tumors.

So in humans, foamy macrophages are caused by the induction of an endogenous foamy virus in response to infections, tumors, toxins, etc.. , and cholesterol is used to support the formation of the vacuoles and the virus particles, both of which involve lipid bilayers. Hence, these cells producing HERV-K102 particles have high cholesterol content.

Whether you induce this protective response or not has nothing to do with elevated cholesterol.

Endogenous Foamy Virus Theory of Foamy Macrophage Accumulation in

Atherosclerosis: 2014*

Marian Laderoute

Presented at the October 2014 Hypertension

Congress in Gatineau

Role of HERV-K102 Particles in Health or Atherosclerosis:

Immunosuppression

and Aminomics Therapy to rebalance your amino acid profile which rebalances your immune system and metabolism and allows a) the release of HERV-K102 particles andb) promotes the ability of particle to undergo lytic infection in transformed cells

Working Hypothesis

Foamy macrophages

Flavonoids and Reduction of Cardiovascular Disease Risks

1. Flavonoids reduce cardiovascular deaths. Yochum L et al, Am J Epi 1999, 149:943-949.

2. Flavonoids protect against cardiovascular disease. Reviewed by Bhardwaj P et al, 2013.

3. Flavonoids normalizes the Cortisol/DHEA ratio. Bouic P & Lamprecht J, Alternative Medicine Review 1999, 4: 170-177.

4. Flavonoids rebalance immunoreactivity favoring Th1 over Th2 associated with a decline in IL-6 (marker of inflammation). Bouic P & Lamprecht J, Alternative Medicine Review 1999, 4: 170-177.

5. Flavonoids and taurine diminish foam cell formation. Uitz E et al, World Journal of Clinical Cases 2014 2:497-506.

Why does immunosuppression and inflammation increase with aging?

And how does this relate to chronic disease risks such as

cardiovascular disease?

So why is hardening of the arteries more common with aging?

DHEA (the youth hormone) diminishes with advancing age [it is immune balancing, counteracts cortisol/stress, and counteracts alpha-fetoprotein (AFP) ]

Immunosuppression and inflammation are more common with advancing age (loss of DHEA, dominance of stress/cortisol, plus cortisol also directly induces AFP)

CVD risks increase with age but also tumors, infections, certain autoimmune diseases (RA, T2D) and chronic diseases in general

Alpha-fetoprotein (AFP)

First immunosuppressive factor discovered (1975), and first tumor marker discovered (1962)

Affects immunity through the 67 kD alpha-fetoprotein receptor on monocytes/macrophages (discovered by Laderoute et al in 1986)

Very difficult to work with pure active AFP as it easily denatures, but in 1986 Laderoute MP et al made novel AFP agonists (MAB) to the 67 kD AFP receptor which mimic binding of AFP to its receptor

These agonists were used to confirm the immunosuppressive effects of AFP on the immune system and also used by Laderoute et al to show that AFP also blocks cell death induction (apoptosis) in macrophages 1991, 1993, 1994

DHEA but not the inactive DHEA-S binds to and inactivates AFP, suggesting as you age, there may be more and more active AFP in your system

“

”

Statins and Cancer RisksControversial as to whether there is a net overall

benefit in cancer prevention or not.

No high quality evidence yet to support whether or not statins are generally detrimental to

outcomes following a cancer diagnosis.

What you need to know

in order to make sense of the literature

Patient or Statistical Manipulation and Clinical Significance

1. Clinical significance is only clear when >20 % of the tested population shows favorable outcomes (due to placebo effect possibly generating a difference of 15% or more). Ex antibiotics, insulin and CSA for kidney transplantation.

2. Must be very careful when using relative ratios versus absolute values. When test has a favourable response (2/200) versus control (1/200) this will look like a 2.0 fold improvement if n is large enough, but in fact the benefit is only for 1/200 people treated. Therefore not clinically significant/relevant.

3. Be wary of clinical trials which do not follow randomized patients for least 5-10 years, for any drug to be used for the longer term. Otherwise cannot judge safety.

4. All clinical trials have contraindications to eliminate complicated patients. Testing healthy persons who are generally younger will underpower the ability to detect adverse side-effects.

5. Frequently there are age and sex differences- was this addressed in the analyses?

6. Most important, is the “risk of all cause death” ANALYSIS after 5-10 years. If this is not addressed then the overall safety of the drug cannot be properly assessed.

Meta-Analysis of Statin Use in Elderly, Short Term

8 trials with 24,674 subjects (42.7 % females, mean age 73 +/-2.9 years, mean follow-up 3.5 +/- 1.5 years)

Risk of MI: RR= 0.61 (CI 0.43 - 0.85)

Risk of Stroke: RR=0.76 (CI 0.63 – 0.93)

Risk of new onset cancer: RR=0.99 (CI 0.85 – 1.15) Not significant

Risk of CV Death: RR= 0.91 (CI 0.69 – 1.20) Not significant

Risk of all cause Death: RR=0.94 (CI 0.86 – 1.04) Not significant

Savarese G et al, Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol 2013 62:2090-9.

The initiation of cancers fall into either (rarely) or both categories (most cancers).

1. Chronic wounding model where DNA damage is caused by reactive oxygen species from the immune system attacking a toxin and/or microbe. Example; Hep B or C associated liver cancer.

2. Non-chronic wounding model where DNA damage is caused by ionizing radiation or other carcinogen exposure. Example; breast cancer.

AGE> 65

Increased Cortisol/DHEA ratio

1. Inflammation Associated Diseases (high cortisol)

2. Immunosuppression Associated Diseases (low DHEA)

Anti-inflammatories:

HELP

HINDER

(increased LDL cholesterol due to stress)

From: Shi M et al, Statin use and risk of liver cancer: an update meta-analysis. BMJ Open 2014 16:e005399.

1. Liver Cancer Initiation

The Relative Risk of a diagnoses of liver cancer among all statin users was reduced compared with controls (RR=0.58, CI 0.51 to 0.67) in this meta-analysis involving 22 randomized trials (35,756 liver cancers).

2. Invasive Breast Cancer Initiation:

From: McDougall JA et al, Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age. Cancer Epidemiol Biomarkers Prev 2013 22: 1529-37.

Risks of invasive breast cancer diagnosis for statin use

longer than 10 years Total With

Hypercholesterolemia

Invasive Ductal Ca 1.83 (CI 1.14-2.93) 2.04 (CI 1.17-3.57)

Invasive Lobular Ca 1.97 (CI 1.25-3.12) 2.43 (CI 1.40-4.21)

Statin Use and Lymphoma DiagnosisLymphomas can be associated with chronic viral infections. In these cases, inflammation can play an important role in carcinogenesis (ie., DNA damage can occur due to ROS liberated by the immune system). Here, statins could block inflammation and thus, could be shown to prevent virus-associated lymphomas.

Otherwise, non-virus associated lymphomas would be like most cancers, where it is reactive oxygen species (inflammation) combined with immunosuppression which may lead to its initiation.

Therefore one would expect weak protection or no net difference on incidence of lymphoma with statin use.

However, this does not address survival (all cause mortality) in lymphoma patients who continue to take statins.

Statin Use and Lymphomas

Both immunosuppression and chronic inflammation associated with HIV infection are implicated in the pathogenesis of HIV-related NHL [6–8].

Statin use is also linked to reduced inflammation [29], which is a pathogenic mechanism of HIV-related NHL.

This paper concludes a reduction in risk of diagnosis of HIV-associated NHL was not statistically significant. Outcome was not reported.

The associations between statins use and risk of lymphoma in the general population are mixed, although current evidence seems to be more consistent with a reduced risk in statin users [35]. However, a systemic review concluded that the quality of this evidence is weak at best [35].

HIV patients are at a much higher risk of NHL and have more aggressive lymphoma.

From: Chao C et al . HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons. AIDS 2011 25:E328349.

Summary Cholesterol deposits and foamy cells have been found in artery plaques

since the mid 1850’s, but a causal association of LDL-c levels with atherosclerosis in humans has not been shown.

A new theory on the cause of atherosclerosis pertains to the induction of a foamy protector virus (found endogenous only in humans) where in immunosuppressed hosts, these foamy macrophages instead accumulate and contribute to atherosclerosis, rather than host protection against tumors and viruses.

(Laderoute MP, 2014)

Reversal and/or prevention of atherosclerosis can be mediated by flavonoids (given orally or such as by juicing) along with other strategies such as: i) reducing: toxic exposures, stress, immunosuppression (by various means

including Aminomics), and

ii) making dietary and lifestyle changes, etc.

Statins are known to block important metabolic pathways, are strongly immunosuppressive, and are associated with serious side-effects.

The true safety of long term use of statins has not been established.

Marian Laderoute, Ph.D. Medical Sciences -ImmunologyLab Director

Immune System Management Clinic & Lab

80 Aberdeen Street, Ottawa, On

Tel: (613) 656-0983

Email: [email protected]

Website: www.aminomics.com