Dear Friends and Patients: 

In the March 2012 Newsletter I completed the “Top 5 Foods to Avoid” series and also began a series on oxidation and reduction reactions, and aging. I discussed the importance of methylation and glutathione for health, detoxification, and slowing down the aging process. In this issue of our Newsletter I will be sharing how the active forms of vitamin B12 and folate fit in with methylation reactions and glutathione, and why active forms of these vitamins are necessary. But first let’s turn our attention to the new FDA (Food and Drug Administration) warnings on statin drugs that came out in February 2012. 

I first read about Dr. Duane Graveline, a former NASA astronaut and flight surgeon, in a 2008 Discover magazine. I’d like to share that story with you. In 1999 he was found to have an elevated cholesterol on a lab test. He had no heart disease, and like many Americans, his physician prescribed Lipitor to lower his cholesterol level. In just 6 weeks after he began taking this drug, his active and healthy life came crashing down. He lost his memory. His wife rushed him to the hospital, where doctors could find no medical or psychiatric problem, and his brain scan showed no sign of stroke or brain disorder. Just as quickly as his memory disappeared, it came back. Doctors termed the strange episode transient global amnesia or TGA. The cause – unknown. 

Dr. Graveline wondered if the memory loss was related to the new statin drug he was taking and for the next year he decided to leave it in the bottle. When his annual astronaut’s physical came around, he was told that his cholesterol had crept up again and his doctor urged him to go back on Lipitor. He did, and within 10 weeks he suffered an even more severe episode of amnesia. His wife found him wandering around, outside their home, unaware he was a physician and unaware of who she was. That episode also resolved without treatment other than stopping the Lipitor he was on. Dr.Graveline decided never to take statins again. Although Graveline’s case was certainly unusual, what if he had an episode while he was driving his car? Or if a pilot developed TGA during a flight? 


New Safety Warnings for Statin Drugs Issued by the Food and Drug Administration


The Food and Drug Administration added new safety warnings to cholesterol-reducing statin drugs earlier this year, noting increased risks of Type 2 diabetes and memory loss for patients who take the medications. The changes to the prescribing information apply to many popularly prescribed drugs such as Lipitor (atorvastatin), Crestor (rosuvastatin), Zocor (simvastatin) and Vytorin (simvastatin/ezetimibe). The new warnings are based on results from the latest clinical trials and reports of adverse events from patients, physicians and drugmakers. 

The FDA said that statins may increase users’ risk of brain-related effects like memory loss and confusion. The reports have generally not been serious, however, and the symptoms go away once the drug is stopped, the agency said. Statins’ labels will now also warn patients and doctors that the drugs may cause a small increase in blood sugar levels and risk of Type 2 diabetes — an effect that has been shown previously in studies. Type 2 diabetes can further increase the risk of heart disease. 

In addition, the FDA made a label change specific to Mevacor (lovastatin). Mevacor can interact with other drugs, increasing the risk for muscle pain and weakness, another side effect that has previously been associated with high-dose statin use. Other drugs may raise such risks by increasing the amount of statins in the blood, and the FDA warned that Mevacor should not be taken with protease inhibitors, which are used to treat HIV, certain antibiotics and some anti-fungal medications. 


Who Should Take Statins?


Despite the new safety warnings, the FDA said patients should not be scared off statins. “The value of statins in preventing heart disease has been clearly established,” said Dr. Amy G. Egan, deputy director for safety in the FDA’s division of metabolism and endocrinology products, in an agency statement. “Their benefit is indisputable, but they need to be taken with care and knowledge of their side effects.” I and other physicians, including Stephen Sinatra, M.D. (cardiologist), feel the benefit of statins is limited. 

In the 1970s, when I was a medical student and resident physician, a normal cholesterol was 240mg/mL or below. This changed in 1993 where the new guidelines were revised downward to 200mg/mL by a committee of nine doctors, eight of whom were receiving money from statin drug companies. Even a 2006 article in the Annals of Internal Medicine argued that there was no evidence to support this target or the mainstream medical belief that lower cholesterol levels are always better. 

John Abramson, M.D. is a Harvard trained physician and author of the book Overdosed America. He has spent many years in clinical practice as well as years in researching the whole cholesterol story. His research has shown that there is not a single randomized control trial that shows cholesterol-lowering statin drugs are beneficial for women of any age or men over 65 who do not already have heart disease or diabetes. Diet and exercise are far more important risk factors in the development of heart disease. Statin drugs are not a substitute. 


Determining Risks vs. Benefits


Cholesterol plays an important role in brain function and cases like Dr. Graveline’s raise questions about exactly how statins can affect memory. The brain contains more cholesterol than any other organ in the body and has to produce its own cholesterol or it won’t function properly. Cholesterol is required by neurons to form synapses (connections) with other cells. A decrease in cholesterol could affect how nerves function for behavior, memory, data processing, pain and even motor activity. Research by Yeon-Kyun Shin, a biophysics professor in the department of biochemistry, biophysics and molecular biology at the University of Iowa has studied statin drugs and brain function. What his research suggests is that these drugs not only inhibit cholesterol production by the liver but also by the brain. His research also suggests that cholesterol-lowering drugs also affect neurotransmitter release from brain cells. 

What if the potential benefits of statins may not outweight their risks. The only way to weigh risks vs. benefits is to evaluate all-cause morbidity (sickness) and all-cause mortality (death). However, statin drug studies were not designed to look at all-cause mortality. They were designed to look at cholesterol levels, heart attacks or death from coronary causes. 

Getting back to Dr. Abramson’s research, he found the statin data showed only in a small fraction of the people taking the drugs could statins reduce heart attacks and strokes. Doctors give statins in one of two ways. The first way is to give the drugs to people with elevated cholesterol as primary prevention – to prevent a heart attack, stroke or other serious cardiovascular event. These are people who have never suffered an event. Over 75% of statin prescriptions are written for this reason. As I stated earlier, Dr. Abramson found that there were no studies that showed statins were beneficial for primary prevention for women of any age or men over age 65. The other way to give statins is as secondary prevention, after people have had a heart attack or stroke, or develop diabetes. Dr. Abramson found that even when statins are used for men at the highest risk, “you have to treat about 238 men for one year to prevent one heart attack. . .” These findings were published by Dr. Abramson in the prestigious British medical journal The Lancet. Another way of stating this conclusion is if you are a man and are at very high risk for developing heart disease, there are 237 out of 238 chances taking a statin won’t benefit you. 

One of the reasons doctors overlook risks and believe statins to be safe is that most controlled studies of statins wind up excluding people who originally began to participate in a study but stopped taking the drug due to side effects. These test participants are then dropped from the study as “non-complaint.” By excluding these group test participants, the evidence is then wrongly interpreted as absence of harm. 

“You can lower cholesterol levels with a drug, yet provide no health benefits whatsoever . . . And dying with corrected cholesterol is not a successful outcome.”


The other problem with the statin studies, according to Abramson, is they measure outcomes that are associated with the disease, but not the disease itself. If a drug reduces cholesterol it is said to be “effective.” But lowering cholesterol doesn’t mean the drug will reduce a bad outcome such as death or heart attack. An example of this is the non-statin drug ezetimibe (Zetia) which is contained in Vytorin. The drug, while lowering cholesterol effectively, failed to slow the progression of carotid artery plaque formation. Another study was the ASCOT study, which looked at 10,000 people with hypertension and three other risk factors for heart disease. The study put half on Lipitor and half on a placebo. There was around a 36% decrease in the risk of heart disease in the people on Lipitor. The problem was there was not a statistically significant reduction in overall mortality, which is the key factor or outcome. A second problem with the study was there were 2000 women, 1000 of whom were put on Lipitor and developed 10% more heart attacks than the women who were put on placebo. In spite of these findings, the FDA allowed the drug companies to change their labels to say that Lipitor does prevent heart attacks, when, in fact, there was no evidence. Dr. Abramson sums things up – “You can lower cholesterol levels with a drug, yet provide no health benefits whatsoever . . . And dying with corrected cholesterol is not a successful outcome.” 


How Often is ‘Medical Fact’ not So?


John Ioannidis, an epidemiologist at Tufts University School of Medicine in Boston and also on the faculty of the University of Ioannina School of Medicine in Greece wanted to determine how often today’s medical breakthroughs become tomorrow’s discredited science. He examined the most-cited clinical studies in the top three medical journals over a ten year period from 1990 to 2000 and what he found were nearly 1/3 of the original research claims were either false or exaggerated. Ioannidis found that design flaws, small study size, failure to publish negative results, and drug-industry influence were among the problems that caused the false or exaggerated claims. Jerome Hoffman, M.D., a professor of medicine and emergency medicine at UCLA was also alarmed at how often medical fact is later found to be erroneous. He teaches a course to medical students and residents on how to interpret the medical literature. Hoffman states the truth in any drug study can be camouflaged by how it is reported. For example, a cholesterol lowering drug can be tested for its effect on cholesterol level, blood pressure, and/or rates of heart failure, heart attack or death. By combining two or more of these outcomes to create a single category, you can say it helped “A and B” even if it helped only A and not B. Another way to make drugs look better and safer is to report only successful studies while ignoring those with bad outcomes. Erick Turner, a former FDA reviewer, published research in the NEJM (New England Journal of Medicine) showing that “when studies of antidepressants were negative, they were reported as negative only 8% of the time, but when studies were positive, they were reported as positive 97% of the time.” Another problem in analyzing drug studies is that they are usually carried out for a short period of time, and only after a drug is in use in the general population for a longer period of time, drug side effects become more apparent. When I see a patient at the Center who comes into my practice on multiple medications, my “alert antennae” go up that some of their symptoms may be drug side effects rather than disease symptoms, especially in elderly patients whose metabolisms are different. 


Summary


Memory loss, confusion, and diabetes are now risks recognized by the FDA in patients using statin drugs. Dr. 
Abramson and others have reviewed the medical research data on statin drugs and have determined they should not be used in women of any age and are of limited benefit in men under the age of 65 who are at high risk for heart disease but do not yet have it. 

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Continued from the March 2012 Newsletter – Oxidation/Reduction, Methylation and Glutathione
And How Vitamin B12 and Folate Fit In


Glutathione is needed to convert inactive forms of vitamin B12 into the active forms. The active form of vitamin B12 is methylcobalamine. The active form of folate is methylfolate. Both are essential to the methylation process. Most B12 vitamin preparations contain cyanocobalamine, which is not active and is less useful than the active form for treating deficiency states. Some people have a genetic defect that doesn’t allow them to fully convert cyanocobalamine into methycobalamine. This is why at the Center we use a pharmaceutically compounded methylcobalamine for B12 shots, rather than the commercial cyanocobalamine. We also use oral supplements that contain 5 methyl-tetrahydrafolate. I should point out that we ourselves cannot make vitamin B12. Bacteria make if for us and since vegetables do not carry those bacteria, vegans can be deficient for B12. Also, as we age we can have more difficulty absorbing B12 from foods that contain vitamin B12 such as meat, fish, poultry, and eggs. 

Methyl B12 is constantly recycled by the body. It donates its methyl group to homocysteine, which then turns into another amino acid, methionine. Once B12 is missing its methyl group, it needs to get a fresh one, and that’s where methylfolate comes in. When your level of methyl B12 is low, homocysteine builds up and this can cause heart disease and hardening of the arteries. Elevated homocysteine levels are also found in Alzheimer’s disease. Homocysteine levels are measured by a simple lab test. 

Inflammation of the nerves is a complication of diabetes called diabetic neuropathy. It is a very painful condition. In a 2011 study reported in the Review of Neurological Diseases, patients with diabetic neuropathy were given a mixture of methyl B12, methylfolate, and the active form of vitamin B6 (pyridoxal-5’-phosphate). Tissue biopsies were taken before and after treatment with these vitamins. 73% of diabetic patients showed improvement on their biopsies and 82% reported reduced frequency and intensity of pain and numbness using this vitamin therapy. 

Another study reported that patients with major depression responded to methylfolate in combination with antidepressants. In this 2011 study only 16.3% of patients responded to antidepressants alone while 40% with the combined therapy experienced major improvements. In a 2009 study at Harvard Medical School, methylfolate by itself helped in reducing depression both in patients with low and normal folate levels. It also helped in elderly patients with dementia. This may be because folate is a necessary co-factor in the production of three neurotransmitters — serotonin, dopamine and epinephrine. Methyl B12 and methylfolate may help some children with autism. In a 2009 research study of 40 autistic children treated with methylcobalamine and folinic acid, there were significant increases in cysteine and glutathione after three months. Low levels of folate are also associated with anemia, heart disease, fetal abnormalities such as spina bifida, neuropathies and ADHD. 


Summary


Aging can be described as a process of gradual oxidation. Reducing the effects of free radical damage and oxidative stress is critical for health. The glutathione antioxidant system is a common target for so many different environmental toxins and infections and adequate glutathione levels keep us healthy by flushing out toxins and by boosting our immune function. The two B vitamins, folate and B12, are also essential in keeping a healthy oxidation-reduction balance. The body must be able to convert these two vitamins into the active forms so the body can methylate when needed and can make more glutathione when needed. Some of the functions of folate and B12 are production of DNA and RNA, protection against DNA mutations that might lead to cancer, prevention of anemia, protection against neuropathy, heart disease, depression, and high homocysteine. 

[Again, I would like to give credit to articles published in the October 2011 Focus Newsletter of Allergy Research Group for some of the data presented in this section.] 

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Patient Success Story – I.V. Glutathione Therapy Relieving Fatigue and Headache


Mr. H. is a 65 year old man who was being treated by me for general health and also osteoporosis. In 2009 he was found to be severely osteopenic (bordering on osteoporosis) in his lumbar spine and hip following a bone density study ordered by his primary care physician. After a complete evaluation for underlying causes of bone loss was completed, a bone building program of chelated calcium and minerals, vitamin D, strontium and vitamin K2 was initiated with return to normal density of his lumbar spine within 2 years. In addition to the supplements I prescribed, he was taking dozens of other supplements on his own. At his last visit he complained of fatigue, lethargy, and a low grade generalized headache that had been present for the previous 1-2 months. His physical exam was unremarkable including his neurological exam but the kinesthetic testing of his acupuncture points showed liver meridian stress. I felt his symptoms were compatible with a detoxification reaction. He was given an I.V. with Glutathione and B vitamins. He was also placed on Phosphatidylcholine and he was taken off all other supplements for 2 weeks. Within 1 day his fatigue, malaise, and headache resolved and he was back to his normal healthy self. His kinesthetic testing also returned to negative reflexes. 

At times we see patients come in taking multiple supplements. If a person is healthy, the excess supplements are removed by the liver and kidneys. Sometimes too much of a good thing can cause symptoms. I suggested Mr. H. continue on the bone health supplements that I had prescribed, but to reduce his many other supplements to a multivitamin/multimineral and omega-3 oil supplement only. 

Another patient recently treated with IV Glutathione and B vitamins was Ms. M. She is a 60 year old lady who has multiple medical problems, including hypertension and D.M. Type II. Ms. M had been under a great deal of stress for about a year, having gone through a divorce, but the preceding 3 months were especially bad for her. She recently had a bout of food poisoning and just felt “off.” She found herself awakening at 1:30 – 2:00AM most nights. In the Chinese acupuncture system this early morning time corresponds to the liver meridian. I suspected she was having a detoxification reaction. Ms. M received an IV with Glutathione and B vitamins, and in the middle of the IV felt dramatically better with no further malaise and improved mood. She was scheduled to see me the following week but elected to receive one more treatment prior to her office visit.