Medical Compass

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It is important to check MMA blood levels and supplement with B12 where needed

I am not a big believer in supplements, unless they are used to treat a proven deficiency. However, we may be deficient in vitamin B12 (cobalamin) without knowing it. Contradictory recommended levels of B12 across the world, the lack of sensitivity in B12 deficiency tests and confusing symptoms all add to the complexity of diagnosing and treating it.
B12 is an integral part of many of the body’s systems. For example, B12 plays a role in proper immune system functioning (www.medscape.com).

What are the symptoms of B12 deficiency?

Symptoms of B12 deficiency include fatigue, diarrhea or constipation, exercise-induced shortness of breath and neurological deficits, such as difficulty concentrating, memory problems and paresthesias (tingling and numbness in the appendages) (Geriatrics. 2003 Mar;58(3):30-4, 37-8). However, these symptoms can mimic many different diseases. Typically, physicians test for B12 and anemia levels when symptoms occur. However, approximately half of those with B12 deficiency are in the “normal” range (Am Fam Physician. 2003 Mar 1;67(5):979-986). To add to the complexity, early B12 deficiency may be asymptomatic.

Minimum blood levels of B12

Unfortunately, there is no worldwide consensus on minimum acceptable B12 levels. Other countries, such as Japan, have significantly higher recommended levels than the United States.

In Japan, minimum recommended blood levels of B12, 500 pg/ml (Jpn. J. Psychiatry Neurol. 1988 Mar:42(1):65–71), are more than twice the minimum acceptable levels in the U.S., 200 pg/ml (www. nlm.nih.gov). There are those who suggest U.S. B12 recommended levels are too low (J Am Geriatr Soc 1996 Oct;44(10):1274–5). If we were to follow Japanese guidelines, we would still be far below the upper limit of the U.S. recommended range.

Diagnostic tests to avoid deficiency

B12 blood levels may not be the most accurate test for determining deficiency (Proc Nutr Soc. 2008 Feb;67(1):75-81). There is a much more specific blood test: methylmalonic acid (MMA). If this level is high, then it is a reliable indicator that B12 levels are low (Subcell Biochem. 2012;56:301-22). Deficient levels of B12 lead to increased MMA levels, since MMA requires B12 to metabolize (Am Fam Physician. 2003 Mar 1;67(5):979-986). Both B12 and MMA levels should be checked.

Who needs to have their levels monitored?

The elderly should be tested regularly, but surprisingly people from young adulthood to middle age can also be affected. The Framingham Offspring Study found that more young adults may be affected than thought previously (Am J Clin Nutr. 2000;71:514-22). Interestingly, those in three different age groups ranging from 26 to 65 years old and older were impacted similarly (Am Fam Physician. 2003 Mar 1;67(5):979-986).

When I attended the Harvard-Brigham and Women’s CME program, we went over a B12 deficiency case in the aptly named “Can’t Miss Diagnoses” seminar. The case involved a 40-year-old woman with symptoms of tingling in her right foot. Her B12 levels were 250 pg/ml — the low end of normal. Three months later, she complained of being tired, having memory problems plus tingling in both feet. Her labs showed no anemia. Five months later, her MMA levels were checked; they were abnormally high. She was given B12 injections and her symptoms diminished.

What causes B12 deficiency?
Sixty to 70 percent of the time, B12 deficiency is caused by absorption issues (CMAJ. 2004;171(3):251–259). Affected populations include those taking medications, such as Glucophage (metformin) and proton pump inhibitors (PPIs); those who have autoimmune diseases, such as pernicious anemia or Crohn’s disease; alcoholism; and those who have had bariatric surgery (www.ncbi.nlm.nih.gov).

PPIs impact

The reason that proton pump inhibitors such as Protonix (pantoprazole), Nexium (esomeprazole) and Prevacid (lansoprazole) reduce B12 absorbed from diet is that acid in the stomach is required to free B12 from protein molecules in food. PPIs reduce this much-needed pepsin (acid). Therefore, those on PPIs should be monitored for B12 deficiency. It can take approximately three years of continuous use before someone becomes deficient (Aliment Pharmacol Ther. 2008 Jun 1;27(11):1110-21).

Treatments

The amount of B12 absorbed is limited. In a dose of 500 mcg of B12, only 10 mcg are actually absorbed (Blood 2008;112:2214-21). Unless patients have significant symptoms, it may be best to give oral B12 supplements to patients who have high MMA levels and/or low “normal” B12 levels.

One recommendation for B12 oral treatment is 1000 to 2000 mcg daily for one week and then 1000 mcg daily for maintenance (JAMA. 1991;265:94–5). For those with significant symptoms, B12 injections may be preferable.

Dietary sources

Foods with the most B12 are fish and seafood, as well as meat and dairy. This means that those who focus on a primarily vegetable-based diet require B12 supplementation.

Don’t wait until symptoms are severe. Have your B12 blood levels and MMA levels checked, regardless of your age. Symptoms, including peripheral neurologic symptoms, are potentially reversible if treated early.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Commonly used medications, both prescription and OTC, may have deleterious effects on vision

When we refer to adverse events with medications, we usually focus on systemic consequences. However, we rarely address the fact that eyes can be adversely affected by medications. There have been several studies recently that illustrate this very important point.

It is vital that we recognize the symptoms of eye distress. Some of these may indicate ophthalmic emergencies. The medications recently studied include common therapeutics, such as bisphosphonates, aspirin, a class of antibiotics called fluoroquinolones and a migraine therapy. I will explain the symptoms to be cognizant of with each.

The impact of bisphosphonates

The class of drugs known as bisphosphonates is the mainstay for the prevention and treatment of osteoporosis. Recent adverse news focused on atypical femur fractures and osteonecrosis (death of part of the jawbone), not on an ocular effect. However, in a large retrospective study (looking at past data), oral bisphosphonates were shown to increase the risk of uveitis and scleritis, both inflammatory eye diseases, by 45 percent and 51 percent respectively (CMAJ. 2012 Apr 2. [Epub ahead of print]). One out of every 1,100 patients treated with the drugs suffered from uveitis, and one out of every 370 patients treated suffered from scleritis.

Why is this important? The consequences of not treating uveitis can lead to complications, such as glaucoma and cataracts. The symptoms of uveitis typically include eye redness, pain, light sensitivity, decreased vision and floaters (www.mayoclinic.org).

For scleritis, the symptoms are severe pain that radiates to the face and around the orbit, with worsening in the evening and morning and with eye movements (www.uptodate.com). Uveitis affects the iris and ciliary body (fluid inside the eye and muscles that help the eye focus), while scleritis affects the sclera, or white part of the eye.

These adverse eye events occurred only in first-time users. The authors believe the mechanism of action may involve the release of inflammatory factors by the bisphosphonates.

Aspirin yet again?

It seems aspirin can never get a break. It has been implicated in gastrointestinal bleeds and hemorrhagic (bleeding) strokes. Now the European Eye Study suggests that aspirin increases the risk of age-related macular degeneration (Ophthalmology. 2012;119:112-118). The primary effect is seen, unfortunately, with wet AMD, which is the form that leads to central vision loss. The risk of wet AMD is directly related to the frequency of aspirin use. When aspirin is used at least once a week, but not daily, the risk is increased by 30 percent. When it is used daily, the risk of wet AMD jumps to 226 percent. Aspirin also increased the risk of early AMD.

This study was large and retrospective in design, and it included fundoscopic (retinal) pictures, making the results more reliable. The authors recommend that AMD patients not use aspirin for primary prevention, meaning without current cardiovascular disease. However, aspirin use for secondary prevention — for those with heart disease or a previous stroke — the benefits of the medication outweigh the risks.

The role of antibiotics: fluoroquinolones in retinal detachment

Fluoroquinolones may have toxic effects on the synthesis of collagen and on connective tissue, potentially resulting in retinal detachments and Achilles tendon rupture. This is a common class of antibiotics used to treat acute diseases, such as urinary tract infections and upper respiratory infections.

In a recent epidemiologic study, these drugs were shown to increase the risk of retinal detachment by 4.5 times (JAMA. 2012;307:1414-1419). Common fluoroquinolones include ciprofloxacin (Cipro), levofloxacin (Levaquin) and gatifloxacin (Tequin).
Although it sounds like an impressive number, it’s not a common occurrence. It takes the treatment of 2,500 patients before one patient is harmed. Also, this was only noticed in current users, not in recent or past users. However, it is a serious condition.

Retinal detachment is an ophthalmic emergency, and patients need to be evaluated by an ophthalmologist urgently to avoid irreparable damage and vision loss. Retinal detachments are treatable with surgery. Best results are seen within 24 hours of symptoms, which include many floaters, bright flashes of light in the periphery and a curtain over the visual field (www.ncbi.nlm.nih.gov). Fortunately, retinal detachments usually only affect one eye.

Migraine medication

Topiramate (Topomax) is a drug used to treat and prevent migraines. In a recent case-control (with disease vs. without disease) study, topiramate increased the risk of glaucoma in current users by 23 percent. The risk more than doubled to 54 percent in first-time users (Am J Ophthalmol. 2012 May;153(5):827-30). The mechanism of action may be related to the fact that topiramate increases the risk of intraocular pressure.

It is important to be aware that medications not only have systemic side effects, but ocular ones as well. Many of these medications cause adverse effects that require consultation with an ophthalmologist. If you have ocular symptoms related to medications, contact your physician immediately.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Rheumatoid arthritis is one of many autoimmune diseases, where the body’s immune system begins to attack the body’s own tissue. RA results in systemic (throughout the body) inflammation which initially affects the synovium (lining) of the small joints in both the hand and the feet bilaterally, as well as the wrists and ankles (www.ncbi.nlm.nih.gov). It causes pain, stiffness and swelling of the joints.

RA, like most autoimmune diseases, affects significantly more women than men (www.mayoclinic.com) and can be incredibly debilitating. It affects approximately 1 percent of the U.S. population (Arthritis Rheum. 2008;58:15-25). Fortunately, treatments have helped to significantly improve sufferers’ quality of life.

RA may be treated initially with acetaminophen and NSAIDs (such as ibuprofen), depending on its severity. To help stop progression and preserve the joints, disease modifying anti-rheumatic drugs (known as DMARDs) may be used. They are considered the gold standard of treatment for RA and include methotrexate, which has been around the longest and is a first-line therapy; plaquenil (hydroxycholorquine); and TNF inhibitors, such as Enbrel (etanercept), Humira (adalimumab) and Remicade (infliximab).

DMARDs work by reducing inflammation and acting as immunosuppressives, basically tamping down or suppressing the immune system. These drugs have helped RA patients improve their quality of life, preserving joint integrity and causing RA to go into remission.

The downside of using immunosuppressive drugs

Unfortunately, DMARDs have significant adverse effects. They include black-box warnings of serious or life-threatening side effects, such as opportunistic infections — more likely in combination with other immunosuppressives — and malignancy.

Anecdotally, I recently had a patient who had previously developed pneumonia twice, multiple basal-cell carcinomas and one episode of melanoma. These were attributed to use of a TNF inhibitor.

Skin cancer risk

In 2009, the FDA warned that there is an increased risk of cancer after about 30 months of treatment, especially with TNF inhibitors. A 2011 meta-analysis (a group of 28 studies) found that TNF inhibitors may increase the risk of cancers, including skin cancers (Ann Rheum Dis. 2011 Nov;70(11):1895-904). In four of the studies, there was a 45 percent elevated risk of developing skin cancer other than melanoma. However, in data pooled from two of the studies, there was a 79 percent greater chance of developing melanoma. All the studies in this analysis were observational studies, and the absolute risk of developing cancer is small. The good news is that this analysis did not appear to show increased risk of lymphoma.

Complications from RA

RA can also affect organs and the surrounding tissue. Thus, complications from RA include heart disease, stroke, atrial fibrillation, chronic obstructive pulmonary disease, fracture risk, as well as uveitis and scleritis (inflammatory disorders of the eye).

Cardiovascular disease

Patients with RA are at a threefold increased risk of developing coronary artery disease, compared to the general population (Ann Rheum Dis. 2007;66(1):70). Those RA patients who stopped taking statins for high cholesterol and/or heart disease, had a 60 percent increased risk of cardiovascular mortality and a 79 percent increased risk of all-cause death after three months (Arthritis Care Res [Hoboken]. 2012 Mar 29). Though statins have their pitfalls, they can be potentially lifesaving in the right context. Don’t discontinue statins before consulting your physician.

Non-pharmacologic approaches

Exercise and fish oil have shown reductions in symptomatology and joint inflammation. In a meta-analysis (a group of 17 trials), omega-3 fish oil reduced joint pain intensity, as reported by patients, minutes of morning stiffness, number of painful joints and NSAID use significantly (Pain. 2007 May;129(1-2):210-23). The dose was at least 2.7 g of EPA plus DHA in the omega-3 fish oil and took at least 12 weeks of treatment to see a benefit.

Exercise is also important to relieve joint pain and stiffness. In a meta-analysis of 14 studies, there was a 69 percent reduction in pain with aerobic exercise (Br J Sports Med. 2011;45(12):1008-1009). Understandably, however, a study found that 42 percent of RA patients don’t work out at the recommended minimum of 10 minutes of moderate exercise daily (Arthritis Care Res [Hoboken]. 2012 Apr;64(4):488-93). The reasons were that half were either not motivated or believed that exercise had no benefit.

Prevention

In the Iowa Women’s Health Study, results showed that supplemental vitamin D decreased the risk of RA by 34 percent (Arthritis Rheum. 2004 Jan;50(1):72-7). This study involved almost 30,000 women followed over an 11-year period.

The best way to treat an autoimmune disease like rheumatoid arthritis is to prevent it with an anti-inflammatory diet, exercise and omega-3 fish oil. Barring that, however, it is encouraging that DMARD treatments may be effective at half the dose once the disease has been suppressed significantly. Therefore, a low-dose pharmacological approach coupled with non-pharmacological lifestyle adjustments may produce the best outcomes with the fewest adverse reactions.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Dehydration is a topic that is often overlooked or is given only cursory thought, but it’s very important. Dehydration is simple to avoid, right? Not necessarily. We may be dehydrated prior to experiencing symptoms of thirst. With summer right around the corner, especially with this year’s above-average temperatures, this seems an appropriate topic. Complications and symptoms of dehydration can be mild to severe, ranging from constipation, mood changes, headaches and heart palpitations to heat stroke, migraines and heart attacks.

Effect on headaches and migraines

Temperature is a potential trigger for headaches and migraine. As the temperature rises by intervals of 9 degrees, the risk for headache and migraines increases by 8 percent (Neurology. 2009 Mar 10;72(10):922-7). This study involved 7,054 participants from one emergency room site. Warmer temperatures can potentially reduce blood volume in the body, causing dilation of the arteries, resulting in higher risk of headaches and migraines.

In another study, those who drank four cups more water had significantly fewer hours of migraine pain than those who drank less (Handb Clin Neurol. 2010;97:161-72). Headache intensity decreased as well. Anecdotally, I had a patient recently who experienced a potentially dehydration-induced migraine after playing sports in the sweltering heat of Florida. He had the classic aura and was treated with hydration, tylenol and caffeine, which helped avoid much of the suffering.

The impact on heart palpitations

Heart palpations are very common and are broadly felt as a racing heart rate, skipped beat, pounding sensation or fluttering. Dehydration and exercise are contributing factors (my.clevelandclinic.org). They occur mainly when we don’t hydrate prior to exercise. All we need to do is drink one glass of water prior to exercise and then drink during exercise to avoid palpitations. Though these are not usually life threatening, they are anxiety producing for patients.

Heart attacks

The Adventist Health Study, an observational study, showed a dose-response curve for men (Am J Epidemiol 2002 May 1; 155:827-33). In other words, group one, which drank more than five glasses of water daily, had the least risk of death from heart disease than group two, which drank more than three glasses of water daily. Those in group three, which drank less than two glasses per day, saw the least amount of benefit, comparatively. For women, there was no difference between groups one and two; both fared better than group three.

The reason for this effect, according to the authors, may relate to blood or plasma viscosity (thickness) and fibrinogen (a substance that helps clots form).

Mood and energy levels

In a recent study, mild dehydration resulted in decreased concentration, subdued mood, fatigue and headaches in women (J. Nutr. February 2012 142: 382-388). In this small study the mean age of participants was 23, and they were neither athletes nor highly sedentary. Dehydration was caused by walking on a treadmill with or without taking a diuretic (water pill) prior to the exercise. The authors concluded that adequate hydration was needed, especially during and after exercise.

I would also suggest, from my practice experience, hydration prior to exercise.

Different ways to remain hydrated

Now we realize we need to stay hydrated, but how do we go about this? How much water we need to drink depends on circumstances, such as diet, activity levels, environment and other factors. It is not true necessarily that we all should be drinking eight glasses of water a day. In a recent review article, the authors analyzed the data, but did not find adequate studies to suggest that eight glasses is supported in the literature (AJP – Regu Physiol. 2002;283:R993-R1004). It may actually be too much for some patients.

You may also get a significant amount of water from the foods in your diet. Nutrient-dense diets, like the Mediterranean or DASH, have a plant-rich focus. A study mentions that diets with a focus on fruits and vegetables increases water consumption (Am J Lifestyle Med. 2011;5(4):316-319). As you may know, 95 percent of their weights are attributed to water. An added benefit is an increased satiety level without eating calorically dense foods.

The myth: Coffee is dehydrating

In a recent review, it was suggested that caffeinated coffee and tea don’t increase the risk of dehydration, even though caffeine is a mild diuretic (Exerc Sport Sci Rev. 2007;35(3):135-140). With moderate amounts of caffeine, the liquid has a more hydrating effect than the diuretic effect.

Thus, it is important to stay hydrated to avoid complications — some are serious, but all are uncomfortable. Diet is a great way to ensure that you get the triple effect of high amount of nutrients, increased hydration and sense of feeling satiated without calorie-dense foods. However, don’t go overboard with water consumption, especially if you have congestive heart failure or open-angle glaucoma (Br J Ophthalmol. 2005:89:1298–1301).

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Alcohol: weighing the risks versus the benefits

There is much confusion over whether alcohol is beneficial or detrimental to your health. The short answer is: It depends on your circumstances, including your family history and consideration of diseases you are at high risk of developing. Alcohol is one of the most widely used over-the-counter drugs.

Several new studies have been published, some touting alcohol’s health benefits with others warning of its risks. The diseases addressed by these studies include breast cancer, heart disease and stroke. It is important that context becomes the determining factor for alcohol intake.

Breast cancer impact

In a meta-analysis (group of 113 studies), there was an increased risk of breast cancer with daily consumption of alcohol (Alcohol and Alcoholism: published online March 29). The increase was a modest but statistically significant 4 percent, and the effect was seen at less than one drink per day. The authors warned that women who are at high risk of breast cancer should not drink alcohol or should drink it only occasionally.

It was also shown in the Nurses’ Health Study (an observational study) that drinking three to six glasses per week increases the risk of breast cancer modestly over a 28-year period (JAMA. 2011;306:1884-1890).

This study involved over 100,000 women. Even a half-glass daily of alcohol was associated with a 15 percent elevated risk of invasive breast cancer. The risk was dose-dependent, with one to two drinks per day increasing risk to 22 percent, while those having more than drinks per day had a 51 percent increased risk.

A drink several times a week may have the least impact on breast cancer, if you are going to consume alcohol. According to an accompanying editorial, alcohol may work by increasing the levels of sex hormones, including estrogen, and we don’t know if stopping diminishes the effect, although it probably does (JAMA. 2011;306(17):1920-1921).

Stroke effects

On the positive side, the Nurses’ Health Study demonstrated a decrease in the risk of both ischemic strokes (caused by clots) and hemorrhagic strokes (caused by bleeding) with low to moderate amounts of alcohol (Stroke: published online March 8). This analysis involved 83,578 women. Those who drank less than 0.5 glasses of alcohol daily were 17 percent less likely than nondrinkers to experience a stroke. Those who consumed 0.5 to 1.5 glasses a day had a 21 percent decreased risk of stroke, compared to nondrinkers.

However, women who consumed more experienced a decline in benefit, and drinking more than three glasses resulted in a nonsignificant increased risk of stroke. The reasons for alcohol’s benefits in stroke have been postulated to involve an anti-platelet effect (preventing clots) and increasing HDL (“good”) cholesterol. Patients shouldn’t drink alcohol solely to get the stroke protection benefits.

Heart effect

In the Health Professionals follow-up study, there was a substantial decrease in the risk of death after a heart attack from any cause, including heart disease, in men who drank moderate amounts of alcohol compared to those who drank more or were nondrinkers (Eur Heart J: published online March 28).

Those who drank less than one glass experienced a 22 percent reduction in risk, while those who drank one to two glasses saw a 34 percent reduction in risk. The authors mention that binge drinking negates any benefits. This study has a high durability spanning 20 years.

Alternative to alcohol for nondrinkers or in addition to alcohol for drinkers

An analysis of the Nurses’ Health Study recently showed that those who consumed more citrus fruits had approximately a 19 percent reduction in the risk of stroke (Stroke: published online Feb. 23). These results were similar to the reduction seen in the Nurses’ Health Study with modest amounts of alcohol.

The citrus fruits used most often in this study were oranges and grapefruits. Of note, grapefruit may interfere with medications such as Plavix (clopidogrel), a commonly used anti-platelet medication to prevent strokes (www.medscape.com). Grapefruit inhibits the CYP3A4 system in the liver, thus increasing the levels of certain medications.

Alcohol in moderation

Moderation is the key with alcohol. It is very important to remember that alcohol is a drug that has side effects, such as insomnia. The American Heart Association recommends that women drink up to one glass a day of alcohol.

I would say that less is more. To get the stroke benefits and avoid the increased breast cancer risk, half a glass of alcohol per day may be the ideal amount.

Moderate amounts of alcohol for men are up to two glasses daily, though one glass showed significant benefits. Remember, there are other ways of reducing your risk of these maladies that don’t require alcohol.

If you like to drink, it doesn’t mean you can’t and you can even garner advantages for your health. However, don’t force yourself to drink.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Should medications be used for primary prevention of disease?

There may be drugs that help prevent disease. As physicians, we want to do what is best and right — and easiest — for our patients. In an ideal world, we could prescribe a pill to drastically reduce the risk of chronic disease. In our zeal, we have to tread cautiously, though, and remember the adage from the Hippocratic Oath: first, do no harm.
More drugs are being evaluated for primary prevention, meaning stopping disease from occurring in the first place. Doesn’t it seem paradoxical that we would give “healthy” people medications? However, there are several recent trials with seemingly impressive results that looked at preventing cancer and its metastases, prostate cancer, high blood pressure, diabetes, strokes and even heart attacks.

Preventing cancer and its metastases

There has been much discussion over the years about using aspirin for the prevention of colorectal cancer. I was at a lecture a month ago where the lecturer said the results were so convincing he might even consider taking aspirin. There are three new studies investigating aspirin’s potential role in cancer and its distant metastases — tumors in other parts of the body.

One of the trials was a meta-analysis (group of 34 trials) of over 69,000 participants that was published in The Lancet online on March 21. The results showed a 15 percent reduction in the risk of deaths from cancer when taking aspirin on a daily basis compared to no aspirin. This means we should all be taking aspirin, right? Not so fast.

This trial had several limitations (The Lancet editorial online, March 21). First, there was a significant risk of bleeding in the first three years of taking the drug, after which time the bleed risk diminished and the cancer benefit continued. Second, these trials were designed for cardiovascular disease, so there was no initial assessment for cancer.

Third, two very large, randomized clinical trials, the Women’s Health Study and the Physicians’ Health Study, were excluded from the analysis, because they gave aspirin every other day. However, neither of these trials showed any cancer reduction benefit. Therefore, in order to benefit, it would seem that people would have to be diligent about taking medication every day, even without symptoms. We all know how well that works.

Another meta-analysis (group of five studies) showed a significant reduction in distant metastases — 36 percent. For those who developed cancer, there was a 70 percent reduction in distant metastases (The Lancet online, March 21). These results are impressive. However, yet again, the analyses were of trials designed for cardiovascular disease, not cancer.

In a third meta-analyses using aspirin, there were conflicting results. Five studies showed a reduction in disease metastases of 31 percent, while seven studies did not show this effect (The Lancet Oncology online, March 21). We may need studies focused on preventing cancer deaths as their primary endpoints in order to make definitive statements about using aspirin in healthy patients.

Prevention of prostate cancer

Avodart (dutasteride) is a drug used for the treatment of enlarged prostate: BPH. In a randomized controlled trial called the REDUCE trial, results showed that Avodart could reduce the risk of prostate cancer by almost 23 percent over four years with healthy men who were at high risk of the disease (N Engl J Med. 2010;363;1192-1202). These positive results were due mainly to a reduction in low-risk benign tumors.

However, beyond the drug’s common side effect of impotence, it also has a twofold increased risk of metastatic prostate cancer. Therefore, the FDA not only rejected the drug for prevention, but also issued a warning about the risk of high-grade prostate cancer risk. These drugs also appear to suppress PSA levels, giving patients a false sense of security.

Prevention of strokes and heart attacks

In last week’s article on the role of statins, I wrote that the JUPITER trial showed statins may be beneficial for primary prevention (N Engl J Med 2008; 359). The FDA approved a statin, Crestor (rosuvastatin) for primary prevention of heart disease in patients without high cholesterol but a slightly elevated inflammatory factor, hsCRP, in February 2010. However, a Cochrane meta-analysis of 14 studies refuted this claim (Cochrane Database Syst Rev 2011; 1: CD004816).

Unfortunately, there is not a panacea. With many, if not all, drugs come side effects. One of the big problems with drugs is that they throw off our bodies’ homeostasis (equilibrium), making them hard to justify for primary prevention. However, we control our own fates, and lifestyle changes play a tremendous role in shaping our futures. All of the diseases mentioned above are impacted substantially by the choices we make every day: our environment, exercise and the food we eat.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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The FDA recently added a warning for memory impairment and diabetes risk

When statins were developed and approved, they were thought to be a drug class with a very clean side-effect profile. They are among the most widely prescribed medications in the U.S. Statins are used to treat high cholesterol and to prevent cardiovascular disease. Under the right circumstances, they can be quite effective. However, their side-effect profile is no longer considered benign or pristine.

The FDA, in a Feb. 28, press release, announced new warnings for statin labels related to memory loss and increased risk of diabetes. The one positive change to the label is that serial blood tests to monitor liver enzymes are no longer required when taking this class of drug (www.fda.gov).

Examples of statins include Lipitor (atorvastatin), Crestor (rosuvastatin), Zocor (simvastatin) and Vytorin (simvastatin/ezetimibe).

The heyday of statins: the JUPITER trial

In the JUPITER trial, which I mentioned in a previous article entitled “High cholesterol: a cautious tale on treatment” (June 23, 2011), it was shown that statins may lower the relative risk of heart attacks by 54 percent and strokes by 48 percent. This trial showed that statins were useful potentially for primary prevention; healthy patients without high cholesterol, but with moderately raised inflammation (high-sensitivity C-reactive protein of greater than 2.0 mg/l), may benefit from statin use (N Engl J Med 2008; 359:2195-2207).

However, controversy brews with statins. There was a meta-analysis (a group of 14 trials with over 34,000 patients) done that disputes the benefit of using statins for primary prevention. The authors concluded that, although statins reduced mortality in this setting, the benefit may not outweigh the risks and cost (Cochrane Database Syst Rev 2011; 1 [CD004816]).

Muscle-ache side effects

Ironically, the reason I wrote my previous article was mainly due to the FDA warning about using high dose simvastatin, 80 mg, and the increased risk of muscle aches and pains, referred to as myopathies (www.fda.gov). It seems that the higher the dose of any of the statins, not just simvastatin, the greater the chances of muscle-related pain (Pharmacotherapy. 2010 Jun;30(6):541-53).

Effects on exercise

It appears now that statins may interfere with exercise. Myopathies affect about 10 percent of the patients; however, that percentage increases to 25 percent of people who regularly exercise. Statins have a detrimental epigenetic effect, which means they affect gene expression, with skeletal muscle. Genes associated with muscle building and repair in the legs were suppressed to some degree in healthy young patients taking statins (Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2560-6).

The authors concluded that statins could potentially cause increased risk of muscle damage during and after exercise. This creates an unusual dynamic, since these results are in stark contrast to the recommendations that all Americans exercise.

The diabetes evidence

The JUPITER trial showed that healthy participants had a 27 percent increased risk of type 2 diabetes from the use of statins (N Engl J Med 2008; 359:2195-2207).
This was reinforced by the Women’s Health Initiative study. The results of this study showed an adjusted 48 percent increased risk of type 2 diabetes in postmenopausal women ages 50 to 79 taking statins (Arch Intern Med. 2012 Jan 23;172(2):144-52). The authors emphasize a need for lifestyle changes. There were 153,000 women in the WHI study. It did not matter which statin was used — it was a class effect.

Mild cognitive impairment data

It appears that statins may be associated with mild cognitive impairment, including memory loss and confusion in patients who are susceptible. In a large case series involving 171 patients, approximately 75 percent of cognitive decline was most likely related to statin use. In this group, 143 patients stopped statins, and 90 percent of them subsequently recorded significant improvements in cognitive functioning. According to the authors, the higher the dose, the more pronounced the memory loss and confusion became (Pharmacotherapy. 2009 Jul;29(7):800-11).

What can be done?

Lifestyle modification may provide significant results in a short time. A patient in my practice, who adopted intensive lifestyle modifications, including increasing fiber, lowered his total cholesterol and his LDL (“bad”) cholesterol dramatically over only two weeks. Increasing fiber has been shown to decrease heart disease through lowering of cholesterol and lowering blood pressure (Curr Atheroscler Rep. 2003 Nov;5(6):500-5).

The good news with the side effects is that they seem to be transient and dose related, meaning the higher the dose, the greater the side effects. After stopping statins, symptoms from side effects seem to dissipate, although time frames for this vary.

In many cases, statins’ benefits still outweigh their side effects. They can be highly effective in treating high cholesterol and preventing heart attacks and strokes. However, lifestyle modifications should either be done in concert with these drugs or as the first line of therapy before statins are initiated.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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The lifetime risk of heart disease can be reduced to less than 1 percent

What if I told you that you could practically eliminate your chances of getting heart disease? I was at a Harvard/Brigham and Women’s Hospital conference last week in Boston where several seminars addressed this very topic. I had to share the good news with you.

The risk of mortality from heart disease has decreased by 30 percent over the last few decades, which is very impressive (www.cdc.gov; www.nhlbi.nih.gov).

However, before we start celebrating, it is still the No. 1 cause of death in the United States; in 2008, heart disease was responsible for one in four deaths (National Center for Health Statistics. 2011).

The seven factors

There are two recent studies that look at the reduction in risk factors for heart disease. If we reduce the seven key modifiable risk factors, the chance of heart disease goes down to about 1 percent. These seven factors are smoking, body mass index (goal BMI of less than 25 kg/m2), physical activity (at least 150 minutes of moderate activity weekly), diet (at least similar to the DASH diet), cholesterol (total cholesterol less than 200 mg/dl without medication), blood pressure (less than 120/80 mmHg without medication) and blood glucose (fasting glucose less than 100 without medication).

So what did the researchers find?

In one recent study, researchers found that we are doing best with smoking cessation (Circulation. 2012;125(1):45-56). The prevalence of nonsmoking ranged from 60 percent to 90 percent, depending on demographics.

On the other hand, healthy diet scores were not very good; from 0.2 percent to 2.6 percent of participants have achieved ideal levels. Obviously, diet is an area that needs attention. This observational study involved 14,515 participants who were at least 20 years old. The authors garnered their results from NHANES data from 2003 through 2008.

How many participants actually reached all seven goals? About 1 percent. This means we have the ability to alter our history of heart disease dramatically. There is a dose-response curve. In other words, there is a direct relationship between the effort you apply to attain these goals and the outcomes of reduced risk.

In the other study, those who had an optimal risk factor profile at age 55 were significantly less likely to die from cardiovascular disease than those who had two or more risk factors. These differences were maintained at least through the age of 80 (N Engl J Med 2012; 366:321-329). The lifetime risk of fatal heart disease or a nonfatal heart attack in the optimal group was less than 1 percent for women and 3.6 percent for men.

In terms of sex differences, men were 10 times less likely and women were 18 times less likely to die from heart disease if they were in the optimal risk-stratification group. This was a meta-analysis (a group of 18 observational studies) with more than 250,000 participants.

Dietary approaches

The good news is that there are several diets that have shown dramatic results in preventing and treating heart disease, such as the Ornish, DASH, Mediterranean-type and Esselstyn diets. These diets all have one thing in common: they rely on nutrient-dense, plant-based foods. As I wrote in my March 1 article, “Heart attacks and women: There is a difference,” both the Ornish and the Esselstyn diets showed reversal of atherosclerosis (JAMA. 1998;280(23):2001-2007; J Fam Pract. 1995;41(6):560-8) and, as we know, atherosclerosis (plaques in the arteries) is the foundation for heart disease.

Exercise affect

For the most beneficial effects on preventing heart disease, both the American College of Sports Medicine and the U.S. Department of Health and Human Services recommend that most Americans get at least 30 minutes of moderate aerobic exercise five times a week, for a total of 150 minutes, or 75 minutes of vigorous aerobic exercise per week (Med Sci Sports Exerc. 2011;43(7):1334-59).

Moderate aerobic exercise includes brisk walking, as demonstrated in the Women’s Health Initiative, a large observational study. This study showed a 28 percent to 53 percent reduction in heart disease risk in women ages 50 to 79 (N Engl J Med 2002; 347:716-725). Resistance training is also very important. The Health Professionals Follow-up Study showed at least 30 minutes a week resulted in a 23 percent risk reduction for heart disease and running for only 60 minutes resulted in a 42 percent risk reduction (JAMA. 2002;288(16):1994-2000).

Interestingly, although medications may be important for people who have high levels of blood pressure, cholesterol and glucose, they do not get you to the goal of achieving lowest-risk stratification. Lifestyle modification is the only way to approach ideal cardiovascular health. Thus, if we worked on these factors to attain the appropriate levels, this disease would no longer be on the top 5 list for highest incidence and mortality rates.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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A heart attack is a heart attack, right? Not necessarily. All heart attacks cause infarction (death of heart tissue/muscle), but in terms of severity and presentation, they vary significantly. There may be gender differences in symptoms between men and women.

Most of us are familiar with the classic sign of a heart attack. It is chest pain, or pressure in the center of your chest. However, many patients experience heart attacks without chest pain. And women tend to have atypical symptoms more frequently than men.

Anecdotally, I have always erred on the side of caution. I was summoned on a plane to help a 52-year-old diabetic female suffering from nausea, sweating, indigestion, fatigue and a weak and inconsistent (thready) pulse. We had to make an emergency landing — the patient was having a heart attack.

In general, those with atypical symptoms, such as these, tend to present later for treatment and are treated less urgently and aggressively, resulting in a twofold increase in hospital mortality versus those with chest pain (JAMA. 2000;283(24):3223–3229).

Gender differences in symptoms and severity

JAMA reports in its Feb. 22-29 issue on an observational study of over one million patients that examined heart attacks which occurred without chest pain as it related to gender, age and mortality (JAMA. 2012;307(8):813-822). Two out of five women having heart attacks did not have chest pain associated, a significantly higher proportion compared to men. This difference was greatest among those women who were younger than 55. The good news is that this difference seems to dissipate with increasing age.

Moreover, there was a 50 percent higher risk of mortality in women than men in the same age group. These atypical symptoms may delay treatment, resulting in women’s higher death rate.

In addition, women who have had a heart attack have a much greater risk of death two years after discharge from the hospital versus men. These results were significant for women less than 60 years old (Ann Intern Med. vol. 134 no. 3 173-181).

Cholesterol impact

There is some good news for women on the heart-attack front. In the Women’s Health Study, HDL (“good” cholesterol) was shown to reduce the risk of heart attacks (Ann Intern Med 2011;155:742). In fact, those patients who had an HDL of less than 40 mg/dl compared to those who had more than 62 mg/dl were at two-times higher risk of a cardiovascular event. This study followed 27,000 women over an 11-year period. Unfortunately, HDL-raising drug therapies do not seem to change the outcomes for women with low HDL.

Aerobic exercise, however, may raise HDL. According to the Mayo Clinic, HDL may rise by 5 percent within two months with 30 minutes per day of vigorous exercise five times a week (www.mayoclinic.com). This includes playing sports, swimming, running or even raking leaves.

Solution: risk reduction

How do we avoid sending patients with indigestion to the emergency room? We don’t want to flood hospitals and waste a finite amount of resources by raising the number of false alarms significantly.

The answer lies in reducing the risk factors. Approximately 90 percent of heart attacks are a result of atherosclerosis (plaques in arteries) that result in the blockage of a coronary artery (www.medscape.com). Dean Ornish, M.D., showed that, with intensive lifestyle modifications, including a plant-based diet, exercise and stress reduction, it is possible to reverse atherosclerosis.

The study showed an 8 percent reversal in the treatment group compared to a 28 percent worsening in the group that followed more common moderate changes (JAMA. 1998;280(23):2001-2007).

Caldwell Esselstyn, M.D., did a small study with patients who had severe coronary artery disease. These patients followed a plant-based diet and did not have a single cardiac event over a 10-year period. They also experienced some reversal in atherosclerosis (J Fam Pract. 1995;41(6):560-8). These patients had a combined 50 cardiac events within the eight years before the study.

Fiber has been shown to decrease the risk of heart attacks. In a meta-analysis (a group of 10 studies), for every 10 gram increase in fiber there was an inverse 14 percent reduction in cardiac events (Arch Intern Med. 2004;164(4):370-376). If we increased the fiber intake daily by threefold to fourfold, we would achieve around a 50 percent reduction in risk. Considering most of us get 8 to 15 grams, it should be easy.

Raising the awareness that patients who are having a heart attack can present without chest pain, especially women, is extremely important in improving mortality. In addition, lifestyle modifications have shown a very powerful effect time and time again in reducing the risk of heart attacks and reversing the cause: atherosclerosis.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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The numbers of patients on proton pump inhibitors has grown precipitously

Last week I wrote that proton pump inhibitors and H2 blockers are two mainstays of medical treatment for gastroesophageal reflux disease. Since GERD affects so many people, these are two of the most widely prescribed classes of medications. Here, I will focus on PPIs, for which more than 113 million prescriptions are written every year in the U.S. (JW Gen Med. Jun. 8, 2011).

PPIs include Nexium (esomeprazole), Prilosec (omeprazole), Protonix (pantoprazole) and Prevacid (lansoprazole) Many come in two forms — over-the-counter and prescription strength. PPIs have demonstrated efficacy for short-term use in the treatment of H. pylori-induced (bacteria overgrowth in the gut) peptic ulcers, GERD symptoms and complication prevention, and gastric ulcer prophylaxis associated with NSAID use (aspirin, ibuprofen, etc.) as well as upper gastrointestinal bleeds.

However, they are often used long-term as maintenance therapy for GERD. PPIs used to be considered to have mild side effects. Unfortunately, recent evidence is showing that this may not be true. Most of the data in the package inserts is based on short-term studies lasting weeks, not years. The landmark study supporting long-term use approval was only one year, not ten years. Maintenance therapy usually continues over multiple years.

The side effects that have occurred after years of use are increased risk of bone fractures and calcium malabsorption; Clostridium difficile, a bacterial infection in the intestines; potential B12 deficiencies and weight gain (World J Gastroenterol. 2009;15(38):4794–4798).

Fracture risks

There has been a debate about whether PPIs contribute to fracture risk. The Nurses’ Health Study, a prospective (forward-looking) study involving approximately 80,000 postmenopausal women, showed a 40 percent overall increased risk of hip fracture in long-term users (more than two years duration) compared to nonusers (BMJ 2012;344:e372). Risk was especially high in women who also smoked or had a history of smoking, with a 50 percent increased risk. Those who never smoked did not experience significant increased fracture risk. The reason for the increased risk may be due partially to malabsorption of calcium, since stomach acid is needed to effectively metabolize calcium.

In the Women’s Health Initiative, a prospective study that followed 130,000 postmenopausal women between the ages of 50 and 79, hip fracture risk did not increase among PPI users, but the risks for wrist, forearm and spine were significantly increased (Arch Intern Med. 2010;170(9):765-771). The study duration was approximately eight years.

Bacterial infection
The FDA warned that patients who use PPIs may be at increased risk of a bacterial infection called C. difficile. This is a serious infection that occurs in the intestines and requires treatment with antibiotics. Unfortunately, it only responds to a few antibiotics and that number is dwindling.

In the FDA’s meta-analysis, 23 of 28 studies showed increased risk of infection. Patients need to contact their physicians if they develop diarrhea when taking PPIs and the diarrhea doesn’t improve (www.FDA.gov/safety/medwatch/safetyinformation). In one study, there was a 96 percent increased risk of C. difficile with PPIs, compared to a 40 percent increased risk with H2 blockers (Am J Gastroenterol. 2007;102(9):2047-2056).

B12 deficiencies

Suppressing hydrochloric acid produced in the stomach may result in malabsorption issues if turned off for long periods of time. In a study where PPIs were associated with B12 malabsorption, it usually took at least three years duration to cause this effect. B12 was not absorbed properly from food, but the PPIs did not affect B12 levels from supplementation (Linus Pauling Institute; lpi.oregonstate.edu). Therefore, if you are taking a PPI chronically, it is worth getting your B12 and methylmalonic acid (a metabolite of B12) levels checked and discussing possible supplementation with your physician if you have a deficiency (Aliment Pharmacol Ther. 2000;14(6):651-668).

Package insert of the PPIs

Interestingly, the package inserts of PPIs recommend the lowest dose possible for maintenance therapy. While prescription PPIs warn that fractures of the wrist, back and hip may occur, suggesting that it may be appropriate to use vitamin D and calcium supplementation to reduce fracture risk, OTC PPIs are not required to include the fracture risk warning.

The problem with PPIs is that patients taking the medications for more than a year are mostly unwitting participants in long-term, anecdotal, postmarketing study on efficacy and tolerability.

My recommendations would be to use PPIs for the short term, except with careful monitoring by your physician.  If you choose medications for GERD management, H2 blockers might be a better choice, since they only partially block acid. Lifestyle modifications may also be appropriate in some of the disorders, with or without PPIs. Consult your physician before stopping PPIs since there may be rebound hyperacidity (high acid produced) if they are stopped abruptly.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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