Showing posts with label vitamins. Show all posts
Showing posts with label vitamins. Show all posts

Tuesday, May 29, 2018

Most popular vitamin and mineral supplements provide no health benefit, study finds

Most popular vitamin and mineral supplements provide no health benefit, study finds
May 28, 2018, St. Michael's Hospital 

The most commonly consumed vitamin and mineral supplements provide no consistent health benefit or harm, suggests a new study led by researchers at St. Michael's Hospital and the University of Toronto

Published today in the Journal of the American College of Cardiology, the systematic review of existing data and single randomized control trials published in English from January 2012 to October 2017 found that multivitamins, vitamin D, calcium and vitamin C—the most common supplements—showed no advantage or added risk in the prevention of cardiovascular disease, heart attack, stroke or premature death. Generally, vitamin and mineral supplements are taken to add to nutrients that are found in food.

"We were surprised to find so few positive effects of the most common supplements that people consume," said Dr. David Jenkins, the study's lead author. "Our review found that if you want to use multivitamins, vitamin D, calcium or vitamin C, it does no harm—but there is no apparent advantage either."

The study found folic acid alone and B-vitamins with folic acid may reduce cardiovascular disease and stroke. Meanwhile, niacin and antioxidants showed a very small effect that might signify an increased risk of death from any cause.

"These findings suggest that people should be conscious of the supplements they're taking and ensure they're applicable to the specific vitamin or mineral deficiencies they have been advised of by their healthcare provider," Dr. Jenkins said.

His team reviewed supplement data that included A, B1, B2, B3 (niacin), B6, B9 (folic acid), C, D and E; and β-carotene; calcium; iron; zinc; magnesium; and selenium. The term 'multivitamin' in this review was used to describe supplements that include most vitamins and minerals, rather than a select few.

"In the absence of significant positive data—apart from folic acid's potential reduction in the risk of stroke and heart disease—it's most beneficial to rely on a healthy diet to get your fill of vitamins and minerals," Dr. Jenkins said. "So far, no research on supplements has shown us anything better than healthy servings of less processed plant foods including vegetables, fruits and nuts." 

Journal of the American College of Cardiology

Friday, April 6, 2018

Older Americans Are Hooked On Vitamins Despite Scarce Evidence They Work

Older Americans Are Hooked On Vitamins Despite Scarce Evidence They Work
By Liz Szabo April 4, 2018
When she was a young physician, Dr. Martha Gulati noticed that many of her mentors were prescribing vitamin E and folic acid to patients. Preliminary studies in the early 1990s had linked both supplements to a lower risk of heart disease.

She urged her father to pop the pills as well: “Dad, you should be on these vitamins, because every cardiologist is taking them or putting their patients on [them],” recalled Gulati, now chief of cardiology for the University of Arizona College of Medicine-Phoenix.

But just a few years later, she found herself reversing course, after rigorous clinical trials found neither vitamin E nor folic acid supplements did anything to protect the heart. Even worse, studies linked high-dose vitamin E to a higher risk of heart failure, prostate cancer and death from any cause.

“‘You might want to stop taking [these],’” Gulati told her father.

More than half of Americans take vitamin supplements, including 68 percent of those age 65 and older, according to a 2013 Gallup poll. Among older adults, 29 percent take four or more supplements of any kind, according to a Journal of Nutrition study published in 2017.

Often, preliminary studies fuel irrational exuberance about a promising dietary supplement, leading millions of people to buy in to the trend. Many never stop. They continue even though more rigorous studies — which can take many years to complete — almost never find that vitamins prevent disease, and in some cases cause harm.

“The enthusiasm does tend to outpace the evidence,” said Dr. JoAnn Manson, chief of preventive medicine at Boston’s Brigham and Women’s Hospital.

There’s no conclusive evidence that dietary supplements prevent chronic disease in the average American, Manson said. And while a handful of vitamin and mineral studies have had positive results, those findings haven’t been strong enough to recommend supplements to the general U.S. public, she said.

The National Institutes of Health has spent more than $2.4 billion since 1999 studying vitamins and minerals. Yet for “all the research we’ve done, we don’t have much to show for it,” said Dr. Barnett Kramer, director of cancer prevention at the National Cancer Institute.

In Search Of The Magic Bullet
A big part of the problem, Kramer said, could be that much nutrition research has been based on faulty assumptions, including the notion that people need more vitamins and minerals than a typical diet provides; that megadoses are always safe; and that scientists can boil down the benefits of vegetables like broccoli into a daily pill.

Vitamin-rich foods can cure diseases related to vitamin deficiency. Oranges and limes were famously shown to prevent scurvy in vitamin-deprived 18th-century sailors. And research has long shown that populations that eat a lot of fruits and vegetables tend to be healthier than others.

But when researchers tried to deliver the key ingredients of a healthy diet in a capsule, Kramer said, those efforts nearly always failed.

It’s possible that the chemicals in the fruits and vegetables on your plate work together in ways that scientists don’t fully understand — and which can’t be replicated in a tablet, said Marjorie McCullough, strategic director of nutritional epidemiology for the American Cancer Society.

More important, perhaps, is that most Americans get plenty of the essentials, anyway. Although the Western diet has a lot of problems — too much sodium, sugar, saturated fat and calories, in general — it’s not short on vitamins, said Alice Lichtenstein, a professor at the Friedman School of Nutrition Science and Policy at Tufts University.

And although there are more than 90,000 dietary supplements from which to choose, federal health agencies and advisers still recommend that Americans meet their nutritional needs with food, especially fruits and vegetables.

Also, American food is highly fortified — with vitamin D in milk, iodine in salt, B vitamins in flour, even calcium in some brands of orange juice.

Without even realizing it, someone who eats a typical lunch or breakfast “is essentially eating a multivitamin,” said journalist Catherine Price, author of “Vitamania: How Vitamins Revolutionized the Way We Think About Food.”

That can make studying vitamins even more complicated, Price said. Researchers may have trouble finding a true control group, with no exposure to supplemental vitamins. If everyone in a study is consuming fortified food, vitamins may appear less effective.

The body naturally regulates the levels of many nutrients, such as vitamin C and many B vitamins, Kramer said, by excreting what it doesn’t need in urine. He added: “It’s hard to avoid getting the full range of vitamins.”

Not all experts agree. Dr. Walter Willett, a professor at the Harvard T.H. Chan School of Public Health, says it’s reasonable to take a daily multivitamin “for insurance.” Willett said that clinical trials underestimate supplements’ true benefits because they aren’t long enough, often lasting five to 10 years. It could take decades to notice a lower rate of cancer or heart disease in vitamin takers, he said.

Vitamin Users Start Out Healthier
For Charlsa Bentley, 67, keeping up with the latest nutrition research can be frustrating. She stopped taking calcium, for example, after studies found it doesn’t protect against bone fractures. Additional studies suggest that calcium supplements increase the risk of kidney stones and heart disease.

“I faithfully chewed those calcium supplements, and then a study said they didn’t do any good at all,” said Bentley, from Austin, Texas. “It’s hard to know what’s effective and what’s not.”

Bentley still takes five supplements a day: a multivitamin to prevent dry eyes, magnesium to prevent cramps while exercising, red yeast rice to prevent diabetes, coenzyme Q10 for overall health and vitamin D based on her doctor’s recommendation.

Like many people who take dietary supplements, Bentley also exercises regularly — playing tennis three to four times a week — and watches what she eats.

People who take vitamins tend to be healthier, wealthier and better educated than those who don’t, Kramer said. They are probably less likely to succumb to heart disease or cancer, whether they take supplements or not. That can skew research results, making vitamin pills seem more effective than they really are.

Faulty Assumptions
Preliminary findings can also lead researchers to the wrong conclusions.

For example, scientists have long observed that people with high levels of an amino acid called homocysteine are more likely to have heart attacks. Because folic acid can lower homocysteine levels, researchers once hoped that folic acid supplements would prevent heart attacks and strokes.

In a series of clinical trials, folic acid pills lowered homocysteine levels but had no overall benefit for heart disease, Lichtenstein said.

Studies of fish oil also may have led researchers astray.

When studies of large populations showed that people who eat lots of seafood had fewer heart attacks, many assumed that the benefits came from the omega-3 fatty acids in fish oil, Lichtenstein said.

Rigorous studies have failed to show that fish oil supplements prevent heart attacks. A clinical trial of fish oil pills and vitamin D, whose results are expected to be released within the year, may provide clearer questions about whether they prevent disease.

But it’s possible the benefits of sardines and salmon have nothing to do with fish oil, Lichtenstein said. People who have fish for dinner may be healthier due to what they don’t eat, such as meatloaf and cheeseburgers.

“Eating fish is probably a good thing, but we haven’t been able to show that taking fish oil [supplements] does anything for you,” said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic Foundation.

Too Much Of A Good Thing?
Taking megadoses of vitamins and minerals, using amounts that people could never consume through food alone, could be even more problematic.

“There’s something appealing about taking a natural product, even if you’re taking it in a way that is totally unnatural,” Price said.

Early studies, for example, suggested that beta carotene, a substance found in carrots, might help prevent cancer.

In the tiny amounts provided by fruits and vegetables, beta carotene and similar substances appear to protect the body from a process called oxidation, which damages healthy cells, said Dr. Edgar Miller, a professor of medicine at Johns Hopkins School of Medicine.

Experts were shocked when two large, well-designed studies in the 1990s found that beta carotene pills actually increased lung cancer rates. Likewise, a clinical trial published in 2011 found that vitamin E, also an antioxidant, increased the risk of prostate cancer in men by 17 percent. Such studies reminded researchers that oxidation isn’t all bad; it helps kill bacteria and malignant cells, wiping them out before they can grow into tumors, Miller said.

“Vitamins are not inert,” said Dr. Eric Klein, a prostate cancer expert at the Cleveland Clinic who led the vitamin E study. “They are biologically active agents. We have to think of them in the same way as drugs. If you take too high a dose of them, they cause side effects.”

Gulati, the physician in Phoenix, said her early experience with recommending supplements to her father taught her to be more cautious. She said she’s waiting for the results of large studies — such as the trial of fish oil and vitamin D — to guide her advice on vitamins and supplements.

“We should be responsible physicians,” she said, “and wait for the data.”

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Saturday, September 21, 2013

Johns Hopkins - Vitamin and mineral supplements and mortality

PodMed is a weekly podcast from Johns Hopkins Medicine. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, and Rick Lange, MD, professor of medicine at Johns Hopkins and vice chairman of medicine at the University of Texas Health Science Center at San Antonio, look at the top medical stories of the week.

This week's topics include the benefits of colorectal cancer screening, use of braces for scoliosis, vitamin and mineral supplements and mortality, and the salt debate.

Source - MedPage Today

Friday, August 9, 2013

Is There a Role for Vitamins in Cancer Prevention?

Heather Greenlee ND, PhD
Assistant Professor of Epidemiology
Mailman School of Public Health
Columbia University Medical Center
New York, NY

Is There a Role for Vitamins in Cancer Prevention?

August 9, 2013

Posted in: Cancer, Public Health

According to recent national surveys, approximately 40 percent of U.S. adults take multivitamins/multiminerals; many also take calcium, folic acid, vitamin D, and other specific vitamin and mineral supplements.

People take dietary supplements for multiple reasons: to prevent diseases, manage diseases, extend life, and promote general health. Some take supplements with the goal of preventing cancer occurrence or recurrence and of prolonging life after a cancer diagnosis.

The question that people want answered is: Do these supplements work?

Historically, there has always been a quest to find an elixir or “magic bullet” that will stave off disease and promote long life, and in times when nutrient deficiencies were common, vitamin supplementation may have been a valuable public health strategy. However, now that the U.S. food supply is largely fortified with folic acid, iodine, niacin, and vitamin D, this rationale may be less appropriate.

If some of these supplements are effective, which ones are they? What is the appropriate/ necessary dose? And how long must you take the vitamin to see an effect?

Unfortunately, for vitamin/mineral proponents, if we look at data from human studies, we see limited support for the use of vitamins/minerals to broadly prevent cancer.
No Clear Benefit, Some Evidence of Harm

Numerous observational studies (studies in which the study participants were not asked to change their behavior) and clinical trials have shown limited or no benefits from supplemental vitamins and minerals.

In the past, these results provided sufficient evidence to say that at least the supplements were not harmful, even if they provided no specific benefit. However, more recent reports have suggested that some forms of vitamins and minerals may be harmful.

Investigators from the Iowa Women’s Health Study, an observational study of more than 38,000 older women, found that several commonly used vitamin and mineral supplements (multivitamins, vitamin B6, folic acid, iron, magnesium, zinc, and copper) were associated with increased total mortality. This was surprising, as there was little prior evidence suggesting harm.

Our group recently reported on data from the observational Life After Cancer Epidemiology (LACE) study, which suggested that among women with breast cancer who were primarily recruited at Kaiser-Permanente of Northern California, the use of dietary supplements with carotenoids may increase overall mortality, whereas the use of other forms of antioxidants (vitamin C, vitamin E) may be associated with a protective effect (though this may not be real and could be explained by the “healthy user” bias). The most important implication of these results was that different types of antioxidant supplements may have effects.

None of these results stands on its own; all of them need to be replicated in other studies. We must interpret study results and infer causation in light of other data. If, for example, we look at the literature on the use of carotenoid supplements for cancer prevention, we see that there are other trials that have shown harm and that few, if any, have shown any benefit related to cancer prevention.
No Magic Bullet

Clinical trials are our gold standard for testing agents of interest. The SELECT trial was a randomized controlled trial of vitamin E and selenium for prostate cancer prevention among healthy men. While neither supplement prevented prostate cancer, the results suggested that vitamin E increased the risk of prostate cancer.

The most recent vitamin trial to receive attention was the Physicians’ Health Study II, a randomized controlled trial that included more than 14,000 male U.S. physicians 50 years or older. The men were randomized to take either a daily multivitamin or a placebo. The study found that for men taking the multivitamin, there was an 8 percent reduction in total cancer incidence, excluding nonmelanoma skin cancer.

However, there was no difference in overall deaths between the two groups. These results raise the question: From the public health perspective, if multivitamin use decreased cancer incidence but did not decrease overall deaths, what would be the benefit to encourage men to take multivitamins?

These studies are just a few among the many observational and clinical trials that have failed to reveal the magic bullet that will prevent cancer and extend life among the general population. The studies also show the potential for harm with these agents. Additional ongoing studies of supplemental vitamin D, fish oils, and other agents will reveal whether they would be beneficial on the population level.
Focus on Diet, Exercise, Not Supplements

A current approach to cancer prevention trials is to ask whether specific populations may benefit from dietary supplements. For example, vitamin D may be of benefit to individuals with low levels of vitamin D due to darker skin pigmentation or low sun exposure. From a global perspective, individuals with environmental exposures, such as arsenic in groundwater wells in Bangladesh, may benefit from folic acid supplementation to decrease the carcinogenic effects of arsenic. But such supplementation is beneficial to targeted populations—not broadly applicable to all people.

Where does that leave us? Both the American Cancer Society (ACS) and the American Institute for Cancer Research (AICR) clearly state in their clinical guidelines that current evidence does not support the use of any dietary supplements for primary cancer prevention or for the prevention of cancer recurrence.

What should we do? Until we have evidence to suggest otherwise, we can follow the other cancer prevention recommendations from both the ACS and AICR. 1) Eat a diet rich in vegetables and fruits, high in whole grains, and low in processed and energy-dense foods; if your diet is nutritionally balanced, you probably don’t need a multivitamin. 2) Be physically active every day. 3) Maintain a lean body.

If you do feel compelled to take dietary supplements, understand what you are taking, why you think it may be beneficial, and what risks may be involved. Finally, understand that a supplement should never be viewed as a sole means of cancer prevention.

This article originally appeared in NewYork-Presbyterian Hospital’s Cancer Prevention Newsletter.

Monday, August 5, 2013

Should You Take Dietary Supplements?

Should You Take Dietary Supplements?

A Look at Vitamins, Minerals, Botanicals and More

When you reach for that bottle of vitamin C or fish oil pills, you might wonder how well they’ll work and if they’re safe. The first thing to ask yourself is whether you need them in the first place.

More than half of all Americans take one or more dietary supplements daily or on occasion. Supplements are available without a prescription and usually come in pill, powder or liquid form. Common supplements include vitamins, minerals and herbal products, also known as botanicals.

People take these supplements to make sure they get enough essential nutrients and to maintain or improve their health. But not everyone needs to take supplements.

“It’s possible to get all of the nutrients you need by eating a variety of healthy foods, so you don’t have to take one,” says Carol Haggans, a registered dietitian and consultant to NIH. “But supplements can be useful for filling in gaps in your diet.” 

Some supplements may have side effects, especially if taken before surgery or with other medicines. Supplements can also cause problems if you have certain health conditions. And the effects of many supplements haven’t been tested in children, pregnant women and other groups. So talk with your health care provider if you’re thinking about taking dietary supplements.

“You should discuss with your doctor what supplements you’re taking so your care can be integrated and managed,” advises Dr. Craig Hopp, an expert in botanicals research at NIH.

Dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as foods, not as drugs. The label may claim certain health benefits. But unlike medicines, supplements can’t claim to cure, treat or prevent a disease.

“There’s little evidence that any supplement can reverse the course of any chronic disease,” says Hopp. “Don’t take supplements with that expectation.”

Evidence does suggest that some supplements can enhance health in different ways. The most popular nutrient supplements are multivitamins, calcium and vitamins B, C and D. Calcium supports bone health, and vitamin D helps the body absorb calcium. Vitamins C and E are antioxidants—molecules that prevent cell damage and help to maintain health.

Women need iron during pregnancy, and breastfed infants need vitamin D. Folic acid—400 micrograms daily, whether from supplements or fortified food—is important for all women of childbearing age.

Vitamin B12 keeps nerve and blood cells healthy. “Vitamin B12 mostly comes from meat, fish and dairy foods, so vegans may consider taking a supplement to be sure to get enough of it,” Haggans says.

Research suggests that fish oil can promote heart health. Of the supplements not derived from vitamins and minerals, Hopp says, “fish oil probably has the most scientific evidence to support its use.”

The health effects of some other common supplements need more study. These include glucosamine (for joint pain) and herbal supplements such as echinacea (immune health) and flaxseed oil (digestion).

Many supplements have mild effects with few risks. But use caution. Vitamin K, for example, will reduce the ability of blood thinners to work. Ginkgo can increase blood thinning. The herb St. John’s wort is sometimes used to ease depression, anxiety or nerve pain, but it can also speed the breakdown of many drugs—such as antidepressants and birth control pills—and make them less effective.

Just because a supplement is promoted as “natural” doesn’t necessarily mean it’s safe. The herbs comfrey and kava, for example, can seriously damage the liver.

“It’s important to know the chemical makeup, how it’s prepared, and how it works in the body—especially for herbs, but also for nutrients,” says Haggans. “Talk to a health care provider for advice on whether you need a supplement in the first place, the dose and possible interactions with medicine you’re already taking.”

For vitamins and minerals, check the % Daily Value (DV) for each nutrient to make sure you’re not getting too much. “It’s important to consider the DV and upper limit,” says Haggans. Too much of certain supplements can be harmful.

Scientists still have much to learn even about common vitamins. One recent study found unexpected evidence about vitamin E. Earlier research suggested that men who took vitamin E supplements might have a lower risk of developing prostate cancer. “But much to our surprise, a large NIH-funded clinical trial of more than 29,000 men found that taking supplements of vitamin E actually raised—not reduced—their risk of this disease,” says Dr. Paul M. Coates, director of NIH’s Office of Dietary Supplements. That’s why it’s important to conduct clinical studies of supplements to confirm their effects.

Because supplements are regulated as foods, not as drugs, the FDA doesn’t evaluate the quality of supplements or assess their effects on the body. If a product is found to be unsafe after it reaches the market, the FDA can restrict or ban its use.

Manufacturers are also responsible for the product’s purity, and they must accurately list ingredients and their amounts. But there’s no regulatory agency that makes sure that labels match what’s in the bottles. You risk getting less, or sometimes more, of the listed ingredients. All of the ingredients may not even be listed.

A few independent organizations conduct quality tests of supplements and offer seals of approval. This doesn’t guarantee the product works or is safe; it just assures the product was properly made and contains the listed ingredients.

“Products sold nationally in the stores and online where you usually shop should be fine,” Coates says. “According to the FDA, supplement products most likely to be contaminated with pharmaceutical ingredients are herbal remedies promoted for weight loss and for sexual or athletic performance enhancement.”

To make it easy to find reliable information, NIH has fact sheets on dietary supplements at NIH also recently launched an online Dietary Supplement Label Database at This free database lets you look up the ingredients of thousands of dietary supplements. It includes information from the label on dosage, health claims and cautions.

For more personalized, on-the-go information about dietary supplements, check out NIH’s free updated app for your smart phone or tablet: My Dietary Supplements (MyDS). You can access it at

The MyDS app provides the latest supplement information and lets you keep track of the vitamins, minerals, herbs and other products you take. You can even keep track of supplements taken by your parents, spouse or children.

“Deciding whether to take dietary supplements and which ones to take is a serious matter,” says Coates. “Learn about their potential benefits and any risks they may pose first. Speak to your health care providers about products of interest and decide together what might be best for you to take, if anything, for your overall health.”

Source -
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Tuesday, July 23, 2013

A Scientist Debunks The 'Magic' Of Vitamins And Supplements

A Scientist Debunks The 'Magic' Of Vitamins And Supplements

by Jonathan Hamilton
July 23, 2013 6:26 AM

A pediatrician who spent years defending childhood vaccines against the likes of actress/activist Jenny McCarthy has launched an assault on megavitamins and dietary supplements.
"If you take large quantities of vitamin A, vitamin E, beta carotene [or] selenium you increase your risk of cancer, risk of heart disease, and you could shorten your life," says Dr. Paul Offit, a researcher at The Children's Hospital of Philadelphia.
One big problem with dietary supplements is a 1994 law that exempts them from the tighter scrutiny the FDA applies to its regulation of medicines, Offit says. So the makers of a garlic supplement can say that it "supports cardiovascular health" even though a government study found that garlic supplements didn't lower cholesterol. Meanwhile, Offit says, patients clearly benefit from a range of FDA-approved statin drugs that actually do what garlic supplements claim to do.

Read the story here.........

Friday, February 8, 2013

Vitamins? The Magic Bullet Against Hepatitis C

Vitamins? The Magic Bullet Against Hepatitis C
Hans L Tillmann
Expert Rev Anti Infect Ther. 2012;10(11):1273-1277.

Evaluation of: Rocco A, Compare D, Coccoli P et al. Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus.

Gut doi:10.1136/gutjnl-2012-302344 (Epub ahead of print) (2012).

Vitamin B12 was first mentioned to have a role in HCV treatment approximately a decade ago, but it has not been well translated into clinical medicine. Recently, however, a randomized trial has reported significantly better response at all time-points during therapy with pegylated interferon plus ribavirin, if such therapy was combined with vitamin B12. This correlates with reports on vitamin B12 being able to inhibit HCV in vitro and a report that vitamin B12 levels were related to treatment response. If further validated, vitamin B12 is another vitamin reported to be beneficial for HCV therapy. Vitamin D had repeatedly been reported to be associated with response to HCV therapy. It will be interesting to see whether vitamins such as B12 and D will remain relevant in the light of direct antivirals.

Vitamin B12 was reported to inhibit HCV via internal ribosome entry-site inhibition in the early 2000s,[1–3] but the findings were never confirmed nor rejected by anyone other than the group who published the initial reports. The first and so far only published clinical evaluation of vitamin B12 levels in patients concerning clinically relevant outcome was reported by Swedish investigators in 2011,[4] who described that patients achieving an end of treatment response (ETR) had significantly higher baseline vitamin B12 levels (331 pM in ETR vs 260 pM in nonresponders; p = 0.012) and that ETR was achieved in 25 out of 26 patients (96.2%; 95% CI: 81–99%) with vitamin B12 levels >360, versus 50 out of 73 patients (68.5%; 95% CI: 57–78%) with lower levels. For sustained viral response (SVR), the difference, however, was no longer significantly different (17 out of 26 [65%] vs 38 out of 73 [52%]; p = 0.26).

Prior to that publication on baseline vitamin B12 levels to predict antiviral response, a group in Italy initiated a placebo-controlled study in 2006, to evaluate whether supplemental vitamin B dosing would increase response over 'standard of care' (SOC) for HCV, which consisted of pegylated interferon (Peg-IFN) and ribavirin at that time. The study's report will be reviewed here.

Ninety four patients were randomly assigned to Peg-IFN and ribavirin or Peg-IFN and ribavirin plus vitamin B12 5 mg (Dobetin®, Angelini, Rome, Italy) intramuscular (im.) every 4 weeks for the duration of antiviral therapy. Two different Peg-IFNs were used interchangeably, although they are not interchangeable in practice. Interferon was dosed at 180 µg/week for Peg-IFN-α2a and 1.5 µg/kg/week for Peg-IFN-α2b, which is the standard dosing. Ribavirin was used at 800–1200 mg daily.

HCV genotypes were determined and viral loads were assessed by standard assays. Stratification was only performed for HCV genotypes 1 and 4 (although there was actually no genotype 4 patient included) versus 2 and 3, with only a few genotype 3 patients included. HCV RNA was determined using the reverse transcriptase (RT)-PCR, Roche COBAS® AMPLICOR® 2.0 assay (Roche Diagnostics, Basel, Switzerland), which has been reported to have a limit of detection of about 50 IU/ml.[5]

The study included 94 patients; 130 were screened but 36 were excluded owing to previous treatment (n = 21), HBV coinfection (n = 3), heavy alcohol consumption (n = 3), declined antiviral therapy (n = 3), severe depression (n = 2), poorly controlled diabetes (n = 2), plan for pregnancy (n = 1) and known hepatocellular carcinoma (n = 1).

There were two genotype 1a patients, 62 genotype 1b patients, 26 genotype 2 and four genotype 3 patients, with each group of genotypes evenly distributed between the two arms: one, 31, 13 and two patients, respectively. In addition, other patient characteristics were not significantly different between treatment arms such as fibrosis stage, grade of steatosis, age, gender and BMI, as well as IL28B polymorphisms for those where such information was available.

Overall rapid viral response (RVR) defined as HCV RNA <50 IU/ml at week 4 was achieved in 49% of SOC and 68% of those treated with vitamin B12 supplementation 5 g im. 4-weekly. Divided by genotype 1 versus 2/3 shows 34% (11 out of 32 SOC) versus 53% (17 out of 32 SOC plus vitamin B12) and for genotype 2/3: 80% (12 out of 15 SOC) versus 100% (15 out of 15 SOC plus vitamin B12), respectively. At this point, none of the differences were significant.

For week 12, complete viral response, defined as HCV RNA undetectable by HCV RT-PCR (Cobas Amlicor, limit of detection ~50 IU/ml), and the overall differences were significant (64% [30 out of 47] vs 85% [40 out of 47; p = 0.03], and 56% [18 out of 32 SOC] vs 78% [17 out of 32 SOC plus vitamin B12] and 80% [12 out of 15 SOC] vs 100% [15 out of 15 SOC plus vitamin B12], respectively), if divided by genotype 1 versus 2/3. The results split according to genotype were not significantly different, partially owing to small numbers in each subgroup.
At the end of treatment, the viral response rates were: 63% for genotype 1 (29 out of 47) versus 83% for genotype 2/3 (39 out of 47; p = 0.03) overall, and 53% (17 out of 32 SOC) versus 75% (24 out of 32 SOC plus vitamin B12) in genotype 1 patients and 80% (12 out of 15 SOC) versus 100% (15 out of 15 SOC plus vitamin B12) in genotype 2/3 patients, respectively. The most important outcome of SVR was also significantly different, overall (18 out of 47 [38%] vs 34 out of 47 [72%]), and when limited to genotype 1 patients: 22 versus 63% SVR (p = 0.003). However, the very good SVR rate of 11 out of 15 (73%) in genotype 2 out of 3 patients on SOC was higher, but not significantly different, in the patients receiving SOC plus vitamin B12 with 14 out of 15 (93%). No additional side effects were reported on respective therapies; it seems that vitamin B12 dosing at 5 mg im. every 4 weeks does not lead to additional side effects but does appear to increase response.

A decade after the first description of vitamin B12 being able to inhibit HCV replication in vitro, this study is the first one to randomize patients to SOC plus vitamin B12 versus SOC alone. The study reports dramatic improvement in response in the more difficult-to-treat genotype 1 patients with 63% SVR versus 22% SVR (p = 0.003), while the difference was less impressive in the easier-to-treat genotype 2/3 patients, where still a 20% difference was reported, and if confirmed in larger trials, this would be clinically significant.

The study had a few technical shortcomings, as important information concerning treatment response was not well established when the study was started, which limits the certainty of the study findings. Unfortunately, there is a substantial difference in response to Peg-IFN-α2a and Peg-IFN-α2b when used for HCV infection, where Peg-IFN-α2a is superior to Peg-IFN-α2b.[6] Thus, it would have been preferential to have only one of the interferons.
In addition, IL28B genotyping was not available for stratification as that was not a known factor for viral response at the time of the study; however, response rates were shown to vary between 38 and 80% depending on IL28B genotype.[7] Uneven distribution despite randomization cannot be excluded.

[8] However, the authors did the best they could and assessed IL28B genotype in a large proportion of the patients in the study. The data presented with such information available were similar to the overall trend. Data were presented for 42 genotype 1 patients, where IL28B was available, and the results were concordant with the assumption that vitamin B12 would be beneficial across different IL28B genotypes.

The study had another surprising result that might limit their generalizability – that is, the RVR and SVR rates reported for the SOC arm. The RVR rate of 34% (95% CI: 20–52%) is much higher for genotype 1 patients. For most studies, approximately 10% of genotype 1 patients were reported to achieve RVR;[9,10] on the other hand, the SVR rate of 22% (95% CI: 11–39%) in the SOC arm is lower than what is to be expected for patients treated with Peg-IFN plus ribavirin.[9,10] What makes the study findings even more surprising is that RVR and SVR rates were not only unusual, but despite better than expected RVR rates in the SOC arm, the SVR rates at the end of therapy were lower than expected. However, if confirmed the findings are huge.

Expert Commentary
The current aim of most therapies in HCV infection is the eradication of the viral infection, which is considered achieved when HCV RNA remains undetectable for 24 weeks after the end of the therapy: so-called SVR. When the study, cited above, was performed, only approximately 40% of North American patients with HCV genotype 1 infection achieved sustained response when treated with Peg-IFN (180 µg IFN-α2a weekly or 1.5 µg/kg IFN-α2b weekly) and ribavirin (800–1400 mg daily) for 48 weeks.[11] European patients usually respond slightly but not significantly better.

In that regard, the reported mere 22% (seven out of 32 patients; 95% CI: 11–39%) SVR rate in the SOC arm is surprising. This is significantly lower than the expected response rates from Italy. Nevertheless, the response looks promising at 63% (20 out of 32 patients; 95% CI: 46.3–79.7%) in the vitamin B12 treatment arm, where vitamin B12 was added at a dose of 5000 µg 4-weekly im.

However, the lower end of the CI is still at a similar range, as in other studies using Peg-IFN plus ribavirin for 48 weeks.[12] Still, the study supports earlier findings of better treatment response in patients with a vitamin B12 serum level >360 pM compared with patients with a level of ≤360 pM.[4] In addition, both of these clinical studies are concordant with the expectation of an antiviral effect based on the earlier in vitro findings of viral inhibition by vitamin B12. However, it is too early to call it a done deal. Another study, evaluated 102 patients undergoing HCV therapy with median vitamin B12 levels of 490 pg/ml and ranging from 398 to 638 pg/ml (equivalent to median of 361.62 pM and a range from 293.724 to 470.84 pM). Unfortunately, they report on homocystein levels being associated with response but did not comment on the vitamin B12 levels other than indicating that they were normal.[13]

Given the relative safety of vitamin B12, vitamin B12 supplementation warrants further evaluation to see whether those findings can be replicated and, just as importantly, whether the relevance of vitamin B12 is maintained in the setting of newer treatments such as the protease inhibitors that have become the new SOC with generally improved response rates from approximately 40% with Peg-IFN and ribavirin to approximately 65–70% when a protease inhibitor such as boceprevir or telaprevir is added to SOC.

Although unlikely, at this point it cannot be ruled out that the benefit of vitamin B12 may only exist in the setting of interferon plus ribavirin therapy. Given that vitamin B12 has been found to be antivirally active in vitro, there is a likely chance it will also be beneficial in all oral regimens against HCV. In addition, the suggested improved response in easy-to-treat patients with genotype 2/3, who have already high response rates, suggests that vitamin B12 will have a chance to also improve an already highly effective antiviral regimen.

If the role of vitamin B12 is found to be limited to interferon-based therapy, it might be of less relevance than if it was also found to augment direct antiviral therapies. With the in vitro viral inhibition of vitamin B12 alone, it is likely to remain relevant in all oral direct antiviral regimens. Concerning the in vitro data, there is, however, a concern that such data were only reported from one laboratory and have not independently been confirmed. Ideally, the combined effects of vitamin B12 with direct antiviral with or without interferon would be demonstrated in vitro.

It is a reminder of the discussion on vitamin D and response to interferon-based therapies. Vitamin D is very attractive, to explain some of the remaining response difference between African–American compared with Caucasian individuals when controlled for IL28B. Vitamin D levels are lower in African–American individuals, and they respond worse to Peg-IFN plus ribavirin, even when controlled for IL28B.

A study from Israel reported 86% (31 out of 36) SVR rates in patients treated with Peg-IFN and ribavirin plus oral vitamin D (2000 IU/d Vitamidyne D, Fischer Pharmaceuticals, Israel) versus 41% (15 out of 36) in those treated with Peg-IFN and ribavirin alone.[14] In a second study, the same team reported improved SVR rates if genotype 2/3 patients were treated with vitamin D in addition to Peg-IFN and ribavirin (19 out of 20 [95%] vs 23 out of 30 [77%]; p < 0.001).[15] Their findings are in line with a retrospective analysis of 42 patients with recurrent HCV infection after liver transplantation, where the 15 patients who received vitamin D supplementation 800 IU/d in the form of cholecalciferol showed better SVR rates than nonsupplemented patients.[16] Subsequently, it has been reported from independent groups that vitamin D (to be exact 25-hydroxyvitamin D3 [25(OH)D3]) can actually inhibit HCV replication in vitro[17,18] and that resistance development in the NS3 helicase domain of HCV in response to vitamin D dosing was observed. Resistance development is considered a good marker for true antiviral activity (i.e., versus toxicity), as resistance is only expected to emerge against antivirally active substances.

Similar to vitamin B12, it has also been reported for vitamin D that there is a correlation between vitamin D levels in the blood and response to Peg-IFN and ribavirin therapy.[19] This has subsequently been confirmed repeatedly in several studies.[20,21]

There could be a pitfall concerning vitamin D. Lange et al., in an initial study, reported both the CYP27B1-1260 promoter polymorphism (rs10877012: AA, AC and CC), which has substantial impact on 1,25-dihydroxyvitamin D serum levels (72, 61 and 60 pmol/ml for AA, AC and CC, respectively; p = 0.04) and 25-hydroxyvitamin D levels to be related to SVR in interferon-based therapy for HCV, but in their subsequent larger study, they found, in addition to the CYP27B1-1260 polymorphism, that only the bioactive vitamin D (1,25[OH]2D3, calcitriol) but not the calcitriol precursor 25(OH)D3 was predictive of response to treatment in patients with chronic hepatitis C.[20]

Thus, it will be important for future studies on vitamins to evaluate different metabolites, as not all metabolites may have the same predictive value.[21] To make things more complex, the bioactive metabolite of vitamin D (1,25[OH]2D3) was not antivirally active in a cell model where 25 (OH)D3 was active.[18]

For vitamin B12, there is also some consideration required toward the right metabolite to analyze, whether holotranscobalamin might be superior to vitamin B12 (cobalamin) levels,[22,23] or whether vitamin B12 levels should be assessed together with methylmalonic acid (or total homocysteine).[24]
Other genetic markers have yet not been confirmed, but in individual smaller studies, vitamin D receptor (NR1|1: rs1544410, rs7975232 and rs731236)[25] and CYP27B1 (rs4646536) were reported to be related to response in addition to vitamin D levels and IL28B polymorphism.[26]

Other vitamins evaluated in relation to HCV are vitamin E, β-carotine and linoleic acid. Vitamin E when combined with pentoxifylline was reported to be associated with better SVR in an Egyptian study, potentially owing to lower frequency of anemia-associated reductions of ribavirin.[27]

However, vitamin E was also reported to increase HCV replication and, therefore does not appear an attractive approach for HCV infection.[28] By contrast, β-carotine and linoleic acid both had been reported to inhibit HCV replication in vitro.[29,30] In summary, if confirmed that vitamin B12 and/or vitamin D supplementation increase response to HCV-based therapy, these might be relatively cheap ways to augment response to antiviral therapy targeting hepatitis C virus eradication.

Five-year View
Importantly, it needs to be confirmed whether vitamin B12 improves response to HCV-targeted therapy. It will be important to evaluate the role of vitamin B12 in interferon-free regimens. Given the fast development of highly active antiviral therapy regimens, which are expected to eradicate HCV in most patients within 12 weeks or shorter treatment duration in over 90% of patients, an approach that increases response rate to a side-effect-loaded therapy may be of limited attractiveness.
Given the low drug cost for vitamin D and B12 compared with direct antivirals, it might be difficult to find pharmaceutical sponsors to evaluate these approaches further. However, the development of such approaches might be more attractive for resource-limited settings, and in areas where direct antivirals are further away from daily clinical practice due to longer regulatory processes.

  1. Lott WB, Takyar SS, Tuppen J et al. Vitamin B12 and hepatitis C: molecular biology and human pathology. Proc. Natl Acad. Sci. USA 98(9), 4916–4921 (2001).
  2. Takyar SS, Gowans EJ, Lott WB. Vitamin B12 stalls the 80 S ribosomal complex on the hepatitis C internal ribosome entry site. J. Mol. Biol. 319(1), 1–8 (2002).
  3. Li D, Lott WB, Martyn J, Haqshenas G, Gowans EJ. Differential effects on the hepatitis C virus (HCV) internal ribosome entry site by vitamin B12 and the HCV core protein. J. Virol. 78(21), 12075–12081 (2004).
  4. Rosenberg P, Hagen K. Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection. J. Viral Hepat. 18(2), 129–134 (2011).
  5. Desombere I, Van Vlierberghe H, Couvent S, Clinckspoor F, Leroux-Roels G. Comparison of qualitative (COBAS AMPLICOR HCV 2.0 versus VERSANT HCV RNA) and quantitative (COBAS AMPLICOR HCV monitor 2.0 versus VERSANT HCV RNA 3.0) assays for hepatitis C virus (HCV) RNA detection and quantification: impact on diagnosis and treatment of HCV infections. J. Clin. Microbiol. 43(6), 2590–2597 (2005).
  6. Awad T, Thorlund K, Hauser G, Stimac D, Mabrouk M, Gluud C. Peginterferon α-2a is associated with higher sustained virological response than peginterferon α-2b in chronic hepatitis C: systematic review of randomized trials. Hepatology 51(4), 1176–1184 (2010).
  7. Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461(7262), 399–401 (2009).
  8. Thompson AJ, Muir AJ, Sulkowski MS et al. Hepatitis C trials that combine investigational agents with pegylated interferon should be stratified by interleukin-28B genotype. Hepatology 52(6), 2243–2244 (2010).
  9. Jacobson IM, McHutchison JG, Dusheiko G et al.; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N. Engl. J. Med. 364(25), 2405–2416 (2011).
  10. Poordad F, McCone J Jr, Bacon BR et al.; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N. Engl. J. Med. 364(13), 1195–1206 (2011).
  11. McHutchison JG, Lawitz EJ, Shiffman ML et al.; IDEAL Study Team. Peginterferon α-2b or α-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361(6), 580–593 (2009).
  12. Hadziyannis SJ, Sette H Jr, Morgan TR et al.; PEGASYS International Study Group. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann. Intern. Med. 140(5), 346–355 (2004).
  13. Borgia G, Gentile I, Fortunato G et al. Homocysteine levels and sustained virological response to pegylated-interferon α2b plus ribavirin therapy for chronic hepatitis C: a prospective study. Liver Int. 29(2), 248–252 (2009).
  14. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. World J. Gastroenterol. 17(47), 5184–5190 (2011).
  15. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2–3 naïve patients. World J. Gastroenterol. 18(8), 800–805 (2012).
  16. Bitetto D, Fabris C, Fornasiere E et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl. Int. 24(1), 43–50 (2011).
  17. Gal-Tanamy M, Bachmetov L, Ravid A et al. Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology 54(5), 1570–1579 (2011).
  18. Matsumura T, Kato T, Sugiyama N et al. 25-hydroxyvitamin D(3) suppresses hepatitis C virus production. Hepatology doi:10.1002/hep.25763 (2012)(Epub ahead of print).
  19. Petta S, Cammà C, Scazzone C et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 51(4), 1158–1167 (2010).
  20. Lange CM, Bibert S, Kutalik Z et al.; the Swiss Hepatitis C Cohort Study Group. A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-α-based therapy of chronic hepatitis C. PLoS ONE 7(7), e40159 (2012).
  21. Lange CM, Bojunga J, Ramos-Lopez E et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-α based therapy. J. Hepatol. 54(5), 887–893 (2011).
  22. Fragasso A, Mannarella C, Ciancio A et al. Holotranscobalamin is a useful marker of vitamin B12 deficiency in alcoholics. ScientificWorldJournal 2012, 128182 (2012).
  23. Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am. J. Clin. Nutr. 94(1), 359S–365S (2011).
  24. Yetley EA, Pfeiffer CM, Phinney KW et al. Biomarkers of vitamin B-12 status in NHANES: a roundtable summary. Am. J. Clin. Nutr. 94(1), S313–S321 (2011).
  25. Baur K, Mertens JC, Schmitt J et al.; Swiss Hepatitis C Cohort Study Group. The vitamin D receptor gene bAt (CCA) haplotype impairs the response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C patients. Antivir. Ther. (Lond.) 17(3), 541–547 (2012).
  26. D'Avolio A, Ciancio A, Siccardi M et al. Ribavirin pharmacokinetics and interleukin 28B plus cytochrome P450 27B1 single-nucleotide polymorphisms as predictors of response to pegylated interferon/ribavirin treatment in patients infected with hepatitis C virus genotype 1/4. Hepatology 54(6), 2278–2279 (2011).
  27. Assem M, Yousri M. Impact of pentoxifylline and vitamin E on ribavirin-induced haemolytic anaemia in chronic hepatitis C patients: an Egyptian survey. Int. J. Hepatol. 2011, 530949 (2011).
  28. Huang H, Chen Y, Ye J. Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E. Proc. Natl Acad. Sci. USA 104(47), 18666–18670 (2007).
  29. Yano M, Ikeda M, Abe K et al. Comprehensive analysis of the effects of ordinary nutrients on hepatitis C virus RNA replication in cell culture. Antimicrob. Agents Chemother. 51(6), 2016–2027 (2007).
  30. Rocco A, Compare D, Coccoli P et al. Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus. Gut doi:10.1136/gutjnl-2012-302344 (2012) (Epub ahead of print).
Source -  Medscape

Sunday, July 15, 2012

Supplements Failed to Prevent Cancer

GI & HEPATOLOGY NEWS July 2012 Issue

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Supplements Failed to Prevent Cancer

BY MARY ANN MOON Elsevier Global Medical News

Older men and women who took supplements of B vitamins, or omega-3 fatty acids, or both for approximately 5 years were no less likely to develop cancer than people who took placebo, a randomized clinical trial has shown.

“This study does not support dietary use of B vitamins or omega-3 fatty acids for cancer prevention,” wrote Valentina A. Andreeva, Ph.D., and her associates in the Archives of Internal Medicine (2012;172: 540-7).

The B vitamins have been proposed for preventing cancer because deficiency of these nutrients is thought to affect DNA methylation, which in turn modulates cell differentiation and chromosomal stability. Similarly, omega-3 fatty acids have been suggested as chemoprevention because they may restrict tumor cell proliferation, and they modulate inflammation and immunity.

However, research regarding both types of supplements has yielded inconclusive results. Dr. Andreeva and her colleagues studied the issue using data from a randomized clinical trial of cardiovascular disease.

In that trial, 2,501 patients aged 45-80 years who had had an acute myocardial infarction, unstable angina, or ischemic stroke during the preceding year were randomly assigned to one of four supplementation groups and followed for a mean of 5 years for recurrent cardiovascular disease–related events.

The B vitamin and omega-3 fatty acid supplements were not found to affect cardiovascular disease recurrence in that trial. Dr. Andreeva, of the nutritional epidemiology research unit, University of Paris, and associates performed a secondary analysis to assess incident cancers in these study subjects.

The 1,987 men and 514 women had a mean age of 61 years at baseline. The first group took the B vitamins 5-methyltetrahydrofolate (0.56 mg), pyridoxine HCl (vitamin B6, 3 mg), and cyanocobalamin (vitamin B12, 0.02 mg); the second group took eicosapentaenoic and docosahexaenoic acids (600 mg); the third group took both types of supplement; and the fourth group took placebos.

Treatment adherence was judged to be high, based on subjects’ self-report and on their increased blood levels of both types of nutrients.

During follow-up, 174 subjects (7%) developed an incident primary cancer.

The 145 men with cancer included 50 with prostate cancer, 22 with lung cancer, and others with bladder (16 cases), colorectal (13 cases), or other (44 cases) malignancies.

Twenty-nine women developed breast (9 cases), lung (4 cases), colorectal (3 cases), or other (13) malignancies.

Neither B vitamins nor omega-3 fatty acids affected the incidence of cancer, the investigators said. Among men, 74 who took B vitamins developed cancer, compared with 71 in the comparison groups, a nonsignificant difference.

Similarly, 72 men who took fatty-acid supplements developed cancer, compared with 73 in the comparison groups, also a nonsignificant difference.

Among women, 20 who took B vitamins and 9 in the comparison groups developed cancer, a difference of borderline significance.

And 21 who took fatty acid supplements developed cancer, compared with 8 in the comparison groups. This difference was significant, but the low number of cancer cases in women “resulted in unstable and equivocal risk estimates,” the researchers said.

The study was supported by Candia, Danone, Merck Eprova AG, Pierre Fabre Laboratories, Roche Laboratories, Sodexo, Unilever, the French National Research Agency, and the French Ministry of Health. The investigators had no relevant financial disclosures. ■

Tuesday, February 7, 2012

Vitamins and Mortality: In Defense of Supplements

From Medscape Internal Medicine

Vitamins and Mortality: In Defense of Supplements

Ayaz Virji, MD

The article by Mursu and colleagues[1] that was recently reported on in Medscape News (see Medscape article below) indicates that ad libitum use of multivitamins does not reduce all-cause mortality in women; to the contrary, it may slightly increase it. This arm of the Iowa Women's Health Study consisted of 38,772 elderly white women with a mean age of 61.6 years who were followed over 20 years. This well-designed, observational cohort study adjusted for diverse confounders, including body mass index (BMI), physical activity, smoking status, and educational level.

When interpreting these results, as for any other nutraceutical intervention, it would be imprudent to make broad, imprecise statements about the "ineffectiveness" of dietary supplements, although it may be tempting to do so. It is important to consider the limitations of the study to help prevent unscientific conclusions. The authors themselves conceded, "It is not advisable to make a causal statement of excess risk based on these observational data."[1]
Mursu and colleagues' study, although well executed, has several methodological limitations. It used the Harvard Service Food Frequency Questionnaire, which was originally designed to assess the diets of low-income women and gather information on dietary supplements used. However, the dietary supplement portion of the questionnaire has not been independently validated. In addition, a certain subset of patients inappropriately substitutes dietary supplements for medications to manage chronic disease. This concerning, yet uncaptured, trend could potentially confound the results.

The study did not report on the specific doses, excluding calcium and iron, or source of the supplements used. Both of these factors play an important role in the net effect of supplements on patient health. Take vitamin E, for example. Recent studies show that supplemental vitamin E doses > 400 IU may increase risk for congestive heart failure and prostate cancer, although in aggregate the data are inconclusive.[2,3]

The Nurses' Health Study found that women who consumed 100 IU of vitamin E daily had a 44% reduction in developing major coronary disease.[4] Of note, 4 times the therapeutic dose of an angiotensin-converting enzyme inhibitor is likely to result in a similar reversal of outcome. There would be little disagreement regarding the inappropriateness of a conclusion on the safety and efficacy of an angiotensin-converting enzyme inhibitor without considering the dose or the population using it. The same consideration was not given to dietary supplements in this assessment, however. A targeted, rational strategy for supplement use, developed in partnership with a medical provider, is likely to lead to a different outcome than that reported in the current study.

As is the case for pharmaceutical agents, various isomers of the same vitamin have different clinical effects. Considering vitamin E again, alpha-tocopherol (which is more commonly found in supplements) and gamma-tocopherol (which is more commonly found in food sources) have different anti-inflammatory properties and vary in bioavailability. It is likely that a healthy ratio of these 2 substances is more important to preventing coronary artery disease than is taking one isomer in excess, which may deplete the other.[5] In addition, unlike for pharmaceutical agents, the source of vitamin supplement plays an important role. Synthetic vitamin E (dl-alpha-tocopherol) is thought to be much less potent than its natural vitamin E (d-alpha-tocopherol) counterpart and may have a varying clinical effect.

Whether it's chromium and reduced carbohydrate cravings, carnitine and improved claudication symptoms, or green tea and greater life expectancy,[6-8] much remains unanswered regarding the net effect of a particular supplemental nutrient or group of nutrients on overall health. Perhaps advancements in the field of nutrigenomics will help light our way on their utility. Nonetheless, when comparing apples to apples, "polynutrient" is far less toxic than polypharmacy; the latter incurs 100,000 related deaths annually. A conventional multivitamin supplement should still be generally recognized as safe.

  1. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: the Iowa Women's Health Study. Arch Intern Med. 2011;171:1625-1633. Abstract
  2. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306:1549-1556. Abstract
  3. Lonn E, Bosch J, Yusuf S, et al; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA. 2005;293:1338-1347. Abstract
  4. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444-1449. Abstract
  5. Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74:714-722. Abstract
  6. Martin J, Wang ZQ, Zhang XH, et al. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care. 2006;29:1826-1832. Abstract
  7. Brevetti G, di Lisa F, Perna S, et al. Carnitine-related alterations in patients with intermittent claudication: indication for a focused carnitine therapy. Circulation. 1996;93:1685-1689. Abstract
  8. Kuriyama S, Shimazu T, Ohmori K, et al. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA. 2006;296:1255-1265. Abstract

From Medscape Medical News

Vitamin Supplements Associated With Increased Risk for Death
Emma Hitt, PhD

October 10, 2011 — In women aged 55 to 69 years, several widely used dietary vitamin and mineral supplements, especially supplemental iron, may be associated with increased risk for death, according to new findings from the Iowa Women's Health Study.

Although many vitamin supplements did not appear to be associated with a higher risk for total mortality, several were, including multivitamins, vitamins B6, and folic acid, as well as minerals iron, magnesium, zinc, and copper.

Jaakko Mursu, PhD, from the Department of Health Sciences, Institute of Public Health and Clinical Nutrition at the University of Eastern Finland in Kuopio, Finland, and colleagues reported their findings in the October 10 issue of the Archives of Internal Medicine.
"Supplements are widely used, and further studies regarding their health effects are needed," Dr. Mursu and colleagues write. "Also, little is known about the long-term effects of multivitamin use and less commonly used supplements, such as iron and other minerals."
The current study sought to evaluate the link between supplement use and total mortality rate, using data from the Iowa Women's Health Study. A total of 38,772 older women were included in the analysis. Women were aged between 55 to 69 years, with an average of 61.6 years at the beginning of the study in 1986. Self-reported data on vitamin supplement use were collected in 1986, 1997, and 2004.

A total of 15,594 deaths were reported through December 31, 2008, representing about 40% of the initial participants. The use of multivitamins overall was associated with 2.4% increased absolute risk for death (hazard ratio, 1.06; 95% confidence interval, 1.02 - 1.10). Self-reported use of dietary supplements increased substantially between 1986 and 2004. In addition, supplement users had a higher educational level, were more physically active, and were more likely to use estrogen replacement therapy.

Vitamin B6, folic acid, iron, magnesium, and zinc were associated with about a 3% to 6% increased risk for death, whereas copper was associated with an 18.0% increased risk for total mortality when compared with corresponding nonuse.

In contrast, use of calcium was inversely related to risk for death (hazard ratio, 0.91; 95% confidence interval, 0.88 - 0.94; absolute risk reduction, 3.8%).
The researchers assessed the findings for iron and calcium in more detailed analyses conducted during shorter periods (10-year, 6-year, and 4-year follow-up) and found results similar to those for the analyses conducted during the entire time.

"In agreement with our hypothesis, most of the supplements studied were not associated with a reduced total mortality rate in older women," Dr. Mursu and colleagues conclude. "In contrast, we found that several commonly used dietary vitamin and mineral supplements, including multivitamins, vitamins B6, and folic acid, as well as minerals iron, magnesium, zinc, and copper, were associated with a higher risk of total mortality."

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety," the authors add.
In a related editorial, Goran Bjelakovic, MD, DMSc, and Christian Gluud, MD, DMSc, from the Centre for Clinical Intervention Research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen University Hospital, Denmark, note that the current study adds "to the growing evidence demonstrating that certain antioxidant supplements, such as vitamin E, vitamin A, and beta-carotene, can be harmful."

"We cannot recommend the use of vitamin and mineral supplements as a preventive measure, at least not in a well-nourished population," they add. "Those supplements do not replace or add to the benefits of eating fruits and vegetables and may cause unwanted health consequences."

This study was partially supported by the National Cancer Institute and the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program’s Research Grant for a Junior Scholar. One study author is an unpaid member of the Scientific Advisory Board of the California Walnut Commission. The other authors and editorialists have disclosed no relevant financial relationships.
Arch Intern Med. 2011;171:1625-1633,1633-1634.

Authors and Disclosures
Emma Hitt, PhD

Emma Hitt is a freelance editor and writer for Medscape.

Disclosure: Emma Hitt, PhD, has disclosed no relevant financial relationships.
Dr. Hitt does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
Dr. Hitt does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Monday, January 9, 2012

Trash the Vitamins: Convince Your Patients

Trash the Vitamins: Convince Your Patients


A Best Evidence Review

Charles P. Vega, MD; Veena Kulchaiyawat, DO

Posted: 01/05/2012

Mursu J, Robien K, Harnack LJ, Park K, Jacobs Jr DR. Dietary supplements and mortality rate in older women. Arch Intern Med. 2011;171:1625-1633.

Dietary supplements are widely used by older adults, even though the effectiveness of these supplements in preventing illness is questionable. But can dietary supplements actually promote a higher risk for death? A new study suggests that the answer is yes for some of the most common supplements. This Best Evidence Review describes the findings of this study and puts these results in context.


Vitamins and dietary supplements play an important role in the health and healthcare of many adults, and the business of supplements constitutes a multibillion-dollar industry worldwide. Based on the Third National Health and Nutrition Examination Survey, 40% of men and 50% of women older than 60 years of age consume at least 1 vitamin or mineral supplement.[1] A national survey by the US Food and Drug Administration found that 73% of US adults were found to use dietary supplements in 2002, providing annual sale costs in 2005 of over $20 billion.[2,3]

The widespread use of dietary supplements is not supported by practice guidelines. The US Preventive Services Task Force (USPSTF) states that there is insufficient evidence to recommend for or against the use of vitamins A, C, E, or multivitamins with folic acid or antioxidants.[4] Specifically, the USPSTF cites concerns regarding the balance of benefits vs harms of these supplements. The American Medical Association recommends supplements specifically for seniors who have generalized decreased food intake, while the American Dietetic Association advises low-dose multivitamin and mineral supplements depending on individualized dietary assessment.[5] The American Heart Association emphasizes healthy eating patterns rather than supplementation with specific nutrients.[6]

These recommendations against the routine use of supplements are grounded in good evidence. A Cochrane intervention review of 77 randomized controlled trials with 232,550 participants found no evidence to recommend antioxidant supplementation for primary or secondary prevention of mortality.[7] Moreover, there is the possibility of harm related to the use of some supplements. For example, the Alpha-Tocopherol Beta-Carotene Cancer Prevention Trial demonstrated that beta-carotene supplements increased the risk for lung cancer among male smokers.[8]

The Study

The study under discussion by Mursu and colleagues raises even more concerns regarding the safety of dietary supplements. The study enrolled 41,836 women between the ages of 55 and 69 years in 1986. Women completed validated food frequency questionnaires at baseline and in 2004, and the use of any of 15 different dietary supplements was queried in 1986, 1997, and 2004.

The main study outcome was the relationship between supplement use and all-cause mortality, which was assessed from state and national registries. Researchers adjusted this result to account for the following factors: age, energy intake, educational level, place of residence, smoking status, body mass index (BMI), waist-to-hip ratio, physical activity, diet composition, alcohol consumption, the use of estrogen therapy, and the presence of diabetes mellitus and hypertension. Serum lipids or blood pressure were not measured as part of the study.

A total of 38,772 women provided study data. The mean age of participants at enrollment was 61.6 years, and over 99% of women were white. The average BMI was 27 kg/m2 at baseline and follow-up in 2004, and the majority of women were physically active. The average consumption of fruits and vegetables exceeded 6 servings per day during the study period. Out of this population, 36.8% of women reported hypertension, and 6.8% had diabetes.

The use of dietary supplements increased with time; 62.7% of women reported use of at least 1 supplement in 1986, and this figure rose to 85.1% by 2004. The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E.

Women who used supplements generally had better health characteristics compared with nonusers. They had higher educational status, lower BMI and waist-to-hip ratio, and lower rates of diabetes and hypertension compared with nonusers, and they were also less likely to smoke and had a healthier dietary profile. Supplement users were also more likely to use estrogen therapy compared with nonusers.

There were 15,594 deaths (40.2% of the study cohort) during a mean follow-up period of 19 years. In fully adjusted models, the use of multiple supplements was associated with a higher risk for mortality, including multivitamins (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.02-1.10), vitamin B6 (1.10; 1.01-1.21), folic acid (1.15; 1.00-1.32), iron (1.10; 1.03-1.17), magnesium (1.08; 1.01-1.15), zinc (1.08; 1.01-1.15), and copper (1.45; 1.20-1.75). The use of vitamin A, beta-carotene, and selenium were associated with nonsignificant trends toward a higher risk for mortality, and the use of vitamins C, D, and E had nearly no effect on mortality. In contrast, taking calcium supplements significantly reduced the risk for mortality (HR, 0.91, 95% CI, 0.88-0.94).

Researchers performed a number of additional analyses of the data to evaluate the validity of their outcomes. The main study results were not significantly changed after excluding women with a known history of cardiovascular disease or diabetes at baseline. An analysis using shorter follow-up intervals also confirmed the findings of higher risks for mortality with the use of iron. Moreover, there was evidence of a positive dose-response relationship between iron supplements and the risk for mortality. However, no dose-response effect was found for vitamins A, C, D, and E as well as the minerals selenium and zinc.


The principal limitation of the current study was its observational nature, which leaves open the possibility of confounding by indication. Specifically, there is the possibility that women with higher risks for mortality or who developed serious chronic illnesses as they grew older had a wider use of supplements.

Nonetheless, it is worth remembering that women who used supplements had superior health characteristics compared with nonusers. Therefore, supplement users should have experienced a lower risk for death overall. While it is plausible that some women started taking multiple supplements when confronted with news of a severe illness, such as cancer, it is hard to imagine that this practice alone was common enough to tip the scales toward a higher overall risk for mortality associated with the use of supplements.

One of the more fascinating findings in this very interesting study is the higher risk for mortality associated with the use of iron supplements. Higher levels of serum iron and transferrin saturation have been associated with a lower risk for mortality.[9,10] However, another study found that men with a serum ferritin level of 200 mcg/L or more experienced more than a twofold increased risk for myocardial infarction.[11] Finally, both increased serum iron levels and higher transferrin saturation have been associated with an increased risk for death due to cancer.[12] Of course, in this study, women with existing anemia due to any number of chronic serious medical conditions, such as cancer or chronic kidney disease, could have been told to take iron supplements by their physician, and these illnesses might account for their higher mortality. In any case, it appears that the role of iron among adults without iron deficiency is controversial, and there is little data from clinical trials to suggest a benefit to the routine use of iron supplementation among adults.

An additional interesting finding in the current study is the effect of calcium, but not vitamin D, supplements in reducing the risk for mortality. This is another controversial area because calcium supplements have been implicated in promoting a higher risk for myocardial infarction among women.[13] However, in the Women's Health Initiative trial, the use of calcium plus vitamin D reduced the risk for some types of cancer without an overall effect on the risk for mortality.[14]

The findings from the current study offer several lessons to physicians. First, physicians need to pay close attention to nonprescription therapies used by patients. These treatments are routinely omitted from the history of many patients, but the current study suggests that physicians make such errors at the peril of their patients.

Physicians should be a trusted resource for patients interested in dietary supplements. We can help balance self-treatment practices that might be effective against those that appear harmful or excessive. The findings of the current study should be sobering for the most ardent supporters of supplements, and patients need to understand the potential risks inherent in the treatment choices they make.

Clinical Pearls
  • Nearly half of older adults routinely use dietary supplements, with higher rates of use among women compared with men.
  • The routine use of many dietary supplements is discouraged in practice guidelines.
  • The use of multivitamins, vitamin B6, folic acid, iron, magnesium, zinc, and copper was associated with a higher risk for mortality among older women in the current study.
  • Conversely, calcium supplements were associated with a lower risk for mortality.
  • Physicians need to analyze nonprescription therapies used by patients and warn them of potential harms associated with the use of supplements.
Source Medscape

Sunday, March 20, 2011

Beta-carotene, vitamin A, vitamin C, and vitamin E cannot be recommended for treatment of liver diseases.

Antioxidant supplements for liver diseases

Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C


Beta-carotene, vitamin A, vitamin C, and vitamin E cannot be recommended for treatment of liver diseases.

An imbalance between too much oxidative stress and too little antioxidative defence has been suggested to cause a variety of liver diseases. Therefore, antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) could have a potential role in patients with liver disease. The evidence on whether antioxidant supplements are effective in treatment of liver diseases is contradictory.

In this review treatment with antioxidant supplements of alcoholic, autoimmune, hepatitis B or hepatitis C virus liver diseases, or liver cirrhosis is assessed. The review includes 20 randomised clinical trials. In total, 1225 participants were randomised to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. The low number of randomised participants increases the risk of random errors ('play of chance'). Trial quality was low and accordingly the risk of systematic errors ('bias') was high.

Based on the conducted randomised clinical trials, convincing evidence that beta-carotene, vitamin A, vitamin C, and vitamin E or their combinations are beneficial for treatment of alcoholic, autoimmune, hepatitis B or hepatitis C virus liver diseases, or liver cirrhosis could not be found.

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 3, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).

This record should be cited as: Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C. Antioxidant supplements for liver diseases. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD007749. DOI: 10.1002/14651858.CD007749.pub2

Editorial Group: Hepato-Biliary Group

This version first published online: March 16. 2011
Last assessed as up-to-date: February 2. 2011



Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal.


To assess the benefits and harms of antioxidant supplements for patients with liver diseases.

Search strategy

We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to January 2011. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials.

Selection criteria

We considered for inclusion randomised trials that compared antioxidant supplements (beta-carotene, vitamin A, C, E, and selenium) versus placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease, and cirrhosis (any aetiology).

Data collection and analysis

Four authors independently selected trials for inclusion and extracted data. Outcome measures were all-cause mortality, liver-related mortality, liver-related morbidity, biochemical indices at maximum follow-up in the individual trials as well as adverse events, quality-of-life measures, and cost-effectiveness. For patients with hepatitis B or C we also considered end of treatment and sustained virological response. We conducted random-effects and fixed-effect meta-analyses. Results were presented as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI).

Main results

Twenty randomised trials with 1225 participants were included. The trials assessed beta-carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials), and selenium (8 trials).

The majority of the trials had high risk of bias and showed heterogeneity.

Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality (relative risk [RR] 0.84, 95% confidence interval [CI] 0.60 to 1.19, I2 = 0%), or liver-related mortality (RR 0.89, 95% CI 0.39 to 2.05, I2 = 37%).

Stratification according to the type of liver disease did not affect noticeably the results. Antioxidant supplements significantly increased activity of gamma glutamyl transpeptidase (MD 24.21 IU/l, 95% CI 6.67 to 41.75, I2 = 0%).

Authors' conclusions

We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzyme activity.