Flawed Research Used to Attack Multivitamin Supplements

Two flawed studies, a rehashed review, and an editorial published in the December 17 issue of the Annals of Internal Medicine have attempted to discredit the value of multivitamin supplements, according to Life Extension®, the Fort Lauderdale, Fla.-based anti-aging and longevity research organization.

Both of these studies were plagued by flaws and should not discourage individuals from using high-quality, health-promoting multivitamin supplements.


In one study subjects were given a very low-potency multivitamin supplement; treatment adherence and drop-out rates were dreadful in both studies. Nevertheless, mainstream sources are using these botched studies to undermine the value of multivitamins.

One of the studies examined subjects with a history of heart attack who were given a multivitamin supplement or placebo and monitored for about 4.5 years for cardiovascular events.

Despite several flaws, this study actually revealed a trend toward reduced risk of cardiovascular events in those receiving the multivitamin supplement.

The other study, examining cognitive effects of a multivitamin, suffered from several problems including very low potency vitamin supplementation, poor adherence criteria, and reliance upon once-a-year self-reported treatment compliance records.

The weaknesses of these studies are not being discussed by the media; instead the studies are being used as fodder for unfounded attacks on high-quality multivitamin supplements.



Concerns with the Cognitive Function Study

Poor Adherence Criteria

Subjects in the cognition study were considered to have adhered to their multivitamin regimen appropriately if they took it just two-thirds of the time. In other words, even subjects who skipped their multivitamin four months out of the year were deemed "adherent" to the intervention.


Weak Questionnaire Data that Relies on Recollection

The method by which adherence was assessed in this study is inherently weak. Study subjects were simply asked to report how adherent they were to their assigned intervention once a year. This approach is based on recollection and is particularly prone to bias. More rigorous studies properly measure compliance by asking participants to return unused study product so adherence can by directly quantified.


Low-Potency Multivitamin

The multivitamin utilized in this study contained low nutrient concentrations. For example, the formula contained only 60 mg of vitamin C, 25 mcg of vitamin B12, and 20 mcg of selenium.

Health-conscious people know that these miniscule nutrient doses are unlikely to deliver any considerable health benefits. The authors of the study themselves admit "[the] doses of vitamins may be too low."


Other Evidence Shows Nutrient Supplementation Supports Cognitive Function

Multivitamins contain several nutrients shown to mitigate cognitive decline.

Vitamins B6, B12, and folic acid are important for methylation reactions, which are crucial to the health of brain tissue. Deficiency of these nutrients is associated with severe impairment of brain function. One placebo-controlled trial revealed that men and women with mild cognitive impairment who were supplemented with vitamins B6, B12, and folic acid for 24 months experienced 29% less brain atrophy and higher cognitive test scores compared to those who received placebo.

Numerous studies have implicated oxidative stress in the pathology of mild cognitive impairment and Alzheimer's disease. Antioxidant vitamins C, E, and beta-carotene protect the brain from oxidative damage.

Evidence strongly suggests that vitamin A exerts actions on brain physiology and behavior in adult life. For example, an active metabolite of vitamin A, retinoic acid, is a potent signaling molecule in the brain and helps regulate nerve cell growth, nerve survival, and synaptic plasticity.

In a double-blind, placebo-controlled clinical trial, over 200 healthy middle-aged individuals were given either a multivitamin or placebo for more than two months, and both groups were then assessed for cognitive function. It was shown that those taking the multivitamin displayed less fatigue during extended cognitive challenges and were more accurate. Also, those taking multivitamins were able to more quickly complete mathematical processing tests than subjects receiving placebo.

An eight-week, double-blind, placebo-controlled trial of multivitamins in men aged 50 – 74 was published in 2012. The researchers found that multivitamin supplementation significantly improved some aspects of memory and concluded that “… relatively short-term supplementation with a multivitamin can benefit […] risk factors for cognitive decline.


Concerns with the Cardiovascular Event Study

Poor Adherence Standards

In the cardiovascular event study, a staggering 46% of subjects discontinued or became ineligible for the multivitamin regimen during the study.

It is alarming that nearly half of the active-treatment group did not adhere to the treatment; this severely weakens the validity of the study. In addition, the authors of  the Annals of Internal Medicine editorial were remiss in using this methodologically-flawed research to condemn multivitamin supplementation..

Health-conscious individuals are well aware that optimal health benefits cannot be achieved by haphazardly or intermittently eating a healthy diet or taking nutritional supplements. Attaining ideal health is a lifelong endeavor that requires a healthy diet and regular use of high-quality, comprehensive nutritional supplements.


Study Downplays Reduced Cardiovascular Risk associated with Multivitamins

Despite concluding that multivitamins don't protect against cardiovascular risk, the investigators did find important trends to the contrary. The report demonstrated reduced cardiovascular event rates in the multivitamin group, although this did not reach statistical significance. This benefit generally increased over the duration of the 4.5-year follow-up period.

For example, there was an 11% reduction in the primary endpoint (composite of time to death from any cause, heart attack, stroke, coronary revascularization, or hospitalization for angina) among those taking multivitamins. Also, there was an 18% reduction in the secondary endpoint (composite of time to cardiovascular death, heart attack, or stroke).


Absurd Efficacy Assumptions

A major part of study design involves defining effect thresholds that can be statistically elucidated based upon the number of subjects and trial duration. In this study, the authors designed the trial to detect a 25% reduction in cardiovascular risk. In other words, for this trial to conclude that multivitamins provide cardiovascular benefit, the intervention would have had to eliminate 1 in 4 cardiovascular event outcomes.

By setting the bar for efficacy so high, this study was set up to conclude that multivitamins provide no benefit from the outset.


Low Dose Vitamin D

Although the researchers who conducted this study referred to the multivitamin preparation as "high-potency," one of the most critically important components for cardiovascular health was virtually absent from the formula.

The multivitamin utilized in this study contained a mere 100 IU of vitamin D.

Life Extension advocates inclusion of at least 2,000 IU of vitamin D in multivitamins for optimal health benefits.


Critical Importance of Gamma Tocopherol Overlooked

While the alpha tocopherol form of vitamin E was included in the multivitamin, the gamma tocopherol form was not. This is important because evidence shows that in the absence of gamma tocopherol, alpha tocopherol alone may not provide meaningful cardiovascular protection. Moreover, evidence suggests that supplementation with only alpha tocopherol might actually reduce levels of cardioprotective gamma tocopherol.

The alpha form of vitamin E decreases oxidative damage to the arterial lining, reduces dangerous aggregation and clumping of blood cells, and delays clot formation. It also inhibits smooth muscle proliferation (involved in the plaque-forming process), improves stability of fatty plaques, enhances function of cells lining the arteries, regulates vascular tone, and fights inflammation. Despite these impressive findings, however, clinical trials of alpha tocopherol alone have yielded mixed results concerning its cardioprotective effects.

This may be due to the role of gamma tocopherol on cardiovascular health. Some data suggest that high-dose alpha tocopherol supplementation may reduce or displace gamma tocopherol at the cellular level.

Gamma tocopherol is important in defending against cardiovascular disease. Several investigations confirm that higher tissue concentrations of gamma tocopherol are associated with lower rates of illness and death due to cardiovascular events.

In fact, several studies show that patients with advanced cardiovascular disease exhibit normal plasma levels of alpha tocopherol but have substantially lower levels of gamma tocopherol. In a seven-year follow-up study of more than 334,000 postmenopausal women with no previous heart disease, greater intake of dietary vitamin E — consisting predominantly of gamma tocopherol — was strongly associated with a lower risk of death from cardiovascular disease. The data did not appear to demonstrate a similarly protective role for supplemental alpha tocopherol.


The Editorial Downplays the Researched Benefits of Vitamins and Minerals

 In contrast to the nonsensical opinions espoused by the authors of the Annals of Internal Medicine editorial, myriad research has shown multivitamins protect against cancer and cardiovascular disease.

For example, the Physician's Health Study II (PHS-II) found that multivitamin supplementation was associated with an 8% reduction in overall cancer incidence and a 12% reduction in cancer death after 11.2 years of follow up. The PHS-II study also found a 39% reduction in fatal heart attack risk in those taking a multivitamin.

In addition, the Supplementation in Vitamins and Mineral Antioxidants Study (SU.VI.MAX) found a 31% reduction in total cancer incidence in men who supplemented with a multivitamin. When SU.VI.MAX's results in men were combined with the PHS-II results, the risk for all cancer incidence was reduced over 10 years of follow-up. 

A vast body of research has found considerable benefit from supplementing with nutrients found in multivitamins. For example, a 2013 study that enrolled 88,045 postmenopausal women reported that vitamin B6 and riboflavin intake from diet and supplements reduces the risk of colorectal cancer in postmenopausal women, and a 2007 study that enrolled 81,184 subjects found that low vitamin B6 intake is associated with an increased risk of colorectal cancer.

Another 2013 study that examined 77,446 men and women aged 50–76 found an inverse relationship between dietary selenium and the risk of pancreatic cancer.

In 2012, European researchers published results of a large study on 23,943 subjects who took antioxidant vitamin supplements over an average of 11 years. Individuals who used antioxidant multivitamins were 48% less likely to die from cancer and 42% less likely to die due to any cause compared to antioxidant vitamin nonusers.



Based upon critical analysis of these studies and the existing research, Life Extension continues to recommend supplementation with a high-quality multivitamin containing physiologic doses of a broad array of vitamins and minerals. High-dose omega-3 fatty acids, vitamin D, curcumin, coenzyme Q10, PQQ, carnosine, lipoic acid, other nutrients, and hormones can complement a comprehensive multivitamin and provide additional health and longevity benefits.


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Posted on WholeFoods Magazine, 12/23/13