AJCN: Should You Take A Multi VM

[Guest guest]

Please escuse the formatting, but enjoy the article.

Jeff

Am J Clin Nutr 2007;86:522–5.

Evidence-based decision making on

micronutrients and chronic disease: long-term

randomized controlled trials are not enough

Dear Sir:

The State-of-the-Science Conference on

Multivitamin/Mineral

(MVM) Supplements and Chronic Disease of the National

Institutes

of Health was held in May 2006; the report of the

conference was

recently published as a special supplement in this

Journal (1). The

purpose of the conference was to evaluate the science

relevant to the

use of MVM supplements in chronic disease prevention.

A wide

range of epidemiologic, biochemical, and mechanistic

evidence is

relevant to these goals. However, the planning

committee limited the

scope of evidence to long-term randomized controlled

trials (RCTs)

that examined clinical endpoints such as cancer. Such

RCTs, the

panel said, are “generally considered the gold

standard for evidencebased

decision making” (2). Of course these RCTs are of

major

importance, but we strongly criticize the panel’s

decision to base

policy recommendations only on evidence from RCTs.

This does not

make good scientific sense. Policy recommendations

should be

based on the full range of relevant scientific

evidence. Very few

long-term RCTs involving MVMs or individual vitamins

and minerals

have been conducted. In addition, as noted in the

conference’s

summary statement (2), such RCTs are extremely

difficult. They

must be conducted for decades to detect effects on

long-latency

disease incidence, and compliance is difficult to

maintain, particularly

in control subjects who can readily

takeMVMsupplements, as

we discussed in reports prepared for the conference

(3, 4). Such

studies are not likely to yield definitive answers, as

the panel itself

concluded. The experience of the Women’s Health

Initiative trial of

vitamin D and calcium (5) exemplifies many of these

difficulties—

choosing an adequate dose for testing, maintaining a

sufficient level

of adherence, and conducting the trial for a long

enough period to

provide an adequate test of hypotheses. Indeed,

sensible public policy

recommendationsfor notsmoking,physical

activity,andweight control

provide examples of policy decisions that did not

require RCTs. Moreover,

RCTs were misleading with respect to smoking (6, 7).

Yet, there is a great deal of epidemiologic and

mechanistic evidence

concerning the effects of micronutrient deficiencies

on cancer

and other chronic disease endpoints and on biochemical

endpoints

relevant to chronic disease mechanisms. Instead of a

reliance solely

on long-term RCTs, all relevant scientific evidence

should be taken

into account in making supplementation recommendations

(3, 8, 9).

Short-term RCTs that focus on endpoints such as DNA

damage (10)

or markers of inflammation (11) are feasible and are

more likely to

yield informative results. Many other types of

experiments in humans

and animals, including biochemical, mechanistic, and

epidemiologic

studies, are also relevant.

The panel excluded this highly relevant body of

evidence from

consideration, and it came to the conclusion, “[T]he

present evidence

is insufficient to recommend either for or against the

use of MVMs

by the American public to prevent chronic disease”

(2). We contend that, by conveying the impression that

long-term RCTs, which are

inherently limited, represent the only scientific

evidence relevant to

“evidence-based decision making,” the panel presents a

highly biased

and misleading picture.

One of us (BNA), in a report originally prepared for

this conference

but published elsewhere (3), recently discussed the

large body

of evidence indicating that deficiencies in many

micronutrients

cause DNA damage, such as chromosome breaks. Some of

these

micronutrient deficiencies also cause mitochondrial

decay with oxidant

leakage and cellular aging and are associated with

late-onset

diseases such as cancer. Ames also introduced a theory

that provides

a rationale for why micronutrient deficiencies may

lead to greater

risk of chronic diseases such as cancer. He proposed

that DNA

damage and late-onset diseases are consequences of a

“triage allocation

response” to micronutrient scarcity. Episodic

shortages of

micronutrients were common during evolution. Because

natural selection

favors short-term survival at the expense of long-term

health,

Ames hypothesized that short-term survival was

achieved by allocating

scarce micronutrients by triage, in part through an

adjustment

of the binding affinity of proteins for required

micronutrients. The

hypothesis is testable, and, if correct, it predicts

that micronutrient

deficiencies triggering the triage allocation response

would accelerate

cancer, aging, and neural decay but would leave

critical shortterm

metabolic functions, such as ATP production, intact.

In conclusion, whereas we agree that policy decisions

should be

evidence-based and not hasty, we do not agree that the

evidence base

should be constrained to one type of study—in

particular, not to a

study design that is inherently limited. Do we really

want to wait

perhaps decades for results of long-term RCTs, which

almost certainly

will not provide definitive evidence, while ignoring

other

relevant evidence involving shorter-term endpoints? An

example is

provided in the panel’sownsummary statement (2). In

laudingRCTs

as the “gold standard for evidence-based decision

making,” the panel

proudly points to the fact that, even though folate

was well known to

decrease the risk of neural tube defects in animal

studies, policy recommendations

for folate supplementation to prevent neural tube

defects

weredelayed while authorities waitedsomeyears for

confirmationfrom

RCTs. One can only wonder how many infants were born

with neural

tube defects while authorities waited.

Of course, everyone would agree that all persons

should be encouraged

to eat a good diet, but we are far from achieving this

goal,

especially among the poor. In most cases, a simple way

to improve

micronutrient status is to take an MVM. However, even

if one eats

an ideal diet and takes an MVM, some vitamins can

remain below

recommended concentrations in some subgroups. For

example, the

efficiency of absorption of vitamin B-12 decreases

with age, and

supplements containing more than the Recommended

Dietary Allowance

are needed to correct the deficiency (12). The ability

of the

skin to use ultraviolet light to synthesize vitamin D3

also decreases

with age and is inefficient in dark-skinned people.

Because dietary

sources of vitamin D3 are not plentiful, supplements

are recommended

for those groups (13).

A significant fraction of Americans have micronutrient

intakes

below the Estimated Average Requirement. Why establish

values

such as the Estimated Average Requirement and not take

simple

steps to eliminate deficiencies? Because MVMs are

cheap, readily

available, and nontoxic (3), why not recommend that

people take an

MVM, particularly because much epidemiologic,

biochemical, and

other evidence points to the need for an adequate

supply of vitamins

and minerals for optimum function on many levels? At a

minimum,

taking an MVM is good insurance.

None of the authors had a personal or financial

conflict of interest.

Bruce N Ames

Joyce C McCann

Nutrition and Metabolism Center

Children’s Hospital Oakland Research Institute (CHORI)

5700 Luther King Jr Way

Oakland, CA 94609

E-mail: bames@...

Meir J Stampfer

Walter C Willett

Departments of Epidemiology and Nutrition

Harvard School of Public Health

Boston, MA

REFERENCES

1. Multivitamin/mineral supplements and chronic

disease prevention.

Am J Clin Nutr 2007;85(suppl):254S–327S.

2. National Institutes of Health State-of-the-Science

Panel. National Institutes

of Health State-of-the-Science Conference Statement:

multivitamin/

mineral supplements and chronic disease prevention. Am

J Clin

Nutr 2007;85(suppl):257S– 64S.

3. Ames BN. Low micronutrient intake may accelerate

the degenerative

diseases of aging through allocation of scarce

micronutrients by triage.

Proc Natl Acad Sci U S A 2006;103:17589 –94.

4. Fairfield K, Stampfer M. Vitamin and mineral

supplements for cancer

prevention: issues and evidence. Am J Clin Nutr

2007;85(suppl):289S–

92S.

5. Wactawski-Wende J, Kotchen JM, GL, et al.

Calcium plus

vitamin D supplementation and the risk of colorectal

cancer. N Engl

J Med 2006;354:684 –96. [Published erratum appears in

N Engl J Med

2006;354(10):1102.]

6. Shaten BJ, Kuller LH, Kjelsberg MO, et al. Lung

cancer mortality after

16 years in MRFIT participants in intervention and

usual-care groups.

Multiple Risk Factor Intervention Trial. Ann Epidemiol

1997;7:125–36.

7. Rose G, Hamilton PJ. A randomised controlled trial

of the effect on

middle-aged men of advice to stop smoking. J Epidemiol

Community

Health 1978;32:275– 81.

8. Heaney RP. Nutrition, chronic disease, and the

problem of proof. Am J

Clin Nutr 2006;84:471–2.

9. McCann JC, Ames BN. Reply to P Wainwright. Am J

Clin Nutr 2006;

83:920–1 (letter).

10. Fenech M. Nutritional treatment of genome

instability: a paradigm shift

in disease prevention and in the setting of

recommended dietary allowances.

Nutr Res Rev 2003;16:109 –22.

11. Church TS, Earnest CP,WoodKA,Kampert JB. Reduction

of C-reactive

protein levels through use of a

multivitamin.AmJMed2003;115:702–7.

12. Eussen SJ, de Groot LC, e R, et al. Oral

cyanocobalamin supplementation

in older people with vitamin B12 deficiency: a

dose-finding

trial. Arch Intern Med 2005;165:1167–72.

13. Bischoff-Ferrari H, Giovannucci E, Willett W,

Dietrich T, Dawson-

B. Estimation of optimal serum concentrations

of 25-

hydroxyvitamin D for multiple health outcomes. Am J

Clin Nutr 2006;

84:18 –28.

Reply to BN Ames et al

Dear Sir:

The above letter from Ames et al provides the

opportunity for

some useful clarification about National Institutes of

Health (NIH)

State-of-the-Science conferences and about the

particular conference

in which we participated as panel members. The NIH

Stateof-

the-Science Conference on Multivitamin/Mineral

Supplements and

Chronic Disease Prevention was convened primarily to

reflect on the

strength of the available evidence, to identify gaps

in the evidence, and

to offer recommendations to address those gaps. Ames

et al are correct

that the planning committee for the conference—as

distinct from the

panel that authored the conference statement—did

restrict the formal

evidence review (1) to randomized controlled trials

(RCTs). That review,

prepared by an Evidence-based Practice Center under

contract to

theAgencyfor HealthcareResearchandQuality,wasa

resourceusedby

the panel in its preparations for the conference and

in its deliberations.

However, at the conference itself, several

speakers—including Ames

and Stampfer—presented results from important

observational studies.

These studies were considered in, and also were

helpful to, the panel’s

deliberations.

We agree that there are practical challenges to the

conduct of

RCTs in any arena, in particular an arena as complex

as diet, and we

made reference to such limitations in the conference

statement. Similarly,

we noted both the usefulness and the limitations of

observational

studies (2). The panel’s recommendations focused on

measures

that would enhance the ability to answer the key

conference

questions by improving the quality and the quantity of

the evidence

available, including observational studies, and on

measures that

would improve the safety and reliability of the

products marketed to

the American public.

It is important to note that our panel was not charged

with asking

whether vitamins and minerals play a role in human

disease—a topic

that occupies much of the letter by Ames et al, and

for which observational

evidence is indeed central— but, as a State-of-the

Science

Panel, was charged to reflect on the state of the

available evidence for

a treatment recommendation on the use of vitamins and

minerals in

the general population. For treatment decisions, the

RCT is the

established standard. No better proof of this

principle can be found

than in the RCTs reviewed in our report, which showed

serious harm

from vitamin ingestion in certain circumstances.

Hence, on the basis of the evidence and its charge,

the panel made

no recommendation regarding the use of

multivitamin/mineral supplements

to prevent chronic disease; it only observed that

study

results were insufficient to compel a recommendation

either for or

against their use. We were not charged with, and did

not consider,

other factors that may prompt such recommendations by

other

groups or persons.

None of the authors had a personal or financial

conflict of interest.

J McGinnis

Institute of Medicine

The National Academies

500 Fifth Street, NW

Washington, DC 20001

E-mail: mcginnis@...

Diane F Birt

Iowa State University

Ames, IA

[Guest guest]

Hi folks:

I am slowly beginning to realize that when someone inserts the

phrase: " .... is the gold standard for .... " between something

they are pushing and something else that is generally considered

desirable, they are usually trying to cover up something they do not

want examined too closely.

And that those who repeat these 'gold standard' statements, have

generally spent much too much time reading the PR material on the

subject, and far too little time exercising their grey matter to

consider the reality of the issue.

Rodney.

--- In , Jeff Novick <chefjeff40@...>

wrote:

>

> Please escuse the formatting, but enjoy the article.

> Jeff

>

>

> Am J Clin Nutr 2007;86:522–5.

>

> Evidence-based decision making on

> micronutrients and chronic disease: long-term

> randomized controlled trials are not enough

> Dear Sir:

> The State-of-the-Science Conference on

> Multivitamin/Mineral

> (MVM) Supplements and Chronic Disease of the National

> Institutes

> of Health was held in May 2006; the report of the

> conference was

> recently published as a special supplement in this

> Journal (1). The

> purpose of the conference was to evaluate the science

> relevant to the

> use of MVM supplements in chronic disease prevention.

> A wide

> range of epidemiologic, biochemical, and mechanistic

> evidence is

> relevant to these goals. However, the planning

> committee limited the

> scope of evidence to long-term randomized controlled

> trials (RCTs)

> that examined clinical endpoints such as cancer. Such

> RCTs, the

> panel said, are " generally considered the gold

> standard for evidencebased

> decision making " (2). Of course these RCTs are of

> major

> importance, but we strongly criticize the panel's

> decision to base

> policy recommendations only on evidence from RCTs.

> This does not

> make good scientific sense. Policy recommendations

> should be

> based on the full range of relevant scientific

> evidence. Very few

> long-term RCTs involving MVMs or individual vitamins

> and minerals

> have been conducted. In addition, as noted in the

> conference's

> summary statement (2), such RCTs are extremely

> difficult. They

> must be conducted for decades to detect effects on

> long-latency

> disease incidence, and compliance is difficult to

> maintain, particularly

> in control subjects who can readily

> takeMVMsupplements, as

> we discussed in reports prepared for the conference

> (3, 4). Such

> studies are not likely to yield definitive answers, as

> the panel itself

> concluded. The experience of the Women's Health

> Initiative trial of

> vitamin D and calcium (5) exemplifies many of these

> difficulties—

> choosing an adequate dose for testing, maintaining a

> sufficient level

> of adherence, and conducting the trial for a long

> enough period to

> provide an adequate test of hypotheses. Indeed,

> sensible public policy

> recommendationsfor notsmoking,physical

> activity,andweight control

> provide examples of policy decisions that did not

> require RCTs. Moreover,

> RCTs were misleading with respect to smoking (6, 7).

> Yet, there is a great deal of epidemiologic and

> mechanistic evidence

> concerning the effects of micronutrient deficiencies

> on cancer

> and other chronic disease endpoints and on biochemical

> endpoints

> relevant to chronic disease mechanisms. Instead of a

> reliance solely

> on long-term RCTs, all relevant scientific evidence

> should be taken

> into account in making supplementation recommendations

> (3, 8, 9).

> Short-term RCTs that focus on endpoints such as DNA

> damage (10)

> or markers of inflammation (11) are feasible and are

> more likely to

> yield informative results. Many other types of

> experiments in humans

> and animals, including biochemical, mechanistic, and

> epidemiologic

> studies, are also relevant.

> The panel excluded this highly relevant body of

> evidence from

> consideration, and it came to the conclusion, " [T]he

> present evidence

> is insufficient to recommend either for or against the

> use of MVMs

> by the American public to prevent chronic disease "

> (2). We contend that, by conveying the impression that

> long-term RCTs, which are

> inherently limited, represent the only scientific

> evidence relevant to

> " evidence-based decision making, " the panel presents a

> highly biased

> and misleading picture.

> One of us (BNA), in a report originally prepared for

> this conference

> but published elsewhere (3), recently discussed the

> large body

> of evidence indicating that deficiencies in many

> micronutrients

> cause DNA damage, such as chromosome breaks. Some of

> these

> micronutrient deficiencies also cause mitochondrial

> decay with oxidant

> leakage and cellular aging and are associated with

> late-onset

> diseases such as cancer. Ames also introduced a theory

> that provides

> a rationale for why micronutrient deficiencies may

> lead to greater

> risk of chronic diseases such as cancer. He proposed

> that DNA

> damage and late-onset diseases are consequences of a

> " triage allocation

> response " to micronutrient scarcity. Episodic

> shortages of

> micronutrients were common during evolution. Because

> natural selection

> favors short-term survival at the expense of long-term

> health,

> Ames hypothesized that short-term survival was

> achieved by allocating

> scarce micronutrients by triage, in part through an

> adjustment

> of the binding affinity of proteins for required

> micronutrients. The

> hypothesis is testable, and, if correct, it predicts

> that micronutrient

> deficiencies triggering the triage allocation response

> would accelerate

> cancer, aging, and neural decay but would leave

> critical shortterm

> metabolic functions, such as ATP production, intact.

> In conclusion, whereas we agree that policy decisions

> should be

> evidence-based and not hasty, we do not agree that the

> evidence base

> should be constrained to one type of study—in

> particular, not to a

> study design that is inherently limited. Do we really

> want to wait

> perhaps decades for results of long-term RCTs, which

> almost certainly

> will not provide definitive evidence, while ignoring

> other

> relevant evidence involving shorter-term endpoints? An

> example is

> provided in the panel'sownsummary statement (2). In

> laudingRCTs

> as the " gold standard for evidence-based decision

> making, " the panel

> proudly points to the fact that, even though folate

> was well known to

> decrease the risk of neural tube defects in animal

> studies, policy recommendations

> for folate supplementation to prevent neural tube

> defects

> weredelayed while authorities waitedsomeyears for

> confirmationfrom

> RCTs. One can only wonder how many infants were born

> with neural

> tube defects while authorities waited.

> Of course, everyone would agree that all persons

> should be encouraged

> to eat a good diet, but we are far from achieving this

> goal,

> especially among the poor. In most cases, a simple way

> to improve

> micronutrient status is to take an MVM. However, even

> if one eats

> an ideal diet and takes an MVM, some vitamins can

> remain below

> recommended concentrations in some subgroups. For

> example, the

> efficiency of absorption of vitamin B-12 decreases

> with age, and

> supplements containing more than the Recommended

> Dietary Allowance

> are needed to correct the deficiency (12). The ability

> of the

> skin to use ultraviolet light to synthesize vitamin D3

> also decreases

> with age and is inefficient in dark-skinned people.

> Because dietary

> sources of vitamin D3 are not plentiful, supplements

> are recommended

> for those groups (13).

> A significant fraction of Americans have micronutrient

> intakes

> below the Estimated Average Requirement. Why establish

> values

> such as the Estimated Average Requirement and not take

> simple

> steps to eliminate deficiencies? Because MVMs are

> cheap, readily

> available, and nontoxic (3), why not recommend that

> people take an

> MVM, particularly because much epidemiologic,

> biochemical, and

> other evidence points to the need for an adequate

> supply of vitamins

> and minerals for optimum function on many levels? At a

> minimum,

> taking an MVM is good insurance.

> None of the authors had a personal or financial

> conflict of interest.

>

> Bruce N Ames

> Joyce C McCann

> Nutrition and Metabolism Center

> Children's Hospital Oakland Research Institute (CHORI)

> 5700 Luther King Jr Way

> Oakland, CA 94609

> E-mail: bames@...

> Meir J Stampfer

>

> Walter C Willett

> Departments of Epidemiology and Nutrition

> Harvard School of Public Health

> Boston, MA

>

> REFERENCES

> 1. Multivitamin/mineral supplements and chronic

> disease prevention.

> Am J Clin Nutr 2007;85(suppl):254S–327S.

> 2. National Institutes of Health State-of-the-Science

> Panel. National Institutes

> of Health State-of-the-Science Conference Statement:

> multivitamin/

> mineral supplements and chronic disease prevention. Am

> J Clin

> Nutr 2007;85(suppl):257S– 64S.

> 3. Ames BN. Low micronutrient intake may accelerate

> the degenerative

> diseases of aging through allocation of scarce

> micronutrients by triage.

> Proc Natl Acad Sci U S A 2006;103:17589 –94.

> 4. Fairfield K, Stampfer M. Vitamin and mineral

> supplements for cancer

> prevention: issues and evidence. Am J Clin Nutr

> 2007;85(suppl):289S–

> 92S.

> 5. Wactawski-Wende J, Kotchen JM, GL, et al.

> Calcium plus

> vitamin D supplementation and the risk of colorectal

> cancer. N Engl

> J Med 2006;354:684 –96. [Published erratum appears in

> N Engl J Med

> 2006;354(10):1102.]

> 6. Shaten BJ, Kuller LH, Kjelsberg MO, et al. Lung

> cancer mortality after

> 16 years in MRFIT participants in intervention and

> usual-care groups.

> Multiple Risk Factor Intervention Trial. Ann Epidemiol

> 1997;7:125–36.

> 7. Rose G, Hamilton PJ. A randomised controlled trial

> of the effect on

> middle-aged men of advice to stop smoking. J Epidemiol

> Community

> Health 1978;32:275– 81.

> 8. Heaney RP. Nutrition, chronic disease, and the

> problem of proof. Am J

> Clin Nutr 2006;84:471–2.

> 9. McCann JC, Ames BN. Reply to P Wainwright. Am J

> Clin Nutr 2006;

> 83:920–1 (letter).

> 10. Fenech M. Nutritional treatment of genome

> instability: a paradigm shift

> in disease prevention and in the setting of

> recommended dietary allowances.

> Nutr Res Rev 2003;16:109 –22.

> 11. Church TS, Earnest CP,WoodKA,Kampert JB. Reduction

> of C-reactive

> protein levels through use of a

> multivitamin.AmJMed2003;115:702–7.

> 12. Eussen SJ, de Groot LC, e R, et al. Oral

> cyanocobalamin supplementation

> in older people with vitamin B12 deficiency: a

> dose-finding

> trial. Arch Intern Med 2005;165:1167–72.

> 13. Bischoff-Ferrari H, Giovannucci E, Willett W,

> Dietrich T, Dawson-

> B. Estimation of optimal serum concentrations

> of 25-

> hydroxyvitamin D for multiple health outcomes. Am J

> Clin Nutr 2006;

> 84:18 –28.

>

>

> Reply to BN Ames et al

> Dear Sir:

> The above letter from Ames et al provides the

> opportunity for

> some useful clarification about National Institutes of

> Health (NIH)

> State-of-the-Science conferences and about the

> particular conference

> in which we participated as panel members. The NIH

> Stateof-

> the-Science Conference on Multivitamin/Mineral

> Supplements and

> Chronic Disease Prevention was convened primarily to

> reflect on the

> strength of the available evidence, to identify gaps

> in the evidence, and

> to offer recommendations to address those gaps. Ames

> et al are correct

> that the planning committee for the conference—as

> distinct from the

> panel that authored the conference statement—did

> restrict the formal

> evidence review (1) to randomized controlled trials

> (RCTs). That review,

> prepared by an Evidence-based Practice Center under

> contract to

> theAgencyfor HealthcareResearchandQuality,wasa

> resourceusedby

> the panel in its preparations for the conference and

> in its deliberations.

> However, at the conference itself, several

> speakers—including Ames

> and Stampfer—presented results from important

> observational studies.

> These studies were considered in, and also were

> helpful to, the panel's

> deliberations.

> We agree that there are practical challenges to the

> conduct of

> RCTs in any arena, in particular an arena as complex

> as diet, and we

> made reference to such limitations in the conference

> statement. Similarly,

> we noted both the usefulness and the limitations of

> observational

> studies (2). The panel's recommendations focused on

> measures

> that would enhance the ability to answer the key

> conference

> questions by improving the quality and the quantity of

> the evidence

> available, including observational studies, and on

> measures that

> would improve the safety and reliability of the

> products marketed to

> the American public.

> It is important to note that our panel was not charged

> with asking

> whether vitamins and minerals play a role in human

> disease—a topic

> that occupies much of the letter by Ames et al, and

> for which observational

> evidence is indeed central— but, as a State-of-the

> Science

> Panel, was charged to reflect on the state of the

> available evidence for

> a treatment recommendation on the use of vitamins and

> minerals in

> the general population. For treatment decisions, the

> RCT is the

> established standard. No better proof of this

> principle can be found

> than in the RCTs reviewed in our report, which showed

> serious harm

> from vitamin ingestion in certain circumstances.

> Hence, on the basis of the evidence and its charge,

> the panel made

> no recommendation regarding the use of

> multivitamin/mineral supplements

> to prevent chronic disease; it only observed that

> study

> results were insufficient to compel a recommendation

> either for or

> against their use. We were not charged with, and did

> not consider,

> other factors that may prompt such recommendations by

> other

> groups or persons.

> None of the authors had a personal or financial

> conflict of interest.

>

> J McGinnis

> Institute of Medicine

> The National Academies

> 500 Fifth Street, NW

> Washington, DC 20001

> E-mail: mcginnis@...

>

> Diane F Birt

> Iowa State University

> Ames, IA

>