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FOLIC ACID and VITAMIN B6 and MAJOR DISEASE

Abstract:  Risks of heart disease and stroke are reduced about 35% by the lowering of Homocysteine levels in the blood.  This benefit usually can be accomplished by the taking added amounts of Folic Acid and/or Vitamin B6.  Supplements of at least 400 mcg of Folic Acid and 5 mg of Vitamin B6 appear to be appropriate actions of health-interested persons.  Folic Acid also has been confirmed to reduce risk of colorectal cancer.

Homocysteine and Vitamins:  Risks of heart disease and stroke are strongly related to levels of Homocysteine.  Studies #13 to 15 included in Table H accompanying show that lowest usual levels of this factor are associated with only half the disease found for highest levels. These are only some of the many studies published on this.  A Meta analysis (JAMA 2002, 288:2015) of 30 different studies found that a 25% lower Homocysteine level was associated with an average 11% lower risk of coronary heart disease and a 19% lower risk of stroke. Another such study found a 16% reduction in heart disease and a 24% reduction in stroke for a 3 umol/L reduction in blood level of Homocysteine.  Note that the Life Ahead Library usually expresses risk ratios in terms of the lower risk as fraction of higher risk.  Homocysteine differs from most factors because lowest risk is obtained at lowest values of the factor rather than the more usual higher value of factors such as for the accompanying Folic acid and Vitamin B6.

A health interested person faces two problems in using this information.  First, information on Homocysteine levels is not provided in popular blood tests.  Second, we now know of two key things we can do to reduce levels of this harmful factor. These are to increase our intake of Folic acid or Folate and/or of Vitamin B6.  There usually is a strong interrelationship between Homocysteine levels in the blood and blood levels of and intake of these two vitamins.  Vitamin B12 also may contribute here, but evidence in this is not now adequate for inclusion in Life Ahead.  The higher are levels of Folic and B6, the lower usually is the amount of harmful Homocysteine.  In fact there long has been some controversy about which is the cause and which is the result.  Does Homocysteine result from levels of these other factors, or is it the basic cause?   In any event, our actions now must concentrate on obtaining most healthful dietary levels of Folic acid and Vitamin B6.

The Effect of Folic Acid on Risks of Cardiovascular Disease (CVD):  An average risk ratio of 0.65 is obtained from the 8 unusually consistent results on Folic acid from the 7 studies (#6 thru #12) included in Table A following.  These studies provide the main research results to date on risk of this factor on heart disease and stroke.  The largest study #9 of Rimm confirmed this average result with a highly significant risk ratio of 0.69.  A problem here is “What differing values in diet are associated with this risk change?”   Most of the research cited values of folic acid in blood, not differences in diet. An assumption made here from a study of various results is that these measured risks probably result from a difference folic acid in dietary foods of about 300 mcg per day. The use of supplements may have increased this difference to 400 mcg/day.  Much of the research was conducted during a period during which fortification of foods with folic acid may not have been extensive.

A usual value for Folic acid from foods in US diets is about 300 mcg/day.  This is higher than that of a decade earlier because of the fortification of some foods, particularly grains, with Folate.  Also many people take daily dietary supplements, and most supplements now include another 400 mcg or more of Folic acid.  Because the US population file used as a base for Life Ahead assumes no dietary supplements, the average population value is taken at this 300 mcg/day.  Thus the respective dietary values assumed for the research risk ratio valuations probably are from about 150 to 550 mcg per day.

Vitamin B6 and Risk of CVD:  The probable best risk ratio for Vitamin B6 from studies #1 to 4 in Table H is a similar 0.67.  The much lower value from study #2 is accompanied by a very high study margin of error.  The same problem of an associated dietary risk vs the measured amounts in blood exists for B6 as for Folic acid.  This average difference is now assumed at a value of 4 mg/day for B6.  The average US diet probably has a B6 level of about 2 mg per day. A spread of 4 from low to high amounts in diets assumes a low dietary intake of B6 of 1 and a high intake of 5 mg/day that probably provides a conservative valuation of the effectiveness of B6.

The Life Ahead Formula for Folic and B6 on CVD:  A useful formula for consolidating the probable risk change in CVD for various amounts of Folic acid and Vitamin B6 is :

Risk ratio= Exp( -.00108 * (Folic,mcg/d – 300) – 0.05 * (B6, mg/d) – 2) 

This produces a risk ratio of 1.0 for a US average population having 300 mcg/d of folic and 2 mg/d of B6. Results from this are:

For Nutrient                                          Folic Acid                  Vitamin B6

Avg difference in Research                 400 mcg/day                   4 mg/day

Avg risk ratio from Research                 0.65                               0.67

Value from Formula                                  0.65                               0.82

This formula for Folic acid now used in Life Ahead forecasts the actual value from research of 0.65 for a 400 mcg/day difference (150-550) in Folic acid.  Although the effect of folic on stroke may be somewhat larger than that on heart disease, this same value is now taken for all cardiovascular diseases.  A problem here is that we have no measurements of the risk of much higher amounts of Folic Acid on heart disease or stroke, and today many people who take supplements of 400 mcg/day have with fortified foods a total Folic acid intake of  750 mcg/day.  And 800 mcg supplements often are taken. 

A case can be made that these higher values will produce added benefits because the addition of 400 mcg/day only partly reduces the effective amount of Homocysteine present.  The large study #13 of Rimm did show a risk value of 0.55 for combinations of Folic plus B6.  But no population study found explored use of higher value supplements.  A limiting benefit risk ratio of 0.60 is now taken in Life Ahead for any combination of any amounts of Folic acid and Vitamin B6.  This value appears conservative from existing research, and also limits the maximum beneficial computed value of Folic Acid to 800 mcg/day.  This limit also is consistent with the 2 fold change in risk accompanying low vs. high values of Homocysteine.

The value now accepted for B6 in Life Ahead for CVD is less than that estimated directly from best 3 available studies.  Reasons for this are first, using this basis a combined risk ratio value from Folic at a 400 difference and B6 and a 4 mg/day difference is computed at 0.43 vs. the actual risk from both of 0.55 from the Rimm study.  Second, B6 has lesser effect in reducing Homocysteine that does Folic.  The more conservative valuation of B6 from the above formula does forecast the 0.55 value derived in the Rimm study and is more consistent with the effect of B6 on Homocysteine.

The Mechanism:  A popular theory is that Homocysteine damages the endothelial layer in the artery wall. Any such damage leads to rapid atherosclerosis buildup at the site of such damage.  An important implication here is that this can create a much shorter time effect on risk of disease than the usual lifetime and much slower rate of atherosclerosis accumulation that develops from cholesterol.  Thus this factor probably is an additional risk to that of cholesterol and antioxidants, and not simply one that involves duplication. Homocysteine also substantially increases thrombosis.  This can develop a short term or near immediate time increase in CVD risk that differs from the longer term duration related effects of other major factors on atherosclerosis and these diseases.

The duration figures noted in Table H assume a usual ten years of exposure to Folic and/or B6 at baseline for blood values plus half of the duration of an accompanying prospective study and thus are roughly semi-quantitative only.  But they suggest all of studies #1 thru #16 measured effects of  fairly long time exposure. 

Results on Cardiovascular Disease Patients:   The Health Establishment moved rather swiftly to implement benefits of Folic acid on the US population.  This action acknowledges the acceptance of the value of a dietary supplement to enhance amounts present in foods.  Study #17 did confirm that very large amounts of a combination of Folic, B6 and B12 did reduce coronary disease and atherosclerosis in the short time of 1 year on heart disease patients.  But much larger studies 18 and 19 on patients of disease found no useful effect of either Folic, B6 or B12 even at very high dosages even though amounts of homocysteine were reduced .  This now unexplained behavior of no effect on patients of disease vs. well confirmed benefits for healthy people was found similarly for those taking other Vitamins.  Although time of exposure was much lower in the randomized studies 17-19 than that in the other studies it seems unlikely that this alone can explain the disparate findings from the research on healthy people and that on disease patients.  But such patients usually will be taking other powerful medications that could have interfered with the beneficial effect of Folic Acid.

Unfortunately, some health writers' have left the impression that the negative results on studies 18 and 19 showed that "Previous research  on Folic Acid and Vitamin B6 was wrong."   The health-interested person should recognize results from ALL RESEARCH that is shown in the following table.  This clearly suggests that taking folic acid and Vitamin B6 probably will be substantially beneficial for those that are not yet patients of cardiovascular disease.

As a caution, results of more recent clinical trials on Folic Acid may confuse rather than help the present valuation of benefit.  With fortification of foods and the common use of Folic Acid supplements the potential for further improvement in risk from an added supplement is limited. For example, a US average population group today may average 400 mcg of folic from fortified foods plus 200 from half of individuals already using folic supplements. (If people never using any supplements were selected, this would no longer be a randomized trial.)  Life Ahead computes that adding another large supplement to this would only decrease heart disease by about 15%, an amount that probably would be “not significant” from a practical clinical study.  Further, a usual clinical study inherently assumes that the agent studied will benefit in immediate time.  If the full benefit from Folic takes place only over intermediate time of say several years, a five year clinical trial may find little benefit. 

Folic Acid and Cancer:  Table B shows results of five studies found relating Folic acid intake to colorectal cancer that meet the error margin criteria for inclusion in Life Ahead.  These studies show consistent benefits.  A risk ratio for 400 mcg/day of Folic is taken as 0.65, but with a lower limit of 0.60 taken for any amount of the Vitamin.  This value now used in Life Ahead only for colorectal cancer is statistically consistent with all comparisons, and gives more credit to the large study #2 than to the smaller studies.  Information found relating vitamin B6 to cancer was too meager to be used.   More recent data showing a substantial reduction in risk of Pancreatic Cancer supports a possible broader effect of Folic acid on cancer.

Results of two large studies relating risk of breast cancer to Folic Acid in Table B following cited useful reductions in risk only when Folic is included with alcohol intake.  These results are inconsistent with the very small effect of alcohol on breast cancer found from multiple independent studies.  For example the amount of 4 grams per day cited in study #2 represents only one drink per week that would have little independent effect on breast cancer.  A better understanding of these results and the mechanisms involved is needed before this information can be used in Life Ahead.

Benefits of Taking Folic acid and Vitamin B6:  Life Ahead computed benefits for a 50 year old non-smoking US average man with average diet taking a supplement of 400 mcg/day of Folic acid are a gain of 580 Well-Days or 1.6 years of healthful life.  An 800 mcg daily supplement computes to a gain of 710 Well-Days (1.95 years), and maximum use of Folic and Vitamin B6 is estimated at plus 860 Well-Days (2.4 years).  Gains should be higher for those at higher CVD risk as smokers and those with poor diets and lesser for those now having very good health habits.  These gains assume this action is the only change in habits.  Gains in Well-Days for use of Folic acid as a part of multiple habit changes will be smaller.

Other benefits for the Folic acid and Vitamin B6 include a possible slowing of dementia and prevention of some childbirth problems for pregnant women.  With no appreciable offsetting problems known and low involved cost, this research suggests that every health interested person should be taking a minimum supplement of 400 mcg of Folic acid and 5 mg of Vitamin B6.  The use of 800 mcg of Folic may provide some additional benefit.

More on that Mythology:  The results on Folic acid drive another nail into the coffin of that long admonished theory "You can get all the nutrients you need from food."   The chance of getting sufficient Folic from unfortified foods is remote.  Fruits include 20-40 mcg, so one way would be to take 20 to 30 portions of fruit each day.  Another would be 16 to 24 scrambled eggs per day. Other more practical possibilities would be to take 2-3 portions of liver, or 3-4 portions of lentils every day.  Most people would reject any of these options and some would not be healthy overall.   It is more practical and healthful to just take the tiny pill.  The fact that the Health Establishment has decided to fortify foods to provide more population intake of Folic acid shows that there no longer is any serious scientific support for this defunct theory about foods and supplements.