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Adequate folate intake is associated with cardiovascular health, but when heart disease is already present, folic acid supplementation does not further decrease that risk, according to a meta-analysis recently published in the Journal of the American Medical Association.1
Folate is a naturally occurring B vitamin, but folic acid is synthetic, and bioavailability varies among the products on the market.
Many epidemiological findings show that folic acid has a modest protective effect on the heart, decreasing risk of the onset of heart disease. But randomized controlled trials of dietary supplementation with folic acid show inconsistent results in primary prevention of cardiovascular health.
Once cardiovascular disease (CVD) is established, the protective effect of folate or folic acid on the heart is even less clear.
The meta-analysis indicates that folic acid does not have a protective effect on secondary prevention of heart disease.
Principal investigator Lydia A. Bazzano, MD, PhD, of the Department of Epidemiology and School of Medicine at Tulane University in New Orleans, and colleagues at Tulane's Health Sciences Center searched MEDLINE data for the period January 1966–July 2006. Of the 165 relevant reports, 12 were randomized placebo-controlled or usual care-controlled trials with cardiovascular disease as an end point.
The investigators analyzed data from 16,958 individuals with preexisting cardiovascular disease. Overall CVD risk with folic acid supplementation was 0.95; essentially, the supplement had no effect on risk. Relative risk of coronary disease specifically was 1.04, risk for stroke was 0.86, and relative risk of all-cause mortality was 0.96 with folic acid supplementation.1
The risks were consistent among all subjects with preexisting cardiovascular or renal disease.
"Basically, in the case of secondary prevention, folic acid supplements do not have any proven benefit," Bazzano states.
"Clinically, if patients are taking this supplement, thinking it will save them from developing a second heart attack, stroke, or other vascular event, they should be made aware that there is no evidence to support this theory from clinical trials. What the patient really needs to do is to eat right, control his or her blood pressure, exercise, stop smoking, control cholesterol, and so on," Bazzano advises.
SCREENING NOT RECOMMENDED
Vincent J. Bufalino, MD, president of Midwest Heart Specialists in Lombard, Ill., tells DOC News that "the relationship is still soft between high homocysteine levels and elevated risk of cardiovascular disease. The American Heart Association has taken the stand that folic acid does not decrease the risk of MI [myocardial infarction] and stroke. No one is recommending screening at this point."
Bufalino asserts that "patients should just have a goal of 400 µg of folic acid a day, which you can get from fruits and vegetables. More folic acid is not better for decreasing risk. Eating leafy greens and some fruits and taking a multivitamin—that gets you all you need," he says.
Why the controversy? High homocysteine levels are implicated as a risk factor in CVD, and folic acid can reduce these levels. Furthermore, some studies have demonstrated that folic acid supplements help prevent additional heart disease events.
Bazzano has an explanation for the apparent conflict with her findings: "Observational studies, which don't randomize persons to `taking a supplement' versus `not taking' one, have shown a beneficial effect [with folic acid supplementation]. This is most likely because persons taking the supplement have different health habits and lifestyles than persons not taking the supplements. The influence of these lifestyle and health habits is minimized or eliminated in a randomized study since the investigator randomly assigns persons to either take the supplement or not."
According to Bazzano, "randomized controlled trials are considered the single best standard of evidence available for any intervention and, thus far, these show no benefit of folic acid supplementation."
The American Dietetic Association (ADietA) has issued standard values for daily folate intake. Christine Gerbstadt, MD, MPH, RD, LDN, spokeswoman for ADietA, points out that "the Reference Daily Intake (RDI) is the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all [97–98%] healthy individuals in each life-stage and gender group. The 1998 RDI for folate is expressed as the dietary folate equivalent [DFE]. This was developed to help account for the differences in absorption of naturally occurring dietary folate and the more bioavailable synthetic folic acid."
ADULTS DON'T GET ENOUGH FOLATE
The 1998 RDI for folate expressed in micrograms (µg) of DFE are:
19; 19; One µg of food folate is equivalent to 0.6 µg folic acid from supplements and fortified foods, Gerbstadt points out.
Gerbstadt adds that "the National Health and Nutrition Examination Survey [NHANES III, 1988–1991) and the Continuing Survey of Food Intakes by Individuals [CSFII, 1994–1996] indicated that most adults did not consume adequate folate. However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as cereals and grains and, as a result, diets of most adults now provide recommended amounts of folate equivalents."
Gerbstadt says that folate is found in fortified grains and cereals, as well as in green leafy vegetables, sunflower seeds, peas, bananas and certain other fruits, and some meats, such as liver.
"The risk of toxicity from folic acid is low," Gerbstadt says, but she adds that one should exercise caution when using supplements.
"The Institute of Medicine has established a tolerable upper intake level [UL] for folate of 1,000 µg for adult men and women, and a UL of 800 µg for pregnant and lactating [breastfeeding] women less than 18 years of age. Supplemental folic acid should not exceed the UL to prevent folic acid from masking symptoms of vitamin B12 deficiency and cancer."2
Bazzano believes the most recent review of studies that suggests a benefit is that done by David S. Wald, MD, published in the British Medical Journal.3
"That study and mine don't differ in that the randomized controlled trial evidence to date does not show benefit for folic acid supplement takers. Where we differ is in our positions on the relative importance of the randomized trial data versus the cohort and genetic studies," observes Bazzano.
IS HOMOCYSTEINE THE CULPRIT?
Studies of B vitamins and their role in reducing homocysteine levels are ongoing. These studies may show whether reducing homocysteine levels does, in fact, reduce existing heart disease risk.
Wald himself believes that the evidence shows that homocysteine is a cause of CVD.
"Since folic acid reduces homocysteine concentrations, to an extent dependent on background folate levels, it follows that increasing folic acid consumption will reduce the risk of heart attack and stroke by an amount related to the homocysteine reduction achieved," he writes in the British Medical Journal piece.3
Like Bazzano, Wald considers a meta-analysis of the randomized trials to be wanting.
The trials, "even in combination, are too few and too small to be conclusive," Wald tells DOC News. "Very important evidence comes from genetic studies, which are in effect natural randomized trials. These give us more information than the randomized trials that have been reported.
"We therefore take the view that the evidence is now sufficient to justify action in lowering homocysteine concentrations, although the position should be reviewed as evidence from ongoing clinical trials emerges," Wald says.
Bazzano says that "the best evidence will come from the combined analysis of individual level patient data from the B Vitamin Trialists collaboration. They will combine data from various trials with more than 52,000 participants. This pooled analysis will give us a truly definitive answer to the question of whether folate supplementation is beneficial."
She does not expect the results to demonstrate folate supplements can play
a significant role in promoting cardiovascular health. "With my study,
we have already ruled out any large benefit from the supplements,"
Bazzano adds. 
Facts About Folate
Source: Dietary Supplement Fact Sheet: Folate, National Institutes of Health, Offi ce of Dietary Supplements. Available online at http://dietary-supplements.info.nih.gov/factsheets/folate.asp. Accessed March 2, 2007.
Footnotes
More information on folic acid and folate is available from the National Institutes of Health's Office of Dietary Supplements at www.ods.od.nih.gov/factsheets/folate.asp.
References
2. Kendall DM, Riddle MC, Rosentock J, et al.: Effects of exenatide
(exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes
treated with metformin and a sulfonylurea. Diabetes
Care 28:1083–1091, 2005.
3. Wald D, Wald N, Morris J, et al.: Folic acid, homocysteine, and
cardiovascular disease: Judging causality in the face of inconclusive trial
evidence, BMJ 333:1114–1117, 2006.
1. Voutilainen S, Rissanen T, Virtanen J, et al.: Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio ischemic heart disease risk factor study. Circulation 103:2674–2680, 2001.
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