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1 From the Food Science and Human Nutrition Department, University of Florida, Gainesville, FL
2 Address reprint requests to LB Bailey, Food Science and Human Nutrition Department, PO Box 110370, University of Florida, Gainesville, FL 32611. E-mail: lbbailey{at}mail.ifas.ufl.edu.
See corresponding article on page 806.
The link between hyperhomocysteinemia and the risk of vascular disease has been the impetus for numerous controlled intervention studies, which have established the fact that folic acid has a significant homocysteine-lowering effect. The Homocysteine Lowering Trialists' Collaboration was established to estimate by meta-analyses the size of the reduction in homocysteine concentration achieved with different doses of folic acid (with or without vitamin B-12 or B-6) in randomized controlled trials. On the basis of findings from the first meta-analysis, it was concluded that the homocysteine-lowering effect was comparable (25%) for folic acid doses of 0.5–1, 1–3, and >3 mg/d (1). Because the magnitude of the homocysteine response to folic acid intervention depends on the pretreatment concentrations of both folate and homocysteine, the baseline plasma folate and homocysteine concentrations were standardized in the meta-analyses to 12 nmol/L and 12 µmol/L, respectively. Because few data were available, it was not possible to discriminate between the homocysteine-lowering response to folic acid doses that were <0.5 mg/d. In contrast, the second meta-analysis of the Homocysteine Lowering Trialists' Collaboration, reported in this issue of the Journal (2), provides important new insights regarding the homocysteine-lowering effect of low doses of folic acid. This new meta-analysis provides evidence of a graded homocysteine dose response among low folic acid doses, in which the lowest 2 doses each differ from the next dose (ie, 0.2 mg versus 0.4 mg/d and 0.4 mg versus 0.8 mg/d), but there were no differences between 0.8 mg/d and the higher doses (ie, 2.0 or 5.0 mg/d).
The maximum reduction (23%) in plasma homocysteine concentration was observed with 0.8 mg folic acid/d; 20% and 13% reductions were observed with the lower doses (0.4 and 0.2 mg/d). The fact that the response to 0.4 mg folic acid/d was 90% of the maximum response is a finding of key importance, because that is the amount of folic acid most often included as a component of multivitamin supplements.
It is important to note that the conclusions drawn from this European meta-analysis are not directly applicable to studies performed in North America, where, as a direct result of folic acid fortification of food, the mean plasma folate concentration has increased dramatically and simultaneously with decreases in mean plasma homocysteine concentrations (3). The improved folate status resulting from folic acid fortification would be expected to significantly attenuate the homocysteine-lowering response to folic acid. The findings of the latest meta-analysis from the Homocysteine Lowering Trialists' Collaboration suggest that, in North America, additional folic acid supplementation (0.8 mg/d) would likely lower plasma homocysteine concentrations by considerably less than the 25% reduction observed in populations in which the baseline homocysteine concentrations are higher. This prediction was recently confirmed in the Vitamin Intervention for Stroke Prevention trial conducted in the United States and Canada (4), in which the reduction in homocysteine concentration was much smaller than that predicted when the study was designed.
Both the first and the second meta-analyses of the Homocysteine Lowering Trialists' Collaboration led to the conclusion that there is a 7% greater homocysteine-lowering effect when vitamin B-12 is taken in addition to folic acid; in contrast, no increased effect was detected when vitamin B-6 was added to folic acid (1, 2). Since the introduction of folic acid fortification of cereal-grain products in the United States and Canada, the associations between vitamin intakes and plasma homocysteine concentrations appear to have shifted from being primarily dependent on folate status to being more dependent on vitamin B-12 status (5). Evidence to this effect is provided by a recent randomized controlled intervention study conducted in the United States by Tucker et al (5), which found that the combination of folic acid (440 µg/d), vitamin B-12 (4.8 µg/d), and vitamin B-6 (1.8 mg/d) reduced the prevalence of high plasma homocysteine concentrations in a group of healthy older persons from 13% to 3%. Approximately 10% of the treatment group had baseline vitamin B-12 concentrations that were below clinical cutoffs for deficiency; this proportion fell to 3.2% after 12 wk of intervention. The homocysteine-lowering effect of vitamin B-12 provides support for the inclusion of vitamin B-12 in addition to folic acid in future fortification regimens. This concept is of particular importance in countries where low vitamin B-12 status is well documented (6, 7).
The current meta-analysis provided evidence that women are more responsive than are men to the homocysteine-lowering effects of folic acid (2), a finding that warrants further study. Some evidence was previously provided to support the suggestion that sex may modify the association between homocysteine and the risk of vascular disease. In the Women's Health Study (8), the association between homocysteine concentrations and vascular disease risk was stronger than the association observed in males in the Physicians Health Study (9); this conclusion is supported by other observational studies, as previously reviewed (10).
Thus, the question is whether the reductions in plasma homocysteine concentrations are of sufficient magnitude as to be associated with a reduction in the overall incidence of vascular disease. Two recent meta-analyses of observational studies concluded that a 25% reduction in plasma homocysteine concentration (to 3 µmol/L), which is similar to the reduction observed with 0.8 mg folic acid/d in the recent meta-analysis from the Homocysteine Lowering Trialists' Collaboration (2), was associated with decreases of 11–16% in the risk of ischemic heart disease and of 19–22% in the risk of stroke (11, 12). A series of ongoing, large-scale, randomized controlled intervention trials are underway in the United States, Canada, Australia, and several countries in Europe to assess the effect of folic acid given alone or, in some cases, given with vitamins B-12 and B-6 on vascular disease risk (13). The trials conducted in North America are not expected to achieve the same reduction in homocysteine concentration as would occur in European and Australian populations, who are not exposed to mandatory fortification, and, as a result, the North American trials may not have the statistical power necessary to detect a significant effect on vascular disease outcome. For example, the small reduction in homocysteine concentration observed in the postfortification Vitamin Intervention for Stroke Prevention study was substantially less than the reduction needed to detect the 30% decrease in clinical events originally anticipated to prevent atherothrombotic events (4).
In summary, it can be expected that a near-maximum homocysteine-lowering effect would be achieved with the dose of folic acid most commonly included in multivitamins (0.4 mg/d). Because of lower baseline homocysteine values due to consumption of folic acid–fortified food, the magnitude of the homocysteine response to supplemental folic acid would be expected to be considerably less in North American countries than in countries without food fortification.
ACKNOWLEDGMENTS
The author had no personal or financial conflict of interest concerning the article by the Homocysteine Lowering Trialists’ Collaboration or with the study it reported.
REFERENCES
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