Elevated blood concentration of homocysteine is a potentially modifiable risk factor for coronary artery disease, stroke, and dementia. Intake of the B-vitamin folate is a major determinant of blood homocysteine concentrations, and vitamin supplements containing folic acid lower homocysteine concentrations. However, the exact dose of folic acid associated with the maximal reduction in homocysteine concentrations is not known. There have been several large-scale randomized trials, which are currently under way to determine whether lowering homocysteine concentrations with high doses of folic acid reduces the risk of recurrent cardiovascular disease.
The Homocysteine Lowering Trialists' Collaboration was established to determine the size of the reduction in homocysteine concentrations achieved with different oral doses of folic acid and with the addition of vitamin B-12 or B-6. The recent cycle of this collaboration, which involves individual data from 2596 participants in 25 trials was initiated to determine both the dose-dependent effects on plasma homocysteine concentrations of lower daily doses of folic acid (which might be of particular relevance to the fortification of foods with folic acid) and any additive effects of vitamins B-12 or B-6. Investigators aimed to identify all published or unpublished randomized trials that had assessed the effect on plasma homocysteine concentrations of folic acid supplements, with or without the addition of vitamins B-12 or B-6. Twenty-seven such trials were found. Most trials had a parallel-group design, but 2 trials had a crossover design. Only data from the first period of these trials was used to avoid any carry over effects.
For each participant enrolled in the trials, researchers sought details on patient age, sex, smoking habits, history of vascular disease, serum creatinine concentration, vitamin use before randomization, randomly allocated treatment regimen (that is, daily dose of folic acid, daily dose of any vitamin B-12 or B-6, and scheduled duration of treatment), and plasma concentrations of homocysteine, folate, and vitamins B-12 and B-6 before and during the scheduled treatment.
The proportional reductions in plasma homocysteine concentrations produced by folic acid were greater at higher homocysteine (P < 0.001) and lower folate (P < 0.001) pretreatment concentrations; they were also greater in women than in men (P < 0.001). Following standardization for sex and to pretreatment plasma concentrations of 12 micromol homocysteine/L and 12 nmol folate/L, daily doses of 0.2 mg, 0.4 mg, 0.8 mg, 2.0 mg, and 5.0 mg folic acid were associated with reductions in homocysteine of 13% (95% CI: 10%, 16%), 20% (17%, 22%), 23% (21%, 26%), 23% (20%, 26%), and 25% (22%, 28%), respectively. Vitamin B-12 (x: 0.4 mg/c) produced 7% (95% CI: 4%, 9%) further reduction in homocysteine concentrations, but vitamin B-6 had no significant effect.
Daily doses > 0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 mg and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect.
Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr; 82:806-812 (October, 2005) [Correspondence: R. Clarke, Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, OX26HE, UK. E-mail: Robert.clarke@ctsu.ox.ac.uk]
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