Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration

Abstract

Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6.

Design: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6.

Subjects: Individual data on 1114 people included in 12 trials.

Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P < 0.001) and at lower pretreatment blood folate concentrations (P < 0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 mumol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P < 0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect.

Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 mumol/l to 8-9 mumol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.

Figures

Figure 1

Reductions in blood homocysteine concentrations with folic acid supplements according to pretreatment blood concentrations of homocysteine, folate, and vitamin B-12. Squares indicate the ratios of post-treatment blood homocysteine among subjects allocated folic acid supplements to those of controls; size of square is proportional to number of subjects, and horizontal line indicates 95% confidence interval

Figure 2

Predicted proportional reduction in blood homocysteine concentrations with folic acid supplementation (0.5-5 mg daily)

Figure 3

Reductions in blood homocysteine concentrations with varying doses of folic acid at pretreatment blood concentrations of homocysteine of 12 μmol/l and folate of 12 nmol/l. Squares indicate the ratios of post-treatment blood homocysteine among subjects allocated folic acid supplements to those of controls; size of square is proportional to number of subjects, and horizontal line indicates 95% confidence interval