Effect of Supplementation with Folic Acid to Lower Homocysteine Levels

Increased risk of cardiovascular disease (CVD), including coronary heart disease, stroke, and other occlusive vascular conditions, is known to be associated with elevated levels of plasma homocysteine. It is uncertain what effects supplementation with folic acid to lower plasma homocysteine levels have on disease rates. In patients with homocystinuria, supplementation with B vitamins has been shown to lower homocysteine levels and reduce the risk of CVD. A meta-analysis of randomized trials found that in populations without folic acid fortification, supplementation with folic acid lowered homocysteine levels by 23%; if given in combination with vitamin B12 (cyanocobalamin), the levels were reduced by 30%. The results in populations with preexisting folic acid were less pronounced. Researchers recently conducted a meta-analysis of 8 large randomized placebo-controlled trials of folic acid supplementation. The trials involved 37,485 individuals at increased risk of CVD. Meta-analysis results were reported in Archives of Internal Medicine [2010;170(18):1622-1631]. There were 18,723 participants allocated to treatment with folic acid and 18,762 allocated to placebo. Trials were included in the meta-analysis if (1) they involved a double-blind randomized comparison of vitamin B supplements containing folic acid versus placebo for the prevention of vascular disease; (2) the relevant treatment arms differed only with respect to the intervention to lower homocysteine levels; and (3) the trial involved a minimum of 1000 patients for a scheduled treatment duration of at least 1 year. Four of the trials recruited participants with prior CVD, 1 recruited participants with prior stroke, 2 with prior CVD or increased risk of CVD, and 1 with advanced renal disease. Six of the trials recruited partly or entirely from populations of individuals not fortified with folic acid and 4 recruited partly or entirely from populations fortified with folic acid. The analysis involved intention-to-treat comparisons of first events during the scheduled treatment period. Among the participants in all 8 trials, 9326 had a major vascular event during the scheduled treatment period. Allocation to treatment with folic acid versus placebo resulted in a 25% reduction in homocysteine levels. The analysis found that allocation to supplementation with folic acid had no significant effect on major vascular events; there were 4670 first events among participants allocated to folic acid compared with 4656 among participants allocated to placebo (rate ratio [RR], 1.01; 95% confidence interval [CI], 0.97-1.05; P=.6). There was also no significant effect on the numbers of participants experiencing a major coronary event (MCE): there were 2019 MCEs among participants allocated to folic acid compared with 1971 among those in the placebo group (RR, 1.03; 95% CI, 0.97-1.10; P=.3). The effect on the risk of stroke was also nonsignificant (747 vs 781 first events; RR, 0.96; 95% CI, 0.87-1.06; P=.4), as was the effect on the risk of ischemic stroke (RR, 0.96; 99% CI, 0.81-1.14), hemorrhagic stroke (RR, 1.08; 99% CI, 0.66-1.77), and unclassified stroke (RR, 0.94; 99% CI, 0.75-1.18). Finally, allocation to treatment with folic acid had no effect on arterial revascularization (RR, 1.00; 95% CI, 0.94-1.05) or on coronary revascularization or MCE (RR, 1.01; 95% CI, 0.96-1.06). Seven of the trials included data on participants with incident cancer that occurred during randomization. Analysis of those data found that allocation to folic acid had no association with any significant difference in the overall incidence of cancer; there were 1541 new cases of cancer among those allocated to folic acid compared with 1469 among those allocated to placebo (RR, 1.05; 95% CI, 0.98-1.13; P=.14). In conclusion, the researchers said, “dietary supplementation with folic acid to lower homocysteine levels had no significant effects within 5 years on cardiovascular events or on overall cancer or mortality in the populations studied.”