Background: Elevated plasma homocysteine levels have been proposed as a potentially modifiable risk factor for coronary heart disease. Vitamin B supplementation has been shown to lower homocysteine levels and cardiovascular disease (CVD) risk in patients with homocystinuria. However, vitamin B supplementation has not been shown to improve CVD outcomes in randomized trials in the larger population. Clarke and colleagues conducted a meta-analysis of large trials of vitamin B supplementation in patients at increased risk of CVD.

The Study: The authors included randomized, double-blind trials comparing vitamin B supplementation containing folic acid with placebo for the prevention of vascular disease. Eligible trials involved at least 1,000 participants who were treated for at least one year. The primary outcomes included the incidence of major vascular events (i.e., myocardial infarction or coronary death) and strokes (i.e., ischemic, hemorrhagic, or unclassified). Cancer incidence and total and cause-specific mortality rates from eligible studies were also reviewed.

Results: Eight trials involving 37,485 patients were analyzed, with a median treatment duration of five years (range = 2 to 7.3 years). All trials included folic acid supplementation at a dosage of 0.8 to 5.0 mg per day, except for one trial that used 40 mg per day. Seven trials used vitamin B₁₂ (0.4 to 2.0 mg per day), and six trials also included vitamin B₆ supplementation.

Overall, vitamin B supplementation reduced plasma homocysteine levels by 25 percent, with the greatest reduction in patients with the highest initial homocysteine levels. However, no corresponding reduction in cardiovascular event rates occurred compared with the placebo groups. Similarly, no benefit was noted when compared with placebo in regard to cancer incidence or total mortality, including death from coronary heart disease (rate ratio [RR] = 1.02; P = .65), stroke (RR = 0.92; P = .47), or cancer (RR = 1.00; P = .99). Longer treatment duration was not associated with any clinical benefit.

Conclusion: Although vitamin B supplementation lowered plasma homocysteine levels, there was no corresponding benefit on the incidence of major vascular events, cancer, or all-cause mortality.

editor's note: Unfortunately, the interest in reducing homocysteine levels with vitamin B supplementation ultimately may be similar to previous interest in post-menopausal hormone therapy, vitamin E, and beta-carotene to improve a wide range of health issues.¹ Observational studies showed a promising association between the proposed intervention and a variety of outcomes; however, benefits were unable to be replicated with the preferred standard of research: randomized controlled trials. Some randomized trials even showed worsened outcomes, as with beta-carotene supplementation increasing the risk of lung cancer in male smokers, and high-dose antioxidant vitamin supplementation possibly increasing mortality rates.^2,3

Besides the interest in vitamin B supplementation to reduce cardiovascular mortality, which is refuted in this study, observational data have suggested it may help slow cognitive decline. However, a well-powered, long-term study did not show any benefit for this purpose either.⁴

Despite the understandable interest by the public and physicians to improve health outcomes through vitamin supplementation, our efforts should be focused on promoting therapies proven to optimize health, such as exercising, eating right, and avoiding smoking. Although less convenient than taking a pill, these interventions have been shown to improve health outcomes.—k.t.m.