Folic Acid, Homocysteine, and Cardiovascular Disease - Judging Causality in the Face of Inconclusive Trial Evidence

Wald D, Wald N, Morris J, Law M: Folic Acid, Homocysteine, and Cardiovascular Disease - Judging Causality in the Face of Inconclusive Trial Evidence. BMJ. 2006;333:1114-1117.

Background. There are conflicting data over the relationship between elevated serum homocysteine levels and the risk of ischemic heart disease and stroke. It is also unclear whether folic acid can reduce these risks by lowering homocysteine levels. The authors review the nondefinitive findings on this issue and attempt to make recommendations.

Review of the Evidence. Data from cohort studies suggest a significant and positive relationship between serum homocysteine concentrations and ischemic heart disease. In patients with homocysteinuria, reducing homocysteine level significantly lowers cardiovascular risk. Studies of subjects with a common mutation associated with higher homocysteine levels also support the association between homocysteine and ischemic heart disease risk. Trials evaluating the effects of reducing homocysteine levels on myocardial infarction and stroke risk are being performed. So far, these studies have yielded only modest benefits, the significance of which has been questioned. The estimated summary effect suggests a short-term 12% reduction in ischemic heart disease events and a 22% reduction in stroke. Larger effects may emerge on long-term follow-up.

Recommendations. Although no single line of evidence is sufficient to reach this conclusion, summed evidence from various types of studies suggests that homocysteine is a cause of cardiovascular disease. Given the homocysteine-lowering effect of folic acid, it seems likely that increasing folic acid intake will help to reduce the risk of ischemic heart disease and stroke. While awaiting further clinical trial data, the authors conclude that, “[T]he evidence is now sufficient to justify action on lowering homocysteine concentrations.”

Commentary: Even though studies on the link between elevated homocysteine levels and cardiovascular disease are not definitive it is known that folic acid reduces homocysteine concentrations. Given the safety of consuming folic acid as a dietary supplement and the existing scientific evidence, these authors have concluded that increasing folic acid consumption will reduce the risk of heart attack and stroke by reducing homocysteine level in the serum. It seems very reasonable.