Long-term daily supplementation may reduce risk of AMD

Key Points

Fort Lauderdale, FL-Randomized data from a large cohort of women with cardiovascular disease or at high risk for it indicate that 7 years of daily supplementation with folic acid, vitamin B₆, and vitamin B₁₂ may reduce the risk of age-related macular degeneration (AMD), said William G. Christen, ScD, PhD, at the annual meeting of the Association for Research in Vision and Ophthalmology.

Results from the study of more than 5,000 women showed that the combination of folic acid, vitamin B₆, and vitamin B₁₂ reduced the risk of confirmed AMD by 34% and the risk of visually significant AMD by 41% over 7.3 years of treatment and follow-up.

Dr. Christen presented AMD findings from the Women's Anti-oxidant Folic Acid Cardiovascular Study (WAFACS). This was a double-blind, placebo-controlled, 2 X 2 X 2 X 2 factorial trial of folic acid, vitamin B₆, and vitamin B₁₂ conducted among women already randomly assigned to receive vitamin C, vitamin E, and beta-carotene. He is associate professor of medicine, Harvard Medical School, and associate epidemiologist, Brigham and Women's Hospital, Boston.

The intervention that was tested was a combination of folic acid (2.5 mg daily), vitamin B₆ (50 mg daily), and vitamin B₁₂ (1 mg daily).

The study was conducted because there has been speculation that AMD and cardiovascular disease share similar mechanisms and risk factors, one of which is the amino acid homocysteine, Dr. Christen said. Homocysteine is derived from the metabolism of methionine, an essential amino acid derived from dietary protein.

In periods of excess methionine intake, homocysteine is converted to cysteine in a process that involves a vitamin B₆-dependent enzyme. When methionine intake is low, homocysteine is recycled back to methionine in a process involving folic acid and vitamin B₁₂.

According to Dr. Christen, inadequate intake of folic acid and other B vitamins can lead to increased concentrations of homocysteine in the blood. Experimental studies have shown that hyperhomocysteinemia can induce endothelial dysfunction, impair vascular reactivity, and promote inflammatory processes leading to atherosclerosis, all of which are believed to be involved in the pathophysiology of AMD. It also has been demonstrated clearly that supplementation with folic acid and other B vitamins significantly can reduce homocysteine levels in the blood.

Both cross-sectional and case-control studies have reported an association between plasma homocysteine and AMD.

The original trial of which the folic acid study was a part began in late 1994 when 11,280 women were enrolled in a run-in; baseline blood samples were collected from 72% of the group. After successful completion of the run-in period, 8,171 of the women were randomly assigned to the antioxidant arms of the trial. In April 1998, 3 years after this randomization, 5,442 participants were further randomly assigned into the folic acid, vitamin B₆, and vitamin B₁₂ portion of the study. The WAFACS study began several months after folic acid fortification of cereal-grain products was fully implemented in the United States.

Follow-up blood samples were collected from 300 participants in early 2005, and the women completed taking their pills in July of that year. Follow-up was completed in July 2006.

Over the course of the trial, the women completed annual questionnaires in which they reported their compliance with study medication and the occurrence of any relevant study endpoints, such as the development of AMD. When AMD was reported, investigators sought consent to review medical records and sent an AMD questionnaire to the diagnosing eye physician.