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.
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 × 2 × 2 × 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 study population consisted of 5,442 female health professionals aged 40 or more years who had pre-existing cardiovascular disease or three or more coronary risk factors. Among the overall study population, 5,205 individuals did not have a diagnosis of AMD at the beginning of the folic acid arm of the study and were included in Dr. Christen’s analysis.
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 can significantly 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.
“What we sought to do was to determine the date of initial diagnosis of AMD, the date when visual acuity was first noted to be 20/30 or worse, the retinal signs of AMD that were present when [acuity] was first 20/30 or worse, and whether there were other ocular abnormalities that would explain the visual acuity loss, and if so we asked the eye doctor to give us his or her impression as to whether or not the AMD was severe enough to reduce vision to 20/30 or worse,” Dr. Christen said.
The average age of women in WAFACS at baseline was 62.6 years. About 86% of the women in the active treatment and placebo groups reported hypertension at baseline, about 78% reported hyperlipidemia, and about 21% reported diabetes. In both groups, 64% had pre-existing cardiovascular disease. The mean body mass index ([BMI], kg/m2) was 30.6 in the active treatment group and 30.7 in the placebo group.
About 12% reported being current smokers, about 33% reported daily alcohol use, 22% to 23% said they used multi-vitamins, and 62% in both groups said they used aspirin within the past month.
Analysis showed that cases of AMD occurred in both the experimental and placebo groups but at higher rates among the latter.
“Over an average of 7.3 years of treatment and follow-up, a total of 137 cases of confirmed AMD were documented, including 70 cases of visually significant AMD,” Dr. Christen said.
Data on the retinal signs indicative of visually significant AMD showed that about 70% of the cases were characterized by a combination of drusen and retinal pigment epithelium changes. However, these cases still represented a relatively early stage of AMD development, Dr. Christen added.
Investigators were able to document 55 confirmed cases of AMD in the active treatment group and 82 in the placebo arm of the WAFACS. The relative risk (RR) was 0.66 (95% CI, 0.47 to 0.93). Twenty-six cases of visually significant AMD occurred in the active treatment group and 44 occurred in the placebo group (RR 0.59; 95% CI, 0.36 to 0.95). The rates of confirmed AMD in the active treatment and placebo groups began to diverge after about 2 years of treatment and follow-up and remained separated for the duration of the trial. For visually significant AMD, the divergence began later, at about 4 years. Investigators also analyzed the impact of baseline characteristics such as age, cigarette smoking, alcohol use, BMI, and medical history. “We found no evidence that the effect of folic acid and [other] B vitamins on visually significant AMD, or on confirmed AMD for that matter, was modified by any of the risk factors at baseline,” Dr. Christen said.
He also presented results of a blood substudy conducted to evaluate the effect of folic acid fortification and folic acid supplementation on homocysteine levels. At the beginning of the WAFACS trial, the folic acid levels in a sample of 300 participants were a mean of 9.2 ng/ml in the placebo group and 9 ng/ml in the active treatment group.
By the end of the study, folic acid levels in the placebo group had increased to 16.4 ng/ml (p < 0.001). This change presumably reflects the effect of folic acid fortification of food in the United States, Dr. Christen said. In the active treatment arm, the folic acid level more than quadrupled to 39.6 ng/ml (p < 0.001).
Homocysteine levels in this sample did not change between baseline and follow-up in the placebo group despite the fact that folic acid levels had increased significantly; the level remained at 12.3 µmol/l. In the active group, the level declined from 12.2 to 10 µmol/l (p < 0.001), about 18%.
“Additional study will be required to determine to what extent, if any, the beneficial effect of folic acid and [other] B vitamins on AMD is mediated by [their] homocysteine-lowering effect,” Dr. Christen concluded.OT