Homocysteine Is Associated With Future Venous Thromboembolism in 2 Prospective Cohorts of Women.

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Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women.

BACKGROUND: Homocysteine-lowering nutrients may have preventive/ameliorative roles in depression. AIMS: To test whether long-term B-vitamin/folate supplementation reduces depression risk. METHOD: Participants were 4331 women (mean age 63.6 years), without prior depression, from the Women's Antioxidant and Folic Acid Cardiovascular Study - a randomised controlled trial of cardiovascular disease prevention among 5442 women. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), vitamin B6 (50 mg/d) and vitamin B12 (1 mg/d) or a matching placebo. Average treatment duration was 7 years. The outcome was incident depression, defined as self-reported physician/clinician-diagnosed depression or clinically significant depressive symptoms. RESULTS: There were 524 incident cases. There was no difference between active v. placebo groups in depression risk (adjusted relative risk 1.02, 95% CI 0.86-1.21, P = 0.81), despite significant homocysteine level reduction. CONCLUSIONS: Long-term, high-dose, daily supplementation with folic acid and vitamins B6 and B12 did not reduce overall depression risk in mid-life and older women.

Effect of Combined Treatment With Folic Acid, Vitamin B6, and Vitamin B12 on Plasma Biomarkers of Inflammation and Endothelial Dysfunction in Women.

BACKGROUND: The aim of this study was to determine whether reducing plasma homocysteine concentrations with long-term, combined treatment with folic acid, vitamin B6, and vitamin B12 alters plasma biomarkers of inflammation and endothelial dysfunction in women at increased risk of cardiovascular disease. METHODS AND RESULTS: We conducted a blood substudy of 300 treatment-adherent participants (150 in the active treatment group, 150 in the placebo group) in the WAFACS (Women's Antioxidant and Folic Acid Cardiovascular Study), a randomized, double-blind, placebo-controlled trial testing a daily combination of folic acid (2.5 mg), vitamin B6 (50 mg), vitamin B12 (1 mg), or matching placebo, in cardiovascular disease prevention among women at increased risk of cardiovascular disease. Plasma concentration of 3 biomarkers of inflammation (C-reactive protein, interleukin-6, and fibrinogen) and a biomarker of endothelial dysfunction (intercellular adhesion molecule 1) were measured at baseline and at the end of treatment and follow-up. After 7.3 years of combined treatment with folic acid, vitamin B6, and vitamin B12, homocysteine concentrations were reduced by 18% in the active treatment group as compared with the placebo group (P<0.001). However, there was no difference between treatment groups in change in blood concentration from baseline to follow-up for C-reactive protein (P=0.77), interleukin-6 (P=0.91), intercellular adhesion molecule 1 (P=0.38), or fibrinogen (P=0.68). CONCLUSIONS: These findings indicate that long-term, combined treatment with folic acid, vitamin B6, and vitamin B12 lowers homocysteine concentrations, but does not alter major biomarkers of vascular inflammation, consistent with the lack of clinical cardiovascular disease benefit in the trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000541.

Vitamin E and risk of type 2 diabetes in the women's health study randomized controlled trial.

We directly assessed the efficacy of vitamin E supplements for primary prevention of type 2 diabetes among apparently healthy women in the Women's Health Study randomized trial. Between 1992 and 2004, 38,716 apparently healthy U.S. women aged >or=45 years and free of diabetes, cancer, and cardiovascular disease were in two randomly assigned intervention groups and received 600 IU of vitamin E (alpha-tocopherol, n = 19,347) or placebo (n = 19,369) on alternate days. During a median 10-year follow-up, there were 827 cases of incident type 2 diabetes in the vitamin E group and 869 in the placebo group, a nonsignificant 5% risk reduction (relative risk [RR] 0.95 [95% CI 0.87-1.05], P = 0.31). There was no evidence that diabetes risk factors including age, BMI, postmenopausal hormone use, multivitamin use, physical activity, alcohol intake, and smoking status modified the effect of vitamin E on the risk of type 2 diabetes. In a sensitivity analysis taking compliance into account, women in the vitamin E group had an RR of 0.93 (95% CI 0.83-1.04) (P = 0.21) compared with those randomized to placebo. In this large trial with 10-year follow-up, alternate-day doses of 600 IU vitamin E provided no significant benefit for type 2 diabetes in initially healthy women.

The Women's Antioxidant Cardiovascular Study: design and baseline characteristics of participants.

BACKGROUND: The evidence for a potential benefit of antioxidant vitamins and folic acid in cardiovascular disease (CVD) prevention is derived from laboratory, clinical, and observational epidemiological studies but remains inconclusive. Large-scale randomized trials with clinical end points are necessary to minimize confounding and provide unbiased estimates of the balance of benefits and risks, yet data from such trials are scarce, especially among women. METHODS: The Women's Antioxidant Cardiovascular Study (WACS) is a randomized, double-blind, placebo-controlled trial testing whether antioxidant vitamins and a folic acid/vitamin B(6)/vitamin B(12) combination prevent future cardiovascular events among women with preexisting CVD or >or=3 CVD risk factors. This paper describes the design of the trial and baseline characteristics of participants, evaluates the success of randomization, and addresses the generalizability of future findings. RESULTS: In a factorial design, 8171 U.S. female health professionals aged >or=40 years were randomized to vitamin E, vitamin C, beta-carotene, or placebos. Of these women, 5442 were also subsequently randomized to folic acid/vitamin B(6)/vitamin B(12) or placebo. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The clinical profile of participants was similar to that observed in another large trial of women with CVD. CONCLUSIONS: The similar distribution of known potential confounders across treatment groups provides reassurance that unmeasured or unknown potential confounders are also equally distributed. Although a definitive conclusion regarding generalizability requires additional trials in diverse populations, there is little biological basis for supposing that the benefit-risk balance differs in other high-risk women.

Effect of homocysteine-lowering treatment with folic Acid and B vitamins on risk of type 2 diabetes in women: a randomized, controlled trial.

OBJECTIVE: Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress, systemic inflammation, and endothelial dysfunction. We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized, double-blind, placebo-controlled trial of 5,442 female health professionals aged > or = 40 years with a history of cardiovascular disease (CVD) or three or more CVD risk factors, included 4,252 women free of diabetes at baseline. Participants were randomly assigned to either an active treatment group (daily intake of a combination pill of 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12) or to the placebo group. RESULTS: During a median follow-up of 7.3 years, 504 women had an incident diagnosis of type 2 diabetes. Overall, there was no significant difference between the active treatment group and the placebo group in diabetes risk (relative risk 0.94 [95% CI 0.79-1.11]; P = 0.46), despite significant lowering of homocysteine levels. Also, there was no evidence for effect modifications by baseline intakes of dietary folate, vitamin B6, and vitamin B12. In a sensitivity analysis, the null result remained for women compliant with their study pills (0.92 [0.76-1.10]; P = 0.36). CONCLUSIONS: Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD.

Effects of vitamins C and E and beta-carotene on the risk of type 2 diabetes in women at high risk of cardiovascular disease: a randomized controlled trial.

BACKGROUND: Vitamin C, vitamin E, and beta-carotene are major antioxidants and as such may protect against the development of type 2 diabetes via reduction of oxidative stress. OBJECTIVE: The purpose of this study was to investigate the long-term effects of supplementation with vitamin C, vitamin E, and beta-carotene for primary prevention of type 2 diabetes. DESIGN: In the Women's Antioxidant Cardiovascular Study, a randomized trial that occurred between 1995 and 2005, 8171 female health professionals aged > or =40 y with either a history of cardiovascular disease (CVD) or > or =3 CVD risk factors were randomly assigned to receive vitamin C (ascorbic acid, 500 mg every day), vitamin E (RRR-alpha-tocopherol acetate, 600 IU every other day), beta-carotene (50 mg every other day), or their respective placebos. RESULTS: During a median follow-up of 9.2 y, a total of 895 incident cases occurred among 6574 women who were free of diabetes at baseline. There was a trend toward a modest reduction in diabetes risk in women assigned to receive vitamin C compared with those assigned to receive placebo [relative risk (RR): 0.89; 95% CI: 0.78, 1.02; P = 0.09], whereas a trend for a slight elevation in diabetes risk was observed for vitamin E treatment (RR: 1.13; 95% CI: 0.99, 1.29; P = 0.07). However, neither of these effects reached statistical significance. No significant effect was observed for beta-carotene treatment (RR: 0.97; 95% CI: 0.85, 1.11; P = 0.68). CONCLUSION: Our randomized trial data showed no significant overall effects of vitamin C, vitamin E, and beta-carotene on risk of developing type 2 diabetes in women at high risk of CVD. This trial was registered at clinicaltrials.gov as NCT00000541.

Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial.

BACKGROUND: Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with antioxidants, may prevent cancer development. However, findings from randomized trials of the association between antioxidant use and cancer risk have been mostly negative. METHODS: From 8171 women who were randomly assigned in the Women's Antioxidant Cardiovascular Study, a double-blind, placebo-controlled 2 x 2 x 2 factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of alpha-tocopherol every other day), and beta carotene (50 mg every other day), 7627 women who were free of cancer before random assignment were selected for this study. Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index. Cox proportional hazards regression models were used to assess hazard ratios (represented as relative risks [RRs]) of common cancers associated with use of antioxidants, either individually or in combination. Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk. All statistical tests were two-sided. RESULTS: During an average 9.4 years of treatment, 624 women developed incident invasive cancer and 176 women died from cancer. There were no statistically significant effects of use of any antioxidant on total cancer incidence. Compared with the placebo group, the RRs were 1.11 (95% confidence interval [CI] = 0.95 to 1.30) in the vitamin C group, 0.93 (95% CI = 0.79 to 1.09) in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in the beta carotene group. Similarly, no effects of these antioxidants were observed on cancer mortality. Compared with the placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the vitamin C group, 0.87 (95% CI = 0.65 to 1.17) in the vitamin E group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group. Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death. CONCLUSIONS: Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality.