Antioxidant Vitamins E and C

Oxidation of LDL contributes to the development of atherosclerosis. Oxidized LDL is found in atherosclerotic plaques, and oxidation of LDL appears to enhance its uptake by macrophages. This posed the question of whether treatment with antioxidants might retard the development of atherosclerosis. This hypothesis became more compelling when treatment antioxidants was shown to inhibit atherosclerosis in animal models. Epidemiologic studies initially suggested that vitamin E (but not vitamin C) was beneficial in reducing the risk of coronary heart disease in humans. The first two articles cited below are large prospective cohort studies - one in men and the other in women.

Rimm EB, et al.: Vitamin E Consumption and the Risk of Coronary Heart Disease in Men. N Engl J Med 1993; 328:1450-1456

From the abstract:

"In 1986, 39,910 U.S. male health professionals 40 to 75 years of age who were free of diagnosed coronary heart disease, diabetes, and hypercholesterolemia completed detailed dietary questionnaires that assessed their usual intake of vitamin C, carotene, and vitamin E in addition to other nutrients. During four years of follow-up, we documented 667 cases of coronary disease.

After controlling for age and several coronary risk factors, we observed a lower risk of coronary disease among men with higher intakes of vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of vitamin E, the multivariate relative risk was 0.64 (95 percent confidence interval, 0.49 to 0.83) as compared with those consuming less than 7.5 IU per day. As compared with men who did not take vitamin E supplements, men who took at least 100 IU per day for at least two years had a multivariate relative risk of coronary disease of 0.63 (95 percent confidence interval, 0.47 to 0.84). Carotene intake was not associated with a lower risk of coronary disease among those who had never smoked, but it was inversely associated with the risk among current smokers (relative risk, 0.30; 95 percent confidence interval, 0.11 to 0.82) and former smokers (relative risk, 0.60; 95 percent confidence interval, 0.38 to 0.94). In contrast, a high intake of vitamin C was not associated with a lower risk of coronary disease."

Kushi LH, et al.: Dietary Antioxidant Vitamins and Death from Coronary Heart Disease in Postmenopausal Women. N Engl J Med 1996; 334:1156-1162

From the abstract:

"We studied 34,486 postmenopausal women with no cardiovascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease.

In analyses adjusted for age and dietary energy intake, vitamin E consumption appeared to be inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend = 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend = 0.004). There was little evidence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementation and the duration of supplement use could not be definitively addressed. Intake of vitamins A and C did not appear to be associated with the risk of death from coronary heart disease.

These results suggest that in postmenopausal women the intake of vitamin E from food is inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease."

While these findings suggested a benefit of vitamin E in reducing cardiovascular disease, subsequent randomized clinical trials in men and women failed to show any benefit. See the excerpts from the two randomized clinical trials cited below.

Sesso HD, et al.: Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2008 Nov 12;300(18):2123-33.

From the abstract:

"The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31, 2007. There were 14,641 US male physicians enrolled, who were initially aged 50 years or older, including 754 men (5.1%) with prevalent cardiovascular disease at randomization.

INTERVENTION: Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.

MAIN OUTCOME MEASURES: A composite end point of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death).

RESULTS: During a mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, vitamin E had no effect on the incidence of major cardiovascular events (both active and placebo vitamin E groups, 10.9 events per 1000 person-years; hazard ratio [HR], 1.01 [95% confidence interval {CI}, 0.90-1.13]; P = .86), as well as total myocardial infarction (HR, 0.90 [95% CI, 0.75-1.07]; P = .22), total stroke (HR, 1.07 [95% CI, 0.89-1.29]; P = .45), and cardiovascular mortality (HR, 1.07 [95% CI, 0.90-1.28]; P = .43). There also was no significant effect of vitamin C on major cardiovascular events (active and placebo vitamin E groups, 10.8 and 10.9 events per 1000 person-years, respectively; HR, 0.99 [95% CI, 0.89-1.11]; P = .91), as well as total myocardial infarction (HR, 1.04 [95% CI, 0.87-1.24]; P = .65), total stroke (HR, 0.89 [95% CI, 0.74-1.07]; P = .21), and cardiovascular mortality (HR, 1.02 [95% CI, 0.85-1.21]; P = .86). Neither vitamin E (HR, 1.07 [95% CI, 0.97-1.18]; P = .15) nor vitamin C (HR, 1.07 [95% CI, 0.97-1.18]; P = .16) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke (HR, 1.74 [95% CI, 1.04-2.91]; P = .04).

CONCLUSIONS: In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men."

Song Y, et al.: 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. Am J Clin Nutr. 2009;90(2):429-37.

From the abstract:

"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.

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.

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).

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."

Key Concept:


Prospective cohort studies suggested that individuals who ate diets rich in vitamin E had a lower risk of heart disease, but clinical trials demonstrated that supplementation with neither vitamin E nor vitamin C had any effect. Two points might be made:

  • The demonstration of an association doesn't mean that there is a causal relationship.
  • Even in well-done prospective cohort studies, there is always the possibility of uncontrolled confounding. In this case, individuals who ate diets rich in vitamins E and C had a lower risk of heart disease, but these individuals may have had diets that were heart-healthy for other reasons or they may have been more health conscious and perhaps had other characteristics or behaviors that conferred greater risk.


Folic Acid

Numerous observational studies have established that elevated blood levels of homocysteine are associated with a graded increase in risk of coronary artery disease, MI, stroke, venous thromboembolism, and peripheral vascular disease. It is believed that the mechanism for this increased risks is related to oxidative stress. Dietary supplementation with folic acid (folate) and vitamin B12 reduces homocysteine levels, but vitamin therapy has generally not been successful in reducing vascular disease outcomes in subjects with mildly elevated homocysteine levels. The first large, randomized trial found that lowering the total homocysteine level with B vitamins failed to prevent recurrent stroke, myocardial infarction, or death in patients who had had a recent stroke

Bønaa KH, et al.: Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-88.

These authors conducted a randomized clinical trial with 3749 men and women who had had an acute myocardial infarction within seven days before randomization.

From the abstract:

"Patients were randomly assigned, in a two-by-two factorial design, to receive one of the following four daily treatments: 0.8 mg of folic acid, 0.4 mg of vitamin B12, and 40 mg of vitamin B6; 0.8 mg of folic acid and 0.4 mg of vitamin B12; 40 mg of vitamin B6; or placebo. The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease.


The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12, but such treatment had no significant effect on the primary end point (risk ratio, 1.08; 95 percent confidence interval, 0.93 to 1.25; P = 0.31). Also, treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point (relative risk of the primary end point, 1.14; 95 percent confidence interval, 0.98 to 1.32; P = 0.09). In the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk, 1.22; 95 percent confidence interval, 1.00 to 1.50; P = 0.05).


Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. A harmful effect from combined B vitamin treatment was suggested. Such treatment should therefore not be recommended."