The Failure to Measure Dietary Intake Engendered a Fictional Discourse on Diet-Disease Relations

Most studies of US dietary trends have evaluated major macronutrients or only a few dietary factors. Understanding trends in summary measures of diet quality for multiple individual foods and nutrients, and the corresponding disparities among population subgroups, is crucial to identify challenges and opportunities to improve dietary intake for all US adults.

In 15 cohorts of the Seven Countries Study, comprising 11,579 men aged 40-59 years and "healthy" at entry, 2,288 died in 15 years. Death rates differed among cohorts. Differences in mean age, blood pressure, serum cholesterol, and smoking habits "explained" 46% of variance in death rate from all causes, 80% from coronary heart disease, 35% from cancer, and 45% from stroke. Death rate differences were unrelated to cohort differences in mean relative body weight, fatness, and physical activity. The cohorts differed in average diets. Death rates were related positively to average percentage of dietary energy from saturated fatty acids, negatively to dietary energy percentage from monounsaturated fatty acids, and were unrelated to dietary energy percentage from polyunsaturated fatty acids, proteins, carbohydrates, and alcohol. All death rates were negatively related to the ratio of monounsaturated to saturated fatty acids. Inclusion of that ratio with age, blood pressure, serum cholesterol, and smoking habits as independent variables accounted for 85% of variance in rates of deaths from all causes, 96% coronary heart disease, 55% cancer, and 66% stroke. Oleic acid accounted for almost all differences in monounsaturates among cohorts. All-cause and coronary heart disease death rates were low in cohorts with olive oil as the main fat. Causal relationships are not claimed but consideration of characteristics of populations as well as of individuals within populations is urged in evaluating risks.

Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review. To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults. We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials. We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimise the risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Random-effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity. Seventy-eight randomised trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I(2)- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002). We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.