Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies

Abstract

Background: High dietary intake or blood concentrations (as biomarkers of dietary intake) of vitamin C, carotenoids, and vitamin E have been associated with reduced risk of cardiovascular disease, cancer, and mortality, but these associations have not been systematically assessed.

Objective: We conducted a systematic review and meta-analysis of prospective studies of dietary intake and blood concentrations of vitamin C, carotenoids, and vitamin E in relation to these outcomes.

Design: We searched PubMed and Embase up to 14 February 2018. Summary RRs and 95% CIs were calculated with the use of random-effects models.

Results: Sixty-nine prospective studies (99 publications) were included. The summary RR per 100-mg/d increment of dietary vitamin C intake was 0.88 (95% CI: 0.79, 0.98, I2 = 65%, n = 11) for coronary heart disease, 0.92 (95% CI: 0.87, 0.98, I2 = 68%, n = 12) for stroke, 0.89 (95% CI: 0.85, 0.94, I2 = 27%, n = 10) for cardiovascular disease, 0.93 (95% CI: 0.87, 0.99, I2 = 46%, n = 8) for total cancer, and 0.89 (95% CI: 0.85, 0.94, I2 = 80%, n = 14) for all-cause mortality. Corresponding RRs per 50-μmol/L increase in blood concentrations of vitamin C were 0.74 (95% CI: 0.65, 0.83, I2 = 0%, n = 4), 0.70 (95% CI: 0.61, 0.81, I2 = 0%, n = 4), 0.76 (95% CI: 0.65, 0.87, I2 = 56%, n = 6), 0.74 (95% CI: 0.66, 0.82, I2 = 0%, n = 5), and 0.72 (95% CI: 0.66, 0.79, I2 = 0%, n = 8). Dietary intake and/or blood concentrations of carotenoids (total, β-carotene, α-carotene, β-cryptoxanthin, lycopene) and α-tocopherol, but not dietary vitamin E, were similarly inversely associated with coronary heart disease, stroke, cardiovascular disease, cancer, and/or all-cause mortality.

Conclusions: Higher dietary intake and/or blood concentrations of vitamin C, carotenoids, and α-tocopherol (as markers of fruit and vegetable intake) were associated with reduced risk of cardiovascular disease, total cancer, and all-cause mortality. These results support recommendations to increase fruit and vegetable intake, but not antioxidant supplement use, for chronic disease prevention.

FIGURE 1

Flow chart of study selection. COPD, chronic obstructive pulmonary disease.

FIGURE 2

Dietary intake and blood concentrations of vitamin C and coronary heart disease: dose-response analyses. (A) Dietary vitamin C and coronary heart disease: linear dose-response analysis. The summary RR per 100 mg/d was 0.88 (95% CI: 0.79, 0.98, I² = 65%, P_{heterogeneity} = 0.001, n = 11). (B) Vitamin C in blood and coronary heart disease: linear dose-response analysis. The summary RR per 50 µmol/L was 0.74 (95% CI: 0.65, 0.83, I² = 0%, P_{heterogeneity} = 0.71, n = 4). (C) Dietary vitamin C and coronary heart disease: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary vitamin C and coronary heart disease (P_nonlinearity < 0.0001). (D) Vitamin C in blood and coronary heart disease: nonlinear dose-response analysis. There was no evidence of nonlinearity for vitamin C in blood and coronary heart disease (P_nonlinearity = 0.49). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 3

Dietary intake and blood concentrations of vitamin C and stroke: dose-response analyses. (A) Dietary vitamin C and stroke: linear dose-response analysis. The summary RR per 100 mg/d was 0.92 (95% CI: 0.87, 0.98, I² = 68%, P_{heterogeneity} < 0.0001, n = 12). (B) Vitamin C in blood and stroke: linear dose-response analysis. The summary RR per 50 µmol/L was 0.70 (95% CI: 0.61, 0.81, I² = 0%, P_{heterogeneity} = 0.41, n = 4). (C) Dietary vitamin C and stroke: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary vitamin C and stroke (P_nonlinearity < 0.0001). (D) Vitamin C in blood and stroke: nonlinear dose-response analysis. There was no evidence of nonlinearity for vitamin C in blood and stroke (P_nonlinearity = 0.16). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 4

Dietary intake and blood concentrations of vitamin C and cardiovascular disease: dose-response analyses. (A) Dietary vitamin C and cardiovascular disease: linear dose-response analysis. The summary RR per 100 mg/d was 0.89 (95% CI: 0.85, 0.94, I² = 27%, P_{heterogeneity} = 0.19, n = 10). (B) Vitamin C in blood and cardiovascular disease: linear dose-response analysis. The summary RR per 50 µmol/L was 0.76 (95% CI: 0.65, 0.87, I² = 56%, P_{heterogeneity} = 0.05, n = 6). (C) Dietary vitamin C and cardiovascular disease: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary vitamin C and cardiovascular disease (P_nonlinearity < 0.0001). (D) Vitamin C in blood and cardiovascular disease: nonlinear dose-response analysis. There was no evidence of nonlinearity for vitamin C in blood and cardiovascular disease (P_nonlinearity = 0.26). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines. SMHS, Shanghai Men's Health Study; SWHS, Shanghai Women's Health Study.

FIGURE 5

Dietary intake and blood concentrations of vitamin C and total cancer: dose-response analyses. (A) Dietary vitamin C and total cancer: linear dose-response analysis. The summary RR per 100 mg/d was 0.93 (95% CI: 0.87, 0.99, I² = 46%, P_{heterogeneity} = 0.08, n = 8). (B) Vitamin C in blood and total cancer: linear dose-response analysis. The summary RR per 50 µmol/L was 0.74 (95% CI: 0.66, 0.82, I² = 0%, P_{heterogeneity} = 0.49, n = 5). (C) Dietary vitamin C and total cancer: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary vitamin C and total cancer (P_nonlinearity = 0.007). (D) Vitamin C in blood and total cancer: nonlinear dose-response analysis. There was evidence of nonlinearity for vitamin C in blood and total cancer (P_nonlinearity = 0.006). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines. SMHS, Shanghai Men's Health Study; SWHS, Shanghai Women's Health Study.

FIGURE 6

Dietary intake and blood concentrations of vitamin C and mortality: dose-response analyses. (A) Dietary vitamin C and mortality: linear dose-response analysis. The summary RR per 100 mg/d was 0.89 (95% CI: 0.85, 0.94, I² = 80%, P_{heterogeneity} < 0.0001, n = 14). (B) Vitamin C in blood and mortality: linear dose-response analysis. The summary RR per 50 µmol/L was 0.72 (95% CI: 0.66, 0.79, I² = 48%, P_{heterogeneity} = 0.06, n = 8). (C) Dietary vitamin C and mortality: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary vitamin C and mortality (P_nonlinearity < 0.0001). (D) Vitamin C in blood and mortality: nonlinear dose-response analysis. There was no evidence of nonlinearity for vitamin C in blood and mortality (P_nonlinearity = 0.90). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines. SMHS, Shanghai Men's Health Study; SWHS, Shanghai Women's Health Study.

FIGURE 7

Dietary intake and blood concentrations of carotenoids and mortality: dose-response analyses. (A) Dietary carotenoids and mortality: linear dose-response analysis. The summary RR per 5000 µg/d was 0.88 (95% CI: 0.83, 0.93, I² = 2%, P_{heterogeneity} = 0.40, n = 6). (B) Carotenoids in blood and mortality: linear dose-response analysis. The summary RR per 50 µg/dL was 0.69 (95% CI: 0.59, 0.81, I² = 50%, P_{heterogeneity} = 0.04, n = 10). (C) Dietary carotenoids and mortality: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary carotenoids and mortality (P_nonlinearity = 0.01). (D) Carotenoids in blood and mortality: nonlinear dose-response analysis. There was no evidence of nonlinearity for vitamin C in blood and mortality (P_nonlinearity = 0.73). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines. SMHS, Shanghai Men's Health Study; SWHS, Shanghai Women's Health Study.

FIGURE 8

Dietary β-carotene and blood concentrations of β-carotene and coronary heart disease: dose-response analyses. (A) Dietary β-carotene and coronary heart disease: linear dose-response analysis. The summary RR per 5000 µg/d was 0.82 (95% CI: 0.68, 0.98, I² = 45%, P_{heterogeneity} = 0.14, n = 4). (B) β-Carotene in blood and coronary heart disease: linear dose-response analysis. The summary RR per 25 µg/dL was 0.76 (95% CI: 0.62, 0.93, I² = 22%, P_{heterogeneity} = 0.28, n = 4). (C) Dietary β-carotene and coronary heart disease: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary β-carotene and coronary heart disease (P_nonlinearity = 0.006). (D) β-Carotene in blood and coronary heart disease: nonlinear dose-response analysis. There was evidence of nonlinearity for β-carotene in blood and coronary heart disease (P_nonlinearity = 0.002). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 9

(A) Dietary β-carotene and stroke: linear dose-response analyses. The summary RR per 5000 µg/d was 0.81 (95% CI: 0.66, 0.98, I² = 59%, P_{heterogeneity} = 0.02, n = 7). (B) β-Carotene in blood and stroke: linear dose-response analysis. The summary RR per 25 µg/dL was 0.85 (95% CI: 0.74, 0.97, I² = 0%, P_{heterogeneity} = 0.50, n = 3). (C) Dietary β-carotene and stroke: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary β-carotene and stroke (P_nonlinearity < 0.0001). (D) β-Carotene in blood and stroke: nonlinear dose-response analysis. There was evidence of nonlinearity for β-carotene in blood and stroke (P_nonlinearity = 0.07). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 10

Dietary β-carotene and blood concentrations of β-carotene and cardiovascular disease: dose-response analyses. (A) Dietary β-carotene and cardiovascular disease: linear dose-response analysis. The summary RR per 5000 µg/d was 0.87 (95% CI: 0.63, 1.20, I² = 58%, P_{heterogeneity} = 0.10, n = 3). (B) β-Carotene in blood and cardiovascular disease: linear dose-response analysis. The summary RR per 25 µg/dL was 0.85 (95% CI: 0.76, 0.95, I² = 9%, P_{heterogeneity} = 0.36, n = 7). (C) Dietary β-carotene and cardiovascular disease: nonlinear dose-response analysis. There was no evidence of nonlinearity between dietary β-carotene and cardiovascular disease (P_nonlinearity = 0.51). (D) β-Carotene in blood and cardiovascular disease: nonlinear dose-response analysis. There was evidence of nonlinearity for β-carotene in blood and cardiovascular disease (P_nonlinearity = 0.006). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 11

Dietary β-carotene and blood concentrations of β-carotene and total cancer: dose-response analyses. (A) Dietary β-carotene and total cancer: linear dose-response analysis. The summary RR per 5000 µg/d was 0.96 (95% CI: 0.90, 1.02, I² = 25%, P_{heterogeneity} = 0.26, n = 4). (B) β-Carotene in blood and total cancer: linear dose-response analysis. The summary RR per 25 µg/dL was 0.77 (95% CI: 0.68, 0.86, I² = 0%, P_{heterogeneity} = 0.64, n = 7). (C) Dietary β-carotene and total cancer: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary β-carotene and total cancer (P_nonlinearity = 0.003). (D) β-Carotene in blood and total cancer: nonlinear dose-response analysis. There was evidence of nonlinearity for β-carotene in blood and total cancer (P_nonlinearity = 0.60). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 12

Dietary intake and blood concentrations of β-carotene and mortality: dose-response analyses. (A) Dietary β-carotene and mortality: linear dose-response analysis. The summary RR per 5000 µg/d was 0.92 (95% CI: 0.85, 0.98, I² = 66%, P_{heterogeneity} = 0.01, n = 6). (B) β-Carotene in blood and mortality: linear dose-response analysis. The summary RR per 25 µg/dL was 0.81 (95% CI: 0.72, 0.90, I² = 47%, P_{heterogeneity} = 0.08, n = 7). (C) Dietary β-carotene and mortality: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary β-carotene and mortality (P_nonlinearity ≤ 0.0001). (D) β-Carotene in blood and mortality: nonlinear dose-response analysis. There was evidence of nonlinearity for β-carotene in blood and mortality (P_nonlinearity = 0.005). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines.

FIGURE 13

Blood concentrations of α-carotene, β-cryptoxanthin, and lycopene and mortality: dose-response analyses. (A) Blood concentrations of α-carotene and mortality: linear dose-response analysis. The summary RR per 10 µg/dL was 0.71 (95% CI: 0.64, 0.79, I² = 0%, P_{heterogeneity} = 0.86, n = 5). (B) Blood concentrations of β-cryptoxanthin and mortality: linear dose-response analysis. The summary RR per 15 µg/dL was 0.84 (95% CI: 0.76, 0.94, I² = 0%, P_{heterogeneity} = 0.99, n = 3). (C) Blood concentrations of lycopene and mortality: linear dose-response analysis. The summary RR per 25 µg/dL was 0.87 (95% CI: 0.74, 1.02, I² = 26%, P_{heterogeneity} = 0.25, n = 5). (D) Blood concentrations of α-carotene and mortality, nonlinear dose-response analysis. There was evidence of nonlinearity between α-carotene in blood and mortality (P_nonlinearity ≤ 0.0001). (E) Blood concentrations of β-cryptoxanthin and mortality: nonlinear dose-response analysis. There was no evidence of nonlinearity for β-cryptoxanthin in blood and mortality (P_nonlinearity = 0.98). (F) Blood concentrations of lycopene and mortality: nonlinear dose-response analysis. There was evidence of nonlinearity for lycopene in blood and mortality (P_nonlinearity = 0.001). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted using restricted cubic splines.

FIGURE 14

(A) Dietary intake of vitamin E and mortality: linear dose-response analysis. The summary RR per 5 µg/d was 0.99 (95% CI: 0.96, 1.01, I² = 42%, P_{heterogeneity} = 0.10, n = 8). (B) Blood concentrations of α-tocopherol and mortality: linear dose-response analysis. The summary RR per 500 µg/dL was 0.94 (95% CI: 0.90, 0.98, I² = 43%, P_{heterogeneity} = 0.09, n = 8). (C) Dietary intake of vitamin E and mortality: nonlinear dose-response analysis. There was evidence of nonlinearity between dietary vitamin E and mortality (P_nonlinearity < 0.0001). (D) Blood concentrations of α-tocopherol and mortality: nonlinear dose-response analysis. There was indication of nonlinearity for α-tocopherol in blood and mortality (P_nonlinearity = 0.05). Summary RRs and 95% CIs were calculated with the use of random-effects models, and the nonlinear dose-response analyses were conducted with the use of restricted cubic splines. SMHS, Shanghai Men's Health Study; SWHS, Shanghai Women's Health Study.