Eating tofu lower risk of heart disease

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Eating tofu and foods that contain higher amounts of isoflavones was associated with a moderately lower risk of heart disease, especially for younger women and postmenopausal women not taking hormones, according to observational research published today in Circulation, the flagship journal of the American Heart Association.

Researchers at Harvard Medical School and Brigham and Women’s Hospital analyzed data from more than 200,000 people who participated in three prospective health and nutrition studies; all participants were free of cancer and heart disease when the studies began.

After eliminating a number of other factors known to increase heart risk, investigators found:

  • Consuming tofu, which is high in isoflavones, more than once a week was associated with a 18% lower risk of heart disease, compared to a 12% lower risk for those who ate tofu less than once a month; and
  • The favorable association with eating tofu regularly was found primarily in young women before menopause or postmenopausal women who were not taking hormones.

“Despite these findings, I don’t think tofu is by any means a magic bullet,” said lead study author Qi Sun, M.D., Sc.D., a researcher at Harvard’s T.H. Chan School of Public Health in Boston. “Overall diet quality is still critical to consider, and tofu can be a very healthy component.”

Sun noted that populations that traditionally consume isoflavone-rich diets including tofu, such as in China and Japan, have lower heart disease risk compared to populations that follow a largely meat-rich and vegetable-poor diet. However, the potential benefits of tofu and isoflavones as they relate to heart disease needs more research.

Tofu, which is soybean curd, and whole soybeans such as edamame are rich sources of isoflavones.

Chickpeas, fava beans, pistachios, peanuts and other fruits and nuts are also high in isoflavones.

Soymilk, on the other hand, tends to be highly processed and is often sweetened with sugar, Sun noted. This study found no significant association between soymilk consumption and lower heart disease risk.

“Other human trials and animal studies of isoflavones, tofu and cardiovascular risk markers have also indicated positive effects, so people with an elevated risk of developing heart disease should evaluate their diets,” he said.

“If their diet is packed with unhealthy foods, such as red meat, sugary beverages and refined carbohydrates, they should switch to healthier alternatives.

Tofu and other isoflavone-rich, plant-based foods are excellent protein sources and alternatives to animal proteins.”

In the study, researchers analyzed health data of more than 74,000 women from the Nurses’ Health Study (NHS) from 1984 to 2012; approximately 94,000 women in the NHSII study between 1991 and 2013; and more than 42,000 men who participated in the Health Professionals Follow-Up Study from 1986 to 2012.

All participants were free of cardiovascular disease and cancer at the beginning of each study. Dietary data was updated using patient surveys, conducted every two to four years.

Data on heart disease was collected from medical records and other documents, while heart disease fatalities were identified from death certificates.

A total of 8,359 cases of heart disease were identified during 4,826,122 person-years of follow-up, which is the total number of years that study participants were free of heart disease and helps to measure how fast it occurs in a population.

Sun emphasized that the study should be interpreted with caution because their observations found a relationship but did not prove causality. Many other factors can influence the development of heart disease, including physical exercise, family history and a person’s lifestyle habits.

“For example, younger women who are more physically active and get more exercise tend to follow healthier, plant-based diets that may include more isoflavone-rich foods like tofu. Although we have controlled for these factors, caution is recommended when interpreting these results,” said Sun.

In 2000, the U.S. Food and Drug Administration approved health claims that soy edibles protect against cardiovascular disease. However, since then, clinical trials and epidemiological studies have been inconclusive, and the agency is reconsidering its now twenty-year-old decision.

he American Heart Association’s 2006 Diet and Lifestyle Recommendations and a 2006 science advisory on soy protein, isoflavones and cardiovascular health found minimal evidence that isoflavones convey any cardiovascular benefits and any protections provided by higher soy intake was likely due to higher levels of polyunsaturated fats, fiber, vitamins and minerals, and lower levels of saturated fat.


Diet is a determinant of non-communicable diseases, which are responsible for more than 70% of deaths globally.1 One risk factor for such diseases is the shift from intake of traditional, plant based food to energy dense, high fat diets.2 

The intake of soy products, which are still consumed in large amounts in Asian countries,3 might improve the nutrient intake levels in people with a low consumption of plant based food.45

Traditional Asian diets contain several types of processed soy products. Natto (soybeans fermented with Bacillus subtilis), miso (soybeans fermented with Aspergillus oryzae), tofu (soybean curd), and abura-age (fried tofu) are widely consumed in Japan (see supplementary table 1).

Recent prospective studies have shown that intake of fermented soy products, not total soy intake, is associated with a lower risk of high blood pressure6 and that intake of natto (a fermented soy product) is associated with a reduction in cardiovascular disease related mortality.7 

However, few epidemiological studies have focused on the effect of fermented soy product intake on mortality from causes other than cardiovascular disease.

Moreover, two prospective studies that investigated the association between intake of total soy products and all cause mortality presented inconsistent data.89 Components of soy, such as isoflavone and fibre, were shown to have anticancer, anticardiovascular disease, cholesterol lowering, and weight loss effects.101112131415 

Because fermented soy products are made from whole soy beans, the characteristics of fermented soy products are a small loss of these nutrients and an abundance of bioactive components such as polyamine,16 or nattokinase in natto.17

We conducted a large scale prospective study on intake of total and fermented soy products in Japan with follow-up duration of approximately 15 years.

Our aim was to investigate the association between intake of several types of soy products and all cause and cause specific mortality.

Statistical analysis

Hazard ratios and corresponding 95% confidence intervals were calculated for the association between soy product intake and all cause and cause specific mortality using Cox proportional hazards regression models.

We estimated P for trend values with regression models in which ordinal values for each category of soy products were used as continuous variables. Models were adjusted for potential confounding factors.

Model 1 included age at the five year survey (continuous) and public health centre area.

Model 2 was additionally adjusted for BMI at the five year survey (<21, 21-≤23, 23-25, and >25 kg/m2), smoking status (never, former, <20 cigarettes/day, and ≥20 cigarettes/day), alcohol intake (never, occasional, <150 g/week, and ≥150 g/week), leisure time physical exercise or sports (almost never, ≥once/month, and ≥3 times/week), self reported history of diabetes or taking drugs for diabetes (yes or no), taking antihypertensives (yes or no), consumption of coffee and green tea (almost never, >1 cup/week, >1 cup/day, >2 cups/day, and >4 cups/day), undergoing health check-ups (yes or no), menopause status in women (premenopausal or postmenopausal), exogenous female hormone use in women (yes or no), total energy intake (fifths), and energy adjusted amount of vegetables, fruit, fish, and meat (fifths).

We further adjusted for area deprivation index, developed previously—this indicator reflects neighbourhood, rather than individual, deprivation level.2324 

We conducted the same analyses after the exclusion of participants who died during the first three years. Overall, 278 (0.3%) study participants were lost to follow-up during the period. For them, we treated the last confirmed date as the censoring date.

We calculated age adjusted and area adjusted cumulative mortality rate at 10 years in each fifth of soy product intake using the PROC PHREG BASELINE statement (SAS Institute, Cary, NC). Multiple imputations of missing values were performed for covariates (BMI, smoking, alcohol intake, physical exercise, coffee intake, green tea intake, use of exogenous female hormones (women only), and menopausal status (women only)) using multivariate normal imputation. All covariates, follow-up durations, and mortality statuses were included in the model for imputation using the SAS PROC MI procedure.25 

We conducted 10 rounds of multiple imputations, then combined them into final estimates according to Rubin’s rule (SAS PROC MIANALYZE procedure).25 P values were two sided, with P<0.05 considered statistically significant. Statistical analyses were conducted using the SAS software, version 9.4. (SAS Institute, Cary, NC).

Patient and public involvement

Patients were not involved in the study design, implementation, or setting the research questions or the outcome measures directly. Participants in the Japan Public Health Centre-based Prospective Study are community residents and we have held regular meetings with health practitioners in study areas to obtain opinions on health practice since the beginning of this study.

Results

Figure 1 shows the number of eligible participants and participants analysed in this study. Participants with a self reported history of cancer, stroke, or myocardial infarction during the five year period or with a history of these diseases were excluded (n=4634) as were 5923 participants who reported extreme energy intakes (ie, <2.5 and >97.5 centiles).

In total, 92 915 participants (42 750 men and 50 165 women) were included in the analysis. Table 1 presents the baseline characteristics of the participants, divided into fifths of total soy product consumption, and the number of those with missing values.

Table 1

Baseline characteristics of study participants according to fifth of total soy product intake. Values are numbers (percentages) unless stated otherwise

CharacteristicsMen (n=42 750)*Women (n=50 165)*
First (lowest intake)SecondThirdFourthFifth (highest intake)First (lowest intake)SecondThirdFourthFifth (highest intake)
No of participants8550855085508550855010 03310 03310 03310 03310 033
Mean (SD) age (years)55.1 (8.0)55.9 (7.8)56.2 (7.6)56.7 (7.5)57.6 (7.5)55.8 (8.4)56.4 (8.0)56.5 (7.8)57.0 (7.5)58.0 (7.4)
Mean (SD) body mass index (kg/m2)23.5 (2.9)23.5 (2.8)23.6 (2.8)23.6 (2.8)23.8 (2.9)23.2 (3.2)23.3 (3.1)23.4 (3.1)23.5 (3.1)23.9 (3.2)
Current smoker4220 (52.0)4005 (49.2)3804 (46.6)3687 (45.3)3380 (41.8)835 (9.0)565 (6.0)482 (5.1)439 (4.6)424 (4.5)
Alcohol intake (≥1 day/week)5833 (69.0)6064 (71.5)6002 (70.9)5733 (67.6)5323 (63.3)1732 (17.9)1509 (15.5)1375 (14.1)1116 (11.4)917 (9.4)
Diabetes mellitus504 (5.9)564 (6.6)573 (6.7)599 (7.0)755 (8.8)330 (3.3)322 (3.2)312 (3.1)363 (3.6)471 (4.7)
Antihypertensive drugs1320 (15.4)1487 (17.4)1543 (18.1)1635 (19.1)1811 (21.2)1659 (16.5)1871 (18.7)1926 (19.2)1966 (19.6)2329 (23.2)
Health check-up6708 (78.5)7061 (82.6)7132 (83.4)7178 (84.0)7081 (82.8)8063 (80.4)8459 (84.3)8570 (85.4)8677 (86.5)8573 (85.5)
Sports or physical exercise (almost every day)395 (4.8)424 (5.1)423 (5.1)492 (6.0)528 (6.5)426 (4.5)503 (5.2)507 (5.3)533 (5.5)631 (6.7)
Postmenopausal6503 (69.3)7080 (74.3)7189 (75.7)7500 (78.9)7677 (82.6)
Use of exogenous female hormones254 (2.7)239 (2.5)246 (2.6)263 (2.8)270 (2.9)
Coffee intake (>once/day)3567 (44.3)3076 (37.7)2650 (32.5)2409 (29.5)2079 (26.0)4719 (50.0)3918 (40.7)3511 (36.5)2989 (31.2)2611 (27.8)
Green tea intake (>once/day)4010 (49.6)4845 (58.7)5058 (61.2)5028 (60.7)4796 (58.0)5467 (57.8)6210 (64.0)6361 (65.7)6155 (63.2)5512 (57.2)
Median (interquartile range) dietary intake†:
 Energy (kcal/day)2035 (1643-2494)2140 (1744-2607)2129 (1747-2575)2091 (1711-2557)1993 (1615-2487)1742 (1403-2164)1819 (1485-2244)1815 (1498-2209)1778 (1461-2168)1716 (1384-2128)
 Fruit (g/day)115 (51-201)130 (66-219)143 (77-231)149 (79-237)146 (78-239)184 (104-294)203 (127-310)207 (129-309)204 (129-304)193 (118-291)
 Vegetables (g/day)129 (81-193)157 (107-224)172 (119-245)177 (120-252)194 (128-281)163 (110-233)190 (136-265)206 (148-283)212 (152-289)220 (151-309)
 Fish (g/day)71 (47-105)78 (53-112)81 (56-114)82 (56-116)79 (53-115)70 (46-100)78 (53-107)80 (56-109)80 (56-109)75 (50-107)
 Meat (g/day)59 (37-89)57 (36-84)55 (35-80)52 (33-78)49 (29-75)53 (33-80)51 (33-77)49 (31-71)47 (29-69)43 (25-66)
 Total soy products (g/day)‡37 (27-46)67 (60-73)92 (85-98)121 (112-130)178 (157-221)37 (27-45)64 (58-70)87 (81-93)115 (107-124)174 (151-221)
 Natto (g/day)2.5 (1.1-6.9)5.9 (1.5-13.3)10.0 (2.5-19.8)13.6 (3.9-28.0)16.2 (2.8-36.3)3.4 (1.3-7.9)7.3 (2.0-15.0)11.8 (4.0-22.2)15.5 (5.3-28.8)17.4 (4.1-36.8)
 Miso (g/day)6.7 (3.1-11.1)14.8 (9.6-21.7)22.1 (13.5-28.9)26.3 (17.6-34.7)28.8 (19.0-39.3)6.0 (2.7-9.9)12.2 (7.7-17.9)17.6 (10.7-24.5)22.3 (13.4-29.2)24.4 (14.7-33.5)
 Tofu (g/day)17 (10-17)26 (17-38)32 (21-47)44 (28-64)80 (48-121)18 (11-25)28 (19-39)35 (24-49)48 (32-65)83 (52-124)
  • * Numbers of missing men and women were, respectively, 942 and 1347 for body mass index, 2112 and 3134 for smoking, 455 and 1396 for alcohol consumption, 1569 and 2280 for physical exercise, 2232 and 2482 for coffee intake, and 1583 and 1947 for green tea intake. 2745 women were missing for use of exogenous female hormones and 2954 for menopausal status.
  • † Food intakes were adjusted for energy intake using the residual method.
  • ‡ Sum of seven soy foods in the questionnaire. Along with total soy products, the table shows the amount of main soy products. The amount of miso was calculated from the amount of miso soup. Total tofu intake was calculated as the sum of the amount of tofu, tofu in miso soup, and other tofu products.

Among both sexes, those with a higher consumption of soy products tended to be older, have a higher BMI, and be less likely to be current smokers. Supplementary tables 2 to 4 show the characteristics of the participants divided into fifths of intake of fermented soy product, natto, and miso, respectively.

Participants with a higher intake of fermented soy products or miso were older, whereas the trend of age according to the categories of natto consumption was U-shaped.

The percentage of current smokers was lower in the highest category of fermented soy or natto intake than that in the lowest category, whereas a higher percentage of current smokers was observed in the highest category of miso intake compared with the lowest category in men.

The mean follow-up period was 14.8 years, and the total person years were 1 374 643, with 13 303 reported deaths (8370 men and 4933 women)

Fig 1
Fig 1 Flow of participants through study

All cause mortality

Table 2 shows the hazard ratios and corresponding 95% confidence intervals for all cause mortality according to the amount of consumed total, fermented, and non-fermented soy products. In both sexes, total soy product intake was marginally inversely associated with all cause mortality after adjustment for age and area. After further adjustment for potential confounding factors, the associations were attenuated.

Compared with the lowest fifth of intake, the hazard ratios in the highest fifth were 0.98 (95% confidence interval 0.91 to 1.06, Ptrend=0.43) in men and 0.98 (0.89 to 1.08, Ptrend=0.46) in women. Fermented soy intake was inversely associated with all cause death after adjusting for potential confounding factors. Compared with the lowest fifth of intake, the hazard ratios in the highest fifth were 0.90 (0.83 to 0.97, Ptrend=0.05) in men and 0.89 (0.80 to 0.98, Ptrend=0.01) in women. Intake of non-fermented soy products was not significantly associated with all cause mortality.

Table 2 Risk of all cause mortality according to fifths of total soy, fermented soy, and non-fermented soy product intake in Japanese men and women. Values are hazard ratios (95% confidence intervals) unless stated otherwise

VariablesMen (n=42 750)PtrendWomen (n=50 165)Ptrend
FirstSecondThirdFourthFifthFirstSecondThirdFourthFifth
Total soy products*:
 Intake (g/day)<53.253.2-79.279.2-104.6104.6-141.3>141.3<51.651.6-75.375.3-99.799.7-135.9>135.9
 No of deaths153115931626167619449429589179771139
 Cumulative mortality rate (%)†7.306.766.536.296.822.782.652.442.472.61
  Model 1‡1.000.92 (0.86 to 0.99)0.89 (0.83 to 0.96)0.86 (0.80 to 0.92)0.93 (0.87 to 1.00)0.031.000.96 (0.87 to 1.05)0.88 (0.80 to 0.96)0.89 (0.81 to 0.98)0.94 (0.86 to 1.03)0.09
  Model 2§1.000.96 (0.89 to 1.03)0.94 (0.87 to 1.01)0.91 (0.84 to 0.98)0.98 (0.91 to 1.06)0.431.001.01 (0.92 to 1.11)0.95 (0.86 to 1.04)0.96 (0.87 to 1.06)0.98 (0.89 to 1.08)0.46
Fermented soy products¶:
 Intake (g/day)<13.413.4-24.124.1-35.235.3-50.2>50.2<12.512.5-22.222.2-32.932.9-46.6>46.6
 No of deaths1657153016001763182010339559259631057
 Cumulative mortality rate (%)†7.326.636.566.866.402.882.672.502.462.49
  Model 1‡1.000.90 (0.84 to 0.97)0.89 (0.83 to 0.96)0.93 (0.87 to 1.01)0.87 (0.81 to 0.94)0.0091.000.92 (0.85 to 1.01)0.87 (0.79 to 0.95)0.85 (0.77 to 0.94)0.86 (0.78 to 0.95)0.002
  Model 2§1.000.92 (0.85 to 0.98)0.91 (0.85 to 0.98)0.95 (0.88 to 1.03)0.90 (0.83 to 0.97)0.051.000.95 (0.87 to 1.04)0.91 (0.83 to 1.00)0.90 (0.81 to 0.99)0.89 (0.80 to 0.98)0.01
Non-fermented soy products**:
 Intake (g/day)<17.317.3-28.328.3-45.543.5-72.9>72.9<19.219.2-30.730.7-45.945.9-74.7>74.7
 No of deaths1654151516411723183710549098609631147
 Cumulative mortality rate (%)†7.176.386.656.566.712.872.512.272.512.73
  Model 1‡1.000.89 (0.83 to 0.95)0.92 (0.86 to 0.99)0.91 (0.85 to 0.98)0.93 (0.87 to 1.00)0.171.000.87 (0.80 to 0.95)0.79 (0.72 to 0.95)0.87 (0.80 to 0.95)0.95 (0.87 to 1.04)0.31
  Model 2§1.000.94 (0.87 to 1.01)1.00 (0.93 to 1.07)0.99 (0.92 to 1.06)1.01 (0.94 to 1.09)0.321.000.93 (0.85 to 1.02)0.84 (0.77 to 0.93)0.95 (0.86 to 1.04)1.00 (0.92 to 1.10)0.80
  • * Sum of natto, miso, three kinds of tofu (tofu, yushidofu, and koyadofu), fried tofu (abura-age), and soy.
  • † Age and geographical area adjusted mortality risk at 10 years.
  • ‡ Adjusted for age and geographical area.
  • § Adjusted for age, geographical area, smoking, frequency of alcohol intake, body mass index, sports or physical exercise, history of diabetes or taking drugs for diabetes, taking antihypertensives, health check-up, total energy intake, and intake of green tea, coffee, fish, meat, fruit, and vegetables.
  • ¶ Sum of natto and miso.
  • ** Tofu, abura-age, and soy milk.

Table 3 shows the associations between all cause mortality and consumption of soy products (natto, miso, and tofu). The intake of soy products was not significantly associated with total mortality in men, whereas in women intakes of natto and miso were inversely associated with all cause mortality (hazard ratios in the highest fifth of intake were 0.84 (Ptrend=0.001) for natto and 0.89 (Ptrend=0.03) for miso).

Table 3 Hazard ratios (95% confidence intervals) of all cause mortality according to fifth of soy product intake in Japanese men and women

VariablesMen (n=42 750)*PtrendWomen (n=50 165)*Ptrend
FirstSecondThirdFourthFifthFirstSecondThirdFourthFifth
Natto:
 Intake (g/day)01.1-6.76.7-13.513.5-26.2>26.201.0-7.07.0-14.114.1-26.2>26.2
 No of deaths276513341356138615291608743827821934
 Cumulative mortality rate (%)†7.346.786.736.406.083.172.432.642.362.45
 Model 1‡1.000.92 (0.86 to 0.99)0.92 (0.85 to 0.99)0.87 (0.81 to 0.94)0.82 (0.76 to 0.89)<0.00011.000.77 (0.70 to 0.84)0.83 (0.75 to 0.91)0.74 (0.67 to 0.82)0.77 (0.70 to 0.85)<0.0001
 Model 2§1.000.98 (0.91 to 1.05)1.00 (0.93 to 1.08)0.96 (0.89 to 1.03)0.94 (0.87 to 1.02)0.101.000.81 (0.74 to 0.89)0.90 (0.82 to 0.99)0.81 (0.74 to 0.90)0.84 (0.76 to 0.93)0.001
Miso:
 Intake (g/day)<7.77.7–14.314.3–22.522.5–31.1>31.1<6.46.4–11.711.7–18.618.6–26.3>26.3
 No of deaths156415591611166219749899059669531120
 Cumulative mortality rate (%)†7.216.536.486.787.092.952.492.482.452.60
 Model 1‡1.000.90 (0.84 to 0.97)0.90 (0.83 to 0.96)0.90 (0.83 to 0.96)0.98 (0.91 to 1.06)0.901.000.84 (0.77 to 0.92)0.84 (0.77 to 0.92)0.83 (0.75 to 0.91)0.88 (0.80 to 0.96)0.02
 Model 2§1.000.94 (0.87 to 1.01)0.92 (0.85 to 0.98)0.91 (0.85 to 0.98)0.95 (0.87 to 1.02)0.201.000.89 (0.81 to 0.97)0.87 (0.80 to 0.95)0.89 (0.81 to 0.98)0.89 (0.81 to 0.97)0.03
Tofu:
 Intake (g/day)<16.416.4-26.526.5-39.539.5-64.2>64.2<18.018.0-28.628.6-41.541.5-64.8>64.8
 No of deaths1670153716151722182610859178979381096
 Cumulative mortality rate (%)†7.216.446.586.566.622.932.522.372.432.60
 Model 1‡1.000.89 (0.83 to 0.95)0.91 (0.85 to 0.97)0.91 (0.85 to 0.97)0.92 (0.85 to 0.98)0.051.000.86 (0.79 to 0.94)0.81 (0.74 to 0.88)0.83 (0.76 to 0.90)0.89 (0.81 to 0.97)0.006
 Model 2§1.000.94 (0.87 to 1.01)0.97 (0.91 to 1.04)0.98 (0.91 to 1.05)0.99 (0.92 to 1.06)0.881.000.92 (0.84 to 1.00)0.86 (0.79 to 0.95)0.90 (0.82 to 0.99)0.95 (0.86 to 1.03)0.21
  • * Except for natto intake the first to fifth categories comprised 8550 men and 10 330 women. The first fifth of natto intake included participants who did not eat natto (n=12 450 men and 12 227 women). The remaining participants were divided into quarters and are shown in the second to fifth categories (7575 men and 9484, 9485, 9484, and 9485 women from the second to fifth categories, respectively). The first category comprises the lowest amount of soy product consumption and the fifth category is the highest.
  • † Age and area adjusted mortality risk at 10 years.
  • ‡ Adjusted for age and geographical area.
  • § Adjusted for age, geographical area, smoking, frequency of alcohol intake, body mass index, sports or physical exercise, history of diabetes or taking drugs for diabetes, taking antihypertensives, health check-up, postmenopausal status (women only), use of exogenous female hormones (women only), total energy intake, and the intake of green tea, coffee, fish, meat, fruit, and vegetables.

More information:Circulation (2020). DOI: 10.1161/CIRCULATIONAHA.119.041306

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