Red Meat Dangerous?
Here's the newest study on what nutrition factors will kills us (recall the late "low fat diet"):
Red Meat Consumption and Mortality
Background Red meat consumption has been associated with an increased risk of chronic diseases. However, its relationship with mortality remains uncertain.
Methods We prospectively observed 37 698 men from the Health Professionals Follow-up Study (1986-2008) and 83 644 women from the Nurses' Health Study (1980-2008) who were free of cardiovascular disease (CVD) and cancer at baseline. Diet was assessed by validated food frequency questionnaires and updated every 4 years.
Results We documented 23 926 deaths (including 5910 CVD and 9464 cancer deaths) during 2.96 million person-years of follow-up. After multivariate adjustment for major lifestyle and dietary risk factors, the pooled hazard ratio (HR) (95% CI) of total mortality for a 1-serving-per-day increase was 1.13 (1.07-1.20) for unprocessed red meat and 1.20 (1.15-1.24) for processed red meat. The corresponding HRs (95% CIs) were 1.18 (1.13-1.23) and 1.21 (1.13-1.31) for CVD mortality and 1.10 (1.06-1.14) and 1.16 (1.09-1.23) for cancer mortality. We estimated that substitutions of 1 serving per day of other foods (including fish, poultry, nuts, legumes, low-fat dairy, and whole grains) for 1 serving per day of red meat were associated with a 7% to 19% lower mortality risk. We also estimated that 9.3% of deaths in men and 7.6% in women in these cohorts could be prevented at the end of follow-up if all the individuals consumed fewer than 0.5 servings per day (approximately 42 g/d) of red meat.
Conclusions Red meat consumption is associated with an increased risk of total, CVD, and cancer mortality. Substitution of other healthy protein sources for red meat is associated with a lower mortality risk.
Meat is a major source of protein and fat in most diets. Substantial evidence from epidemiological studies shows that consumption of meat, particularly red meat, is associated with increased risks of diabetes,1 cardiovascular disease (CVD),2 and certain cancers.3 Several studies also suggest an elevated risk of mortality associated with red meat intake. However, most of these studies have been performed in populations with a particularly high proportion of vegetarians (such as Seventh-Day Adventists in the United States4 and several studies in Europe5). A recent large cohort study6 with 10 years of follow-up found that a higher intake of total red meat and total processed meat was associated with an increased risk of mortality. However, this study did not differentiate unprocessed from processed red meat, and diet and other covariates were assessed at baseline only. Furthermore, to our knowledge, no study has examined whether substitution of other dietary components for red meat is associated with a reduced mortality risk.
Therefore, we investigated the association between red meat intake and cause-specific and total mortality in 2 large cohorts with repeated measures of diet and up to 28 years of follow-up: the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). We also estimated the associations of substituting other healthy protein sources for red meat with total and cause-specific mortality.
We analyzed data from 2 prospective cohort studies: the HPFS (initiated in 1986, n = 51 529 men aged 40-75 years) and the NHS (started in 1976, n = 121 700 women aged 30-55 years). Detailed descriptions of the cohorts are provided elsewhere.7-8 Questionnaires were administered biennially to collect and update medical, lifestyle, and other health-related information, and the follow-up rates exceeded 90% in each 2-year cycle for both cohorts.
In the present analysis, we used 1986 for the HPFS and 1980 for the NHS as baseline, when we assessed diet using a validated food frequency questionnaire (FFQ); 49 934 men and 92 468 women returned the baseline FFQ. We excluded 5617 men and 5613 women who had a history of CVD or cancer at baseline and 6619 men and 3211 women who left more than 9 blank responses on the baseline FFQ, had missing information about meat intake, or reported implausible energy intake levels (<500 or >3500 kcal/d). After the exclusions, data from 37 698 men and 83 644 women were available for the analysis. The excluded participants and those who remained in the study were similar with respect to red meat intake and obesity status at baseline. The study protocol was approved by the institutional review boards of Brigham and Women's Hospital and Harvard School of Public Health.
ASSESSMENT OF MEAT CONSUMPTION
In 1980, a 61-item FFQ was administered to the NHS participants to collect information about their usual intake of foods and beverages in the previous year. In 1984, 1986, 1990, 1994, 1998, 2002, and 2006, similar but expanded FFQs with 131 to 166 items were sent to these participants to update their diet. Using the expanded FFQ used in the NHS, dietary data were collected in 1986, 1990, 1994, 1998, 2002, and 2006 from the HPFS participants. In each FFQ, we asked the participants how often, on average, they consumed each food of a standard portion size. There were 9 possible responses, ranging from "never or less than once per month" to "6 or more times per day." Questionnaire items about unprocessed red meat consumption included "beef, pork, or lamb as main dish" (pork was queried separately beginning in 1990), "hamburger," and "beef, pork, or lamb as a sandwich or mixed dish." The standard serving size was 85 g (3 oz) for unprocessed red meat. Processed red meat included "bacon" (2 slices, 13 g), "hot dogs" (one, 45 g), and "sausage, salami, bologna, and other processed red meats" (1 piece, 28 g). The reproducibility and validity of these FFQs have been described in detail elsewhere.9-10 The corrected correlation coefficients between the FFQ and multiple dietary records were 0.59 for unprocessed red meat and 0.52 for processed red meat in the HPFS,9 and similar correlations were found in the NHS.10
ASCERTAINMENT OF DEATH
The ascertainment of death has been documented in previous studies.11 Briefly, deaths were identified by reports from next of kin, via postal authorities, or by searching the National Death Index, and at least 95% of deaths were identified.11 The cause of death was determined after review by physicians and were primarily based on medical records and death certificates. We used the International Classification of Diseases, Eighth Revision, which was widely used at the start of the cohorts, to distinguish deaths due to cancer (codes 140-207) and CVDs (codes 390-459 and 795).
ASSESSMENT OF COVARIATES
In the biennial follow-up questionnaires, we inquired and updated information on medical, lifestyle, and other health-related factors, such as body weight; cigarette smoking status; physical activity level; medication or supplement use; family history of diabetes mellitus, myocardial infarction, and cancer; and history of diabetes mellitus, hypertension, and hypercholesterolemia. In NHS participants, we also ascertained menopausal status and postmenopausal hormone use.
We used time-dependent Cox proportional hazards regression models to assess the association of red meat consumption with cause-specific and total mortality risks during follow-up. We conducted analyses separately for each cohort. In multivariate analysis, we simultaneously controlled for intakes of total energy, whole grains, fruits, and vegetables (all in quintiles) and for other potential nondietary confounding variables with updated information at each 2- or 4-year questionnaire cycle. These variables included age; body mass index (calculated as weight in kilograms divided by height in meters squared) (<23.0, 23.0-24.9, 25.0-29.9, 30.0-34.9, or 35.0); race (white or nonwhite); smoking status (never, past, or current [1-14, 15-24, or 25 cigarettes per day]); alcohol intake (0, 0.1-4.9, 5.0-14.9, or 15.0 g/d in women; 0, 0.1-4.9, 5.0-29.9, or 30.0 g/d in men); physical activity level (<3.0, 3.0-8.9, 9.0-17.9, 18.0-26.9, or 27.0 hours of metabolic equivalent tasks per week); multivitamin use (yes or no); aspirin use (yes or no); family history of diabetes mellitus, myocardial infarction, or cancer; and baseline history of diabetes mellitus, hypertension, or hypercholesterolemia. In women, we also adjusted for postmenopausal status and menopausal hormone use.
To better represent long-term diet and to minimize within-person variation, we created cumulative averages of food intake from baseline to death from the repeated FFQs.12 We replaced missing values in each follow-up FFQ with the cumulative averages before the missing values. We stopped updating the dietary variables when the participants reported a diagnosis of diabetes mellitus, stroke, coronary heart disease, angina, or cancer because these conditions might lead to changes in diet.
We conducted several sensitivity analyses to test the robustness of the results: (1) we further adjusted for intakes of other major dietary variables (fish, poultry, nuts, legumes, and dairy products, all in quintiles) or several nutrients or dietary components (glycemic load, cereal fiber, magnesium, and polyunsaturated and trans fatty acids, all in quintiles) instead of foods; (2) we corrected for measurement error13 in the assessment of red meat intake by using a regression calibration approach using data from validation studies conducted in the HPFS9 in 1986 and in the NHS10 in 1980 and 1986; (3) we repeated the analysis by using simply updated dietary methods (using the most recent dietary variables to predict mortality risk in the next 4 years)12 or continue to update a participant's diet even after he or she reported a diagnosis of major chronic disease or using only baseline dietary variables; and (4) we used the energy density of red meat intake (serving/1000 kcalx d–1) as the exposure instead of the crude intake. In addition, we used restricted cubic spline regressions with 4 knots to examine a dose-response relation between red meat intake and risk of total mortality.
We estimated the associations of substituting 1 serving of an alternative food for red meat with mortality by including both as continuous variables in the same multivariate model, which also contained nondietary covariates and total energy intake. The difference in their β coefficients and in their own variances and covariance were used to estimate the hazard ratios (HRs) and 95% CIs for the substitution associations.14 We calculated population-attributable risk (95% CI) to estimate the proportion of deaths in the 2 cohorts that would be prevented at the end of follow-up if all the participants were in the low-intake group.15 For these analyses, we compared participants in the low–red meat intake category (<0.5 servings daily, or 42 g/d) with the remaining participants in the cohorts.
The HRs from the final multivariate-adjusted models in each cohort were pooled to obtain a summary risk estimate with the use of an inverse variance–weighted meta-analysis by the random-effects model, which allowed for between-study heterogeneity. Data were analyzed using a commercially available software program (SAS, version 9.2; SAS Institute, Inc), and statistical significance was set at a 2-tailed α = .05.
In the HPFS, with up to 22 years of follow-up (758 524 person-years), we documented 8926 deaths, of which 2716 were CVD deaths and 3073 were cancer deaths. In the NHS, with up to 28 years of follow-up (2 199 892 person-years), we documented 15 000 deaths, of which 3194 were CVD deaths and 6391 were cancer deaths. For both cohorts combined, we documented 23 926 deaths (including 5910 CVD deaths and 9464 cancer deaths) during 2.96 million person-years of follow-up. Men and women with higher intake of red meat were less likely to be physically active and were more likely to be current smokers, to drink alcohol, and to have a higher body mass index (Table 1). In addition, a higher red meat intake was associated with a higher intake of total energy but lower intakes of whole grains, fruits, and vegetables. Unprocessed and processed red meat consumption was moderately correlated (r = 0.40 in the HPFS and 0.37 in the NHS). However, red meat consumption was less correlated with intakes of poultry and fish (Spearman correlation coefficients, r = –0.04 and –0.18 in the HPFS and r = 0.05 and –0.12 in the NHS, respectively). During follow-up, red meat intake declined in men and women (eFigure). For example, the mean daily intake of unprocessed red meat dropped from 0.75 to 0.63 servings from 1986 to 2006 in men and from 1.10 to 0.55 servings from 1980 to 2006 in women.
Unprocessed and processed red meat intakes were associated with an increased risk of total, CVD, and cancer mortality in men and women in the age-adjusted and fully adjusted models (Tables 2, 3, and 4). When treating red meat intake as a continuous variable, the elevated risk of total mortality in the pooled analysis for a 1-serving-per-day increase was 12% (HR, 1.12; 95% CI, 1.09-1.15) for total red meat, 13% (HR, 1.13; 95% CI, 1.07-1.20) for unprocessed red meat, and 20% (HR, 1.20; 95% CI, 1.15-1.24) for processed red meat. The HRs (95% CIs) for CVD mortality were 1.16 (1.12-1.20) for total red meat, 1.18 (1.13-1.23) for unprocessed red meat, and 1.21 (1.13-1.31) for processed red meat. The HRs (95% CIs) for cancer mortality were 1.10 (1.07-1.13) for total red meat, 1.10 (1.06-1.14) for unprocessed red meat, and 1.16 (1.09-1.23) for processed red meat. We found no statistically significant differences among specific unprocessed red meat items or among specific processed red meat items for the associations with total mortality (eTable 1). However, bacon and hot dogs tended to be associated with a higher risk than other items. Spline regression analysis showed that the association between red meat intake and risk of total mortality was linear (P < .001 for linearity; Figure 1). Furthermore, no significant interaction was detected between red meat intake and body mass index or physical activity level (P > .10 for both tests).
Additional adjustment for other foods (fish, poultry, nuts, beans, and dairy products) or nutrients (glycemic load, cereal fiber, magnesium, and polyunsaturated and trans fatty acids) did not appreciably alter the results. Additional adjustment for saturated fat and cholesterol moderately attenuated the association between red meat intake and risk of CVD death, and the pooled HR (95% CI) dropped from 1.16 (1.12-1.20) to 1.12 (1.07-1.18). Similarly, additional adjustment for heme iron moderately attenuated the association, and the pooled HR (95% CI) dropped from 1.16 (1.12-1.20) to 1.11 (1.05-1.17). Additional adjustment for husband's educational level as a surrogate of socioeconomic status in women did not change the results.
The results were not materially changed when we continued to update dietary information even after the diagnosis of chronic diseases (eTable 2) or simply updated the dietary variables (eTable 3). Also, using the energy density of red meat intake as the exposure showed similar findings (eTable 4). In the sensitivity analysis that accounted for measurement error in diet, the associations became even stronger. For example, the HR was 1.25 (95% CI, 1.16-1.35) for a 1-serving-per-day increase in total red meat intake with mortality in the HPFS, and it was 1.83 (95% CI, 1.54-2.20) in the NHS. However, the associations were attenuated in analyses using only baseline dietary data (eTable 5).
In the substitution analyses, replacing 1 serving of total red meat with 1 serving of fish, poultry, nuts, legumes, low-fat dairy products, or whole grains daily was associated with a lower risk of total mortality: 7% (HR, 0.93; 95% CI, 0.90-0.97) for fish, 14% (HR, 0.86; 95% CI, 0.82-0.91) for poultry, 19% (HR, 0.81; 95% CI, 0.77-0.86) for nuts, 10% (HR, 0.90; 95% CI, 0.86-0.94) for legumes, 10% (HR, 0.90; 95% CI, 0.86-0.94) for low-fat dairy products, and 14% (HR, 0.86; 95% CI, 0.82-0.88) for whole grains (Figure 2). The corresponding substitution estimates were 5%, 13%, 18%, 8%, 9%, and 13% for replacement of unprocessed red meat and 10%, 17%, 22%, 13%, 13%, and 16% for replacement of processed red meat.
We estimated that 9.3% (95% CI, 5.9%-12.7%) in men and 7.6% (95% CI, 3.5%-11.7%) in women of total deaths during follow-up could be prevented if all the participants consumed fewer than 0.5 servings per day of total red meat in these cohorts; the estimates were 8.6% (95% CI, 2.3%-14.7%) in men and 12.2% (95% CI, 3.3%-21.0%) in women for CVD deaths. However, only 22.8% of men and 9.6% of women were in the low-risk category of total red meat intake.
In these 2 large prospective cohorts of US men and women, we found that a higher intake of red meat was associated with a significantly elevated risk of total, CVD, and cancer mortality, and this association was observed for unprocessed and processed red meat, with a relatively greater risk for processed red meat. Substitution of fish, poultry, nuts, legumes, low-fat dairy products, and whole grains for red meat was associated with a significantly lower risk of mortality.
Red meat is a major food source of protein and fat, and its potential associations with risks of diabetes mellitus,1 CVD,2 cancer,3 and mortality4-6 have attracted much attention. Several studies4-5 have suggested that vegetarians have greater longevity compared with nonvegetarians, but this might not be ascribed to the absence of red meat only. Sinha et al6 showed in the National Institutes of Health–AARP (formerly known as the American Association of Retired Persons) study that higher intakes of red and processed meats were associated with an elevated risk of mortality. However, that study did not distinguish unprocessed and processed red meats and did not update dietary information during follow-up.
The strengths of the present study include a large sample size, high rates of long-term follow-up, and detailed and repeated assessments of diet and lifestyle. All the participants were health professionals, minimizing potential confounding by educational attainment or differential access to health care. In addition, the FFQs used in these studies were validated against multiple diet records.9-10 However, the measurement errors inherent in dietary assessments were inevitable, including misclassification of ham or cold cuts as unprocessed red meat and inaccurate assessment of red meat content in mixed dishes. Because of the prospective study design, any measurement errors of meat intake are independent of study outcome ascertainment and, therefore, are likely to attenuate the associations toward the null.16 In the sensitivity analysis accounting for measurement errors, the risk estimates became stronger. Moreover, we calculated cumulative averages for dietary variables to better represent a person's long-term diet pattern and to minimize the random measurement error caused by within-person variation. As expected, the analyses using baseline diet only yielded weaker associations. We also stopped updating the dietary information after a diagnosis of major chronic disease assuming that participants could have changed their diet after receiving the diagnosis. Finally, because the participants were predominantly non-Hispanic white health professionals, the generalizability of the observed associations may be limited to similar populations.
Several mechanisms may explain the adverse effect of red meat intake on mortality risk. Regarding CVD mortality, we previously reported that red meat intake was associated with an increased risk of coronary heart disease,2, 14 and saturated fat and cholesterol from red meat may partially explain this association.12 The association between red meat and CVD mortality was moderately attenuated after further adjustment for saturated fat and cholesterol, suggesting a mediating role for these nutrients. However, we could not assess whether lean meat has the same health risks as meat with higher fat content. Furthermore, dietary iron, particularly heme iron primarily from red meat, has been positively associated with myocardial infarction and fatal coronary heart disease.17-20 The associations between red meat and CVD mortality were moderately attenuated after additional adjustment for heme iron. This finding suggests that heme iron intake may partially explain this association, although some studies using biomarkers of iron status found no association of ferritin and transferrin saturation levels with risk of total mortality.21 Unprocessed and processed meats contain similar amounts of saturated fat and heme iron; however, other constituents in processed meat, particularly sodium and nitrites, might explain the additional harm of processed meats. The high sodium content may increase CVD risk through its effect on blood pressure.22-23 Nitrites and nitrates are frequently used in the preservation of processed meats, and blood nitrite concentrations have been related to endothelial dysfunction24 and impaired insulin response in adults.25
Regarding cancer mortality, red meat intake has been associated with increased risks of colorectal cancer and several other cancers.26 Several compounds in red meat or created by high-temperature cooking, including N -nitroso compounds (nitrosamines or nitrosamides) converted from nitrites,27 polycyclic aromatic hydrocarbons, and heterocyclic amines,28-30 are potential carcinogens. Heme iron and iron overload might also be associated with increased cancer risk through promotion of N -nitroso compound formation,31 increased colonic cytotoxicity and epithelial proliferation,32 increased oxidative stress, and iron-induced hypoxia signaling.33
In conclusion, we found that greater consumption of unprocessed and processed red meats is associated with higher mortality risk. Compared with red meat, other dietary components, such as fish, poultry, nuts, legumes, low-fat dairy products, and whole grains, were associated with lower risk. These results indicate that replacement of red meat with alternative healthy dietary components may lower the mortality risk.