Results 14 019 deaths occurred during 1.2 million person years of follow-up. Increases in red meat consumption over eight years were associated with a higher mortality risk in the subsequent eight years among women and men (both P for trend<0.05, P for heterogeneity=0.97). An increase in total red meat consumption of at least half a serving per day was associated with a 10% higher mortality risk (pooled hazard ratio 1.10, 95% confidence interval 1.04 to 1.17). For processed and unprocessed red meat consumption, an increase of at least half a serving per day was associated with a 13% higher mortality risk (1.13, 1.04 to 1.23) and a 9% higher mortality risk (1.09, 1.02 to 1.17), respectively. A decrease in consumption of processed or unprocessed red meat of at least half a serving per day was not associated with mortality risk. The association between increased red meat consumption and mortality risk was consistent across subgroups defined by age, physical activity, dietary quality, smoking status, or alcohol consumption.

We analyzed the association of changes in red meat consumption over eight years with mortality risk during the subsequent eight years. Participants were US women from the Nurses’ Health Study and US men from the Health Professionals Follow-up Study. The Dietary Guidelines for Americans 2015-2020 include the recommendation: “Strategies to increase the variety of protein foods include incorporating seafood as the protein foods choice in meals . . . and using legumes or nuts and seeds in mixed dishes instead of some meat or poultry.” 12 Therefore, we used statistical models to estimate the effects of replacing red meat with equivalent amounts of other protein sources, such as nuts, poultry, fish, dairy, eggs, and legumes, and whole grains and vegetables.

Red meat is a major component of dietary patterns in Western populations. The average consumption of red meat in the United States has decreased in recent decades, but it remains more than twice the global average. 11 Several epidemiological studies have analyzed the relation between red meat consumption and mortality risk. In this study, we examined whether changes in red meat intake are associated with subsequent risk of total and cause specific mortality.

A large body of evidence has shown that higher red meat consumption, especially processed red meat, is associated with an increased risk of type 2 diabetes, 1 cardiovascular disease, 2 certain types of cancer, including colorectal cancer, 3 and mortality. 4 5 Consumption of processed red meat (eg, bacon, hot dogs, and sausages) has been associated with additional health outcomes, including chronic obstructive pulmonary disease, 6 heart failure, 7 and hypertension. 8 Components of red and processed meats such as proatherosclerotic lipids (eg, saturated fat), 9 potential carcinogens (eg, polycyclic aromatic hydrocarbons), 10 sodium, and preservatives could contribute to adverse health outcomes.

No patients were involved in setting the research question or the outcome measures, nor were they involved in the design and implementation of the study. No plans exist to involve patients in dissemination.

We calculated hazard ratios and 95% confidence intervals from the different models separately for each cohort, and then we pooled the results by using an inverse variance weighted meta-analysis with the fixed effects model. Analyses were performed with SAS version 9.4 for UNIX (SAS Institute, Cary, NC). Statistical tests were two sided and a P value less than 0.05 was considered statistically significant.

In secondary analyses, we estimated short term (four year) and long term (12 year) changes in red meat consumption for associations with total mortality (four year change in red meat consumption predicted four year follow-up, and 12 year change in red meat consumption predicted 12 year follow-up). We also modeled associations of a decrease of one serving per day of red meat substituted with an alternative food over four years with total mortality in the subsequent four years, and the same substitution over 12 years with total mortality in the subsequent 12 years.

We also examined the risk of death associated with a decrease in red meat by one serving per day and a simultaneous increase of one serving per day of poultry (no skin), fish, dairy products, eggs, legumes, nuts, whole grains, or vegetables (no legumes). We included concurrent changes in all these food sources, in addition to red meat, in the same multivariable model. The difference in the β coefficients for change in red meat and change in the alternative food was used to estimate the hazard ratio; the corresponding variances and covariance were used to estimate 95% confidence intervals. 24

We adjusted multivariable models for initial age, calendar year as the underlying time scale, race (white v other), family history of myocardial infarction, diabetes, or cancer (yes v no), initial aspirin use (yes v no), and initial multivitamin use (yes v no). We also adjusted for initial consumption of red meat (in fifths); body mass index categories (<23, 23-24.9, 25-29.9, 30-34.9, and ≥35); menopausal status and hormone therapy use in women (premenopausal, postmenopausal and hormone therapy never user, postmenopausal and hormone therapy current user, postmenopausal and hormone therapy past user, or missing indicator); simultaneous changes in smoking status (never to never, never to current, former to former, former to current, current to former, current to current, or missing indicator); initial and simultaneous changes in physical activity, alcohol consumption, total energy intake, and other main food groups, including vegetables, fruits, whole grains, and sugar-sweetened beverages (all in fifths). In an additional model, we further adjusted for initial history of hypertension, hypercholesterolemia, or diabetes (all yes v no), and simultaneous weight change (in fifths), which were potential mediators of the association between red meat changes and mortality. Unprocessed and processed red meat changes were also estimated separately. Stratified analyses were performed a priori by treating total red meat change as a continuous variable according to initial age, body mass index, smoking status, physical activity, alcohol consumption, and modified alternative healthy eating index. The significance of the interaction terms was tested by including cross product terms for each category and change in red meat consumption in the multivariable models.

We calculated the follow-up person years from the date of returning the 1994 questionnaire to the date of death or the end of follow-up, whichever came first. Updated eight year change in red meat consumption was used as the time varying exposure. We used time dependent Cox proportional hazards regression to estimate the hazard ratios and 95% confidence intervals of total and cause specific mortality in the subsequent eight years; that is, changes in red meat consumption between 1986 and 1994 predicted mortality in 1994-2002, and changes in red meat consumption between 1994 and 2002 predicted mortality in 2002-10. We divided participants into five categories based on their changes in red meat consumption: two increase categories (increase of >0.5 serving per day or 3.5 servings per week; increase of 0.15-0.5 serving per day or 1-3.5 servings per week); two decrease categories (decrease of >0.5 serving per day or 3.5 servings per week; decrease of 0.15-0.5 serving per day or 1-3.5 servings per week), and one reference category (increase or decrease of <0.15 serving per day or <1 serving per week). We also calculated hazard ratios and the corresponding 95% confidence intervals for changes in red meat consumption.

Information on potential confounders was assessed and updated biennially. These confounders included age, race, family history of myocardial infarction, diabetes or cancer, weight, smoking status, aspirin use, multivitamin use, menopausal status and postmenopausal hormone therapy use for women, physical activity, and physician diagnosed hypertension, diabetes, or hypercholesterolemia. Alcohol consumption was assessed and updated from the food frequency questionnaire every four years. Height and weight were used to calculate body mass index. Detailed descriptions of the validity and reproducibility of self reported body weight, physical activity, and alcohol consumption have been published elsewhere. 21 22 23

Death from any cause was the primary outcome of this analysis. We identified deaths by using the state vital statistics records, the national death index, reports by families, and the postal system. 20 Using these methods, we ascertained 98% of deaths in each cohort. 20 We sought death certificates for all deaths, and when appropriate, requested permission from the next of kin to review medical records. A physician reviewed death certificates and medical records and determined the underlying cause of death according to the ICD-8 and ICD-9 (international classification of diseases, eighth and ninth revisions). We grouped causes of death into six major categories (supplementary table 1).

The two cohorts completed a validated semiquantitative food frequency questionnaire in 1986 and every four years thereafter. Participants were asked how often, on average, they consumed a standard portion of each food in the past year. Frequency response categories ranged from never or less than once a month, to six or more times each day. Questionnaire items on unprocessed red meat (one serving, 85 g) included beef, pork, and lamb as a main dish; hamburger; and beef, pork, or lamb as a sandwich or mixed dish. Items on processed red meat included bacon (one serving, two slices, 13 g), hot dogs (one serving, one hot dog, 45 g), and sausage, salami, bologna, and other processed red meats (one serving, one piece, 28 g). Total red meat included unprocessed and processed red meat. The reproducibility and validity of the food frequency questionnaire have been described elsewhere 15 16 17 and show good correlations with several weeks of food records. 16 For the Health Professionals Follow-up Study, the corrected correlation coefficients between the food frequency questionnaire and multiple dietary records were 0.59 for unprocessed red meat and 0.52 for processed red meat 18 ; we observed similar correlations for the Nurses’ Health Study. 16 In a subcohort of the Nurses’ Health Study (n=3690), higher red meat consumption was associated with unfavorable plasma concentrations of inflammatory and glucose metabolic biomarkers. 19 In the current study, we calculated a modified diet score of the alternative healthy eating index to assess overall diet quality after removing the red meat components. 17

The baseline of the current analysis was set as 1994, which is eight years after 1986 when detailed information on diet, physical activity, and other lifestyle factors was collected for both cohorts. The end of follow-up was 2010. We excluded participants who had a history of heart disease, stroke or cancer, missing information on diet and lifestyle covariates, extreme energy intake (men: <800 or >4200 kcal/day; women: <500 or >3500 kcal/day; 1 kcal=4.18 kJ=0.00418 MJ), or those who died before baseline (that is, 1994). The final analysis included 53 553 women and 27 916 men.

The Nurses’ Health Study is a prospective cohort study of 121 700 US registered female nurses aged 30-55 at enrollment. The study started in 1976 and nurses completed a baseline questionnaire about demographic factors, diet habits, lifestyle, and medical history. The Health Professionals Follow-up Study was established in 1986 when 51 529 US male health professionals aged 40-75 returned a baseline questionnaire about detailed medical history, lifestyle, and usual diet. In both cohorts, questionnaires were completed biennially after baseline to collect and update information on lifestyle and occurrence of new onset diseases. The follow-up rates were approximately 90% for both cohorts. Detailed descriptions of the cohorts have been published elsewhere. 13 14

Results

In the Nurses’ Health Study, we identified 8426 deaths during the follow-up (804 685 person years): 1774 deaths from cardiovascular disease, 3138 from cancer, 939 from neurodegenerative diseases, 751 from respiratory diseases, and 1824 from other causes. In the Health Professionals Follow-up Study, we identified 5593 deaths during follow-up (409 073 person years): 1754 deaths from cardiovascular disease, 1754 from cancer, 434 from respiratory diseases, 375 from neurodegenerative diseases, and 1276 from other causes.

Table 1 shows red meat consumption from 1986 to 2006. Total red meat consumption (mean serving per day) decreased from 1.05 to 0.74 in women, and from 1.14 to 1.03 in men. Processed meat consumption decreased from 0.30 to 0.21 (from approximately 9 to 6 g/day) in women, and remained at about 0.35 (approximately 10 g/day) in men. Unprocessed meat consumption decreased from 0.76 to 0.53 (from approximately 65 to 44 g/day) in women, and from 0.78 to 0.69 (from approximately 66 to 59 g/day) in men.

Table 1 Consumption of red meat in Nurses’ Health Study and Health Professionals Follow-up Study (1986-2006). Data are mean (standard deviation) serving/day View this table:

Table 2 shows distributions of lifestyle characteristics in 1994 based on eight year (1986-1994) changes in total red meat consumption. During this period, more women and men decreased red meat consumption than participants who increased consumption. Compared with the participants with a relatively stable consumption of red meat, those who increased or decreased consumption were more likely to have started with a less healthy diet consisting of a higher intake of energy and alcohol; they were also more likely to be less physically active, have a higher body mass index, and be current smokers. Participants who decreased their consumption of red meat were more likely to have hypercholesterolemia. We found that consumption of red meat changed in the same direction as changes in daily energy intake, and in the opposite direction to changes in dietary quality score.

Table 2 Age adjusted characteristics based on eight year changes (1986-1994) in total red meat consumption in Nurses’ Health Study and Health Professionals Follow-up Study. Values are means (standard deviations) unless stated otherwise View this table:

Table 3 shows associations of changes in red meat consumption with total mortality across categories of total red meat, processed meat, and unprocessed meat. In the age adjusted model of pooled women and men, an increase in red meat consumption was associated with a higher risk of death, while a decrease in red meat consumption was related to a lower risk of death. Further adjustment of initial traditional risk factors, initial and concurrent changes in lifestyle, calorie intake, and other food consumption did not substantially change the results for increased consumption (when consumption was increased by more than half a serving per day, pooled hazard ratio 1.10, 95% confidence interval 1.04 to 1.17). However, the initially observed association for decreased consumption was no longer evident after multivariable adjustment (when consumption was decreased by more than half a serving per day, pooled hazard ratio 0.97, 95% confidence interval 0.91 to 1.03). The magnitudes of associations were consistent among women and men (P for heterogeneity=0.97).

Table 3 Overall eight year hazard ratios (95% confidence intervals) for mortality risk according to updated eight year change in total red meat consumption in Nurses’ Health Study and Health Professionals Follow-up Study (1986-2010) View this table:

Changes in processed meat and unprocessed meat were significantly associated with mortality (both pooled P for trend<0.05), and such associations were mainly driven by the increased consumption (table 3). We found that changes in processed meat consumption had a stronger association with mortality than changes in unprocessed meat consumption (table 3). Further adjustment for hypertension, diabetes, and hypercholesterolemia, and concurrent weight change did not substantially alter the results (supplementary table 2). When we adjusted the model for socioeconomic status represented by the educational attainment of the nurses and their husbands, the results in the Nurses’ Health Study did not change (data not shown).

Associations of four year and 12 year changes in consumption of total red meat, processed meat, and unprocessed meat with total mortality (four year and 12 year risk of death, respectively) were in general similar to the results from the eight year analysis (supplementary tables 3 and 4, respectively). In the pooled results for women and men, an increase of more than half a serving per day of red meat over four years was associated with a 20% higher mortality risk in the subsequent four years (pooled hazard ratio 1.20, 95% confidence interval 1.13 to 1.27); and an increase of more than half a serving per day of red meat over 12 years was associated with a 12% higher mortality risk in the subsequent 12 years (1.12, 1.03 to 1.22). However, a decrease in red meat consumption was not associated with mortality in any of the analyses.

The association of changes in red meat consumption with mortality was consistent across participants, irrespective of age, physical activity level, dietary quality, smoking status, or alcohol consumption (fig 1). Among normal weight participants, an increase in one serving per day of red meat over eight years was associated with a 13% higher risk of death (pooled hazard ratio 1.13, 95% confidence interval 1.06 to 1.20). However, among participants who were overweight or obese, the corresponding increased risk was lower (1.06, 1.01 to 1.13, pooled P for interaction=0.02; fig 1). This interaction was significant in women only (P for interaction=0.03; fig 1).

Fig 1 Hazard ratios (95% confidence intervals) for all cause mortality associated with an increase in red meat consumption of one serving per day over eight years according to characteristics of participants. Cox proportional hazards models were adjusted for initial age (years); race (white v other); family history of myocardial infarction, diabetes, or cancer (yes v no); initial aspirin use (yes v no) and multivitamin use (yes v no); initial consumption of red meat (in fifths); body mass index categories (<23, 23-24.9, 25-29.9, 30-34.9, and ≥35); menopausal status and hormone therapy use in women (premenopausal, postmenopausal and hormone therapy never user, postmenopausal and hormone therapy current user, postmenopausal and hormone therapy past user, or missing indicator); simultaneous changes in smoking status (never to never, never to current, former to former, former to current, current to former, current to current, or missing indicator); initial and simultaneous changes in physical activity, alcohol intake, total energy intake, and other main food groups, including vegetables, fruits, whole grains, and sugar-sweetened beverages (all in fifths). P for interaction was calculated using the likelihood ratio test. The cut-off point of physical activity was defined as 150 min/week at a moderate level or at least 75 min/week at a vigorous level (equivalent to at least nine MET hours/week) as recommended.25 Moderate alcohol consumption was defined as equivalent to 14 g/day in women and 28 g/day in men; alternative healthy eating index higher or equal to versus lower than median in each cohort. MET=metabolic equivalent of task

In multivariable analyses, an eight year change in red meat consumption as a continuous variable showed a trend of direct associations with the subsequent eight year risk of total mortality and most causes of death among women and men (supplementary fig 1). In the pooled meta-analysis of women and men, an increase of one serving per day of total red meat was associated with a 9% higher risk of all cause mortality (pooled hazard ratio 1.09, 95% confidence interval 1.04 to 1.13); an increase of one serving per day of processed meat and unprocessed meat was associated with a 17% and 5% higher risk of all cause death, respectively (processed meat: pooled hazard ratio 1.17, 95% confidence interval 1.08 to 1.26; unprocessed meat: 1.05, 1.00 to 1.11). We observed significant positive associations of changes in red meat with deaths from cardiovascular disease and respiratory disease. In particular, an increase of one serving per day of processed meat over eight years was associated with a 19% higher risk of death from cardiovascular disease (1.19, 1.03 to 1.38) and a 57% higher risk of death from neurodegenerative disease (1.57, 1.21 to 2.03) in the subsequent eight years. Associations of changes in unprocessed meat consumption with death from specific causes were weaker and non-significant in general (except for death from respiratory disease or other disease) compared with changes in processed meat consumption.

Table 4 shows the eight year all cause mortality associated with a decrease of one serving per day of red meat consumption and a simultaneous increase of one serving per day of another major dietary protein source, whole grains, or vegetables over the previous eight years. Overall, we found a decrease in red meat and an increase in whole grains, vegetables, or other protein sources was associated with a lower risk of death among women and men. The pooled results showed a substantially lower mortality risk with a decrease in red meat consumption and a simultaneous increase in the consumption of nuts (pooled hazard ratio 0.81, 95% CI 0.79 to 0.84); fish (0.83, 0.76 to 0.91); whole grains (0.88, 0.83 to 0.94); poultry without skin (0.90, 0.86 to 0.95); vegetables without legumes (0.90, 0.87 to 0.93); dairy (0.92, 0.86 to 0.99); eggs (0.92, 0.89 to 0.96); or legumes (0.94, 0.90 to 0.99). A decrease in processed meat and a simultaneous increase in whole grains, vegetables, or other protein sources was even more strongly associated with lower total mortality, with the largest reductions in risk seen with increases in nuts (0.74, 0.70 to 0.79) and fish (0.75, 0.68 to 0.84). We found that a decrease in unprocessed red meat and a simultaneous increase in other protein sources except for legumes, whole grains, vegetables, or dairy was also associated with a substantially lower risk of death. Supplementary table 5 shows the associations of changes in all the above food groups including red meat with eight year mortality in the replacement modeling analyses. We found similar results with changes over four and 12 years (supplementary tables 6 and 7).