During a mean follow-up of 11.8 years, there were 7961 deaths, of which 2598 were due to CVD and 1873 were due to cancers. Compared with zero-intake subjects, those with the highest intake of unprocessed red meat were younger, less educated, and less physically active. They also had higher prevalence of current smoking, alcohol use, and slightly higher BMI. Regarding dietary characteristics, they tended to have lower intakes of cruciferous vegetables, fruits, whole grains, legumes, and nuts and seeds, and higher intakes of dairy, eggs, unprocessed poultry, and processed meat (Table 1
Consumption of red and processed meat were associated with the risk of total, CVD, and cancer mortality among the total cohort when adjusted for age, sex, race and total energy intake (model 1, Table 2
) when using all forms of the exposure (e.g., quartiles of intake versus zero-intake, p
-trend, and both uncalibrated and calibrated 90th percentiles versus zero-intake). The associations were attenuated yet remained significant for total and CVD mortality, but not cancer mortality in the multivariable models without adjustment for other meats (model 2). In the multivariable model with mutual adjustment for other meats (model 3), participants in the 90th percentile intake of unprocessed red meat (compared with zero-intake) had a higher risk of all-cause mortality (uncalibrated, HR: 1.18; 95% CI: 1.07–1.31 and calibrated, HR: 1.51; 95% CI: 1.22–1.98; p
< 0.001) and CVD mortality (uncalibrated, HR: 1.26; 95% CI: 1.05–1.50 and calibrated, HR: 1.64; 95% CI: 1.09–2.57; p
= 0.017). Processed meat alone was not significantly associated with risk of mortality when adjusted for other meats. Red and processed meat (combined) were associated with higher risk of all-cause mortality (uncalibrated, HR: 1.23; 95% CI: 1.11–1.36 and calibrated, HR: 1.50; 95% CI: 1.26–1.83; p
< 0.001) and CVD mortality (uncalibrated, HR: 1.34; 95% CI: 1.12–1.60 and calibrated, HR: 1.73; 95% CI: 1.27–2.51; p
< 0.001) (Table 2
Results from subgroups are presented as forest plots, where 90th percentiles versus zero-intake contrasts were used (Figure 1
). Unprocessed red meat was significantly associated with risk of all-cause mortality among women (HR: 1.17; 95% CI: 1.03–1.33), men (HR: 1.21; 95% CI: 1.03–1.43), and non-Blacks (HR: 1.20; 95% CI: 1.06–1.34), but not among Blacks (HR: 1.18; 95% CI: 0.96–1.45); with CVD mortality among women (HR: 1.30; 95% CI: 1.03–1.64), but not men (HR: 1.15; 95% CI: 0.93–1.79), and among Blacks (HR: 1.69; 95% CI: 1.18–2.40), but not non-Blacks (HR: 1.17; 95% CI: 0.95–1.43). Processed meat was associated with all-cause mortality among women (HR: 1.17; 95% CI: 1.03–1.32), but not men (HR: 0.99; 95% CI: 0.84–1.16), and among Blacks (HR: 1.21; 95% CI: 1.00–1.47), but not non-Blacks (HR: 1.03; 95% CI: 0.92–1.15); with CVD mortality among women (HR: 1.32; 95% CI: 1.06–1.66), but not among men (HR: 0.87; 95% CI: 0.64–1.20), Blacks (HR: 1.07; 95% CI: 0.74–1.55), nor non-Blacks (HR: 1.10; 95% CI: 0.89–1.36). The combined intake of red and processed meat was associated with a higher risk of all-cause mortality among all subgroups and CVD mortality among women and Blacks (Figure 1
). Complete results from subgroup analyses are available as online supplemental materials (Supplementary Tables S1–S4
We also evaluated the linear relationships of these exposures with all-cause, CVD, and cancer mortality using 4-knot restricted cubic splines (Supplementary Figure S1
). Unprocessed red meat intake and combined intake of red and processed meat appeared to have more clearly linear relationships with mortality outcomes as compared to processed meat intake.
To explore the effects of residual confounding by smoking, we conducted separate analyses among participants who had never smoked (Supplementary Table S5
). We report results for the 90th percentiles versus zero-intake: Unprocessed red meat intake was associated with all-cause mortality (HR: 1.16; 95% CI: 1.02–1.31) and CVD mortality (HR: 1.26; 95% CI: 1.02–1.56). Processed meat intake was associated with all-cause mortality (HR: 1.13; 95% CI: 1.00–1.26), but not with CVD mortality (HR: 1.15; 95% CI: 0.94–1.41). Combined intake of red and processed meat was associated with higher risk of all-cause ((HR: 1.22; 95% CI: 1.08–1.37) and CVD (HR: 1.34; 95% CI: 1.08–1.65) mortality among never smokers.
We calculated population attributable risk, in which we compared the 90th percentile of the combined intake of red and processed meat (~49 g/day) with zero-intake. If the relationships were causal, approximately 6.3% and 9% of total and CVD deaths, respectively, could have been prevented if those in the 90th percentile of combined intake of red and processed meat had abstained.
In the Adventist Health Study-2 (AHS-2), we found relatively low levels of consumption of red and processed meat to be positively associated with all-cause and CVD mortality in multivariable-adjusted models, compared to zero-intake. The associations appeared to be linear (i.e., exhibiting a dose–response relationship) and of moderate strength. Stronger associations—though less precise—were observed when the exposures were calibrated suggesting that measurement error biased the uncalibrated results towards the null.
Other studies from the U.S. and Europe have found positive associations between red or processed meat consumption and all-cause and CVD mortality [7
]. In the U.S., three large cohort studies—the Health Professionals Follow-Up Study (HPFS), the Nurses’ Health Study (NHS), and the American Association of Retired Persons (NIH-AARP) study—found associations of red and processed meat intake with all-cause, CVD, and cancer mortality among both men and women [7
]. The relative risks of all-cause and CVD mortality in these studies ranged from 14 to 50% for red meat, and from 9 to 72% for processed meat. From the European Prospective Investigation into Cancer and Nutrition (EPIC) study, Rohrmann et al. found a 14% higher risk of all-cause mortality associated with red meat intake, and found 44% and 72% higher risks of all-cause and CVD mortality, respectively, associated with processed meat [9
]. Furthermore, Bellavia et al., in Sweden, found higher risks of all-cause and CVD mortality by 21% and 29%, respectively, associated with red meat consumption [27
]. Recently, processed meat was associated with 21% and 26% higher (relative) risks of overall and CVD mortality, respectively, in The Netherlands Cohort Study [28
]. These findings appear to be compatible with ours, though they examine higher intake ranges. Meta-analyses have also found positive associations of red and/or processed meat with all-cause and/or CVD mortality [29
]. In contrast, studies in Asia have generally not found associations between red meat intake and mortality [32
] (except for Takata et al., who found a 18% higher risk of all-cause mortality among men) [33
Regarding cancer mortality, the three cohorts in the US have found significant associations, in contrast to our null findings. This could be due to insufficient dietary adjustments in those studies (we adjusted for multiple dietary variables including dairy, whole grains and legumes, which they have been associated with reduced risk of some cancers) [34
]; low and infrequent meat consumption in our cohort (particularly processed meat that has been linked to cancer risk, especially in populations with higher intakes) [37
]; or the relative power limitations of our sample from this low cancer incidence population [40
]. Lack of association for cancer mortality does not necessarily indicate no relationship to cancer incidence; for example, vegetarian dietary patterns (which are low in red and processed meat) were not at lower risk of cancer mortality compared with nonvegetarians [41
], although they have been linked to lower overall cancer incidence in this cohort [42
Previously in AHS–2, Orlich et al. found that vegetarians had a 12% reduced risk of all-cause mortality as compared to nonvegetarians [41
]; this could be due to lower intake of animal foods or higher intake of plant foods among vegetarians. In our analyses, we were able to control for foods commonly consumed by vegetarians such as legumes, whole grains, and nuts and seeds [10
], yet we found that highest intakes of red and processed meat were associated with an 18–51% higher risk of all-cause mortality as compared to zero-intake participants. Such findings suggest a possible effect of red and processed meat in increasing mortality after controlling for plant foods.
Some possible causal mechanisms have been proposed for the link between red and processed meat consumption and mortality. Red meat is rich in saturated fatty acids, which have been associated with dyslipidemia, particularly elevated low-density lipoprotein (LDL) [43
]. High LDL levels are associated with a higher risk of atherosclerosis [44
] and acute myocardial infarction [45
]. Furthermore, red meat intake has been associated with increased levels of inflammatory and oxidative stress markers such as C-reactive protein (CRP) and gamma-glutamyl transferase (GGT) that have been associated with cardiovascular diseases [46
]. Heme iron in red and processed red meats has been associated with higher risk of type 2 diabetes [5
] and cardiovascular diseases [47
] including myocardial infarction [49
] and coronary heart disease [50
]. Also, red meat is rich in L-carnitine, and recent research found that L-carnitine metabolism by intestinal microbiota elevates the level of a metabolite known as trimethylamine-N-oxide (TMAO) [51
], which was linked with a higher risk of cardiovascular diseases, particularly atherosclerosis [51
]. Additionally, large amounts of sodium are used in some meat processing [53
]; high intakes of sodium are associated with elevated blood pressure, a major risk factor for CVD [54
This study fills an important gap in the literature, in that we were able to evaluate the association of red and processed meat at low consumption levels compared to zero-intake subjects, whereas other studies have only compared risk at higher intake levels. For example, the 90th percentile of unprocessed red meat intake in our population was 46.5 g/day, which is approximately equivalent to a half serving per day—meat serving size ranges from 3 to 4 ounces (85–113 g)—in the FFQ of AHS-2. However, in HPFS and NHS, men who consumed 1.46 serving/day were compared with those who consumed 0.17 serving/day, and women who consumed 1.64 serving/day were compared with those who consumed 0.37 serving/day [7
]. In NIH-AARP, the highest intakes ranged from 65.9 to 68.1 g/1000 kcal and were compared with approximately 9 g/1000 kcal as a reference group [8
]. These ranges of intakes are considerably higher than those in our population. No other studies compare low-to-moderate intake with zero-intake. Another strength of this study is the use of regression calibration to minimize the effects of dietary measurement error. Although regression calibration was only used for the exposures of interest, and not for other dietary covariates, it provided less biased association estimates—though also less precise—compared to the uncalibrated results. Another strength is the relatively low prevalence of smoking and alcohol use, reducing the potential residual confounding. To further minimize the effect of confounding by smoking, we separately explored the associations among never-smoked participants, and these findings were consistent with those from the main analyses. Finally, we included detailed adjustments for multiple confounders including lifestyle factors and food groups to minimize the effect of confounding. Intakes of red and processed meat have been associated with several unfavorable lifestyle and dietary confounders including obesity, smoking, physical inactivity, and low intakes of fruits and vegetable [57
]. Besides adjusting for these factors, we additionally adjusted for multiple dietary factors such as dairy, legumes, whole grains, and nuts and seeds.
An inherent limitation in this type of study is measurement error in dietary assessment. In particular, processed meat measurement by FFQ showed low validity compared to multiple recalls. This low validity correlation for processed meat may be due to the infrequent consumption of processed meat; infrequently consumed foods may be missed by dietary recalls. However, validity for unprocessed red meat was relatively high. Another limitation is the single dietary assessment, whereas dietary habits may have changed. However, a majority of subjects in the AHS-2, especially middle-aged and elderly, tend to have fairly stable dietary intakes over time [58
]. Finally, the possibility of unmeasured or residual confounding remains, despite our efforts to adjust for multiple potential confounders.