Conclusions— Consumption of processed meats, but not red meats, is associated with higher incidence of CHD and diabetes mellitus. These results highlight the need for better understanding of potential mechanisms of effects and for particular focus on processed meats for dietary and policy recommendations.

Methods and Results— We performed a systematic review and meta-analysis of evidence for relationships of red (unprocessed), processed, and total meat consumption with incident CHD, stroke, and diabetes mellitus. We searched for any cohort study, case-control study, or randomized trial that assessed these exposures and outcomes in generally healthy adults. Of 1598 identified abstracts, 20 studies met inclusion criteria, including 17 prospective cohorts and 3 case-control studies. All data were abstracted independently in duplicate. Random-effects generalized least squares models for trend estimation were used to derive pooled dose-response estimates. The 20 studies included 1 218 380 individuals and 23 889 CHD, 2280 stroke, and 10 797 diabetes mellitus cases. Red meat intake was not associated with CHD (n=4 studies; relative risk per 100-g serving per day=1.00; 95% confidence interval, 0.81 to 1.23; P for heterogeneity=0.36) or diabetes mellitus (n=5; relative risk=1.16; 95% confidence interval, 0.92 to 1.46; P =0.25). Conversely, processed meat intake was associated with 42% higher risk of CHD (n=5; relative risk per 50-g serving per day=1.42; 95% confidence interval, 1.07 to 1.89; P =0.04) and 19% higher risk of diabetes mellitus (n=7; relative risk=1.19; 95% confidence interval, 1.11 to 1.27; P <0.001). Associations were intermediate for total meat intake. Consumption of red and processed meat were not associated with stroke, but only 3 studies evaluated these relationships.

The 2005 US Dietary Guidelines for Americans recommend that consumption of red and processed meat should be moderated.1 Such recommendations are in large part derived from expected effects of saturated fat in meat on low-density lipoprotein and total cholesterol levels. However, relationships of meat consumption with disease end points such as coronary heart disease (CHD), stroke, and type 2 diabetes mellitus are not well established, with considerably conflicting results in prior studies.2–19 Thus, sufficient evidence for direct relationships with chronic cardiometabolic diseases has been lacking to support more quantitative recommendations about specific consumption levels of meats or potential differences between unprocessed red meat (referred to hereafter as simply “red meat”) versus processed meats.

Clinical Perspective on p 2283

Red versus processed meats may have some important nutritional differences, such as in contents of calories, specific fats, sodium, iron, or additives (eg, nitrites), or differences in their preparation methods (eg, high-temperature commercial cooking) that could produce differing effects on cardiometabolic risk. However, potential differences in effects of red meat versus processed meat consumption on risk of CHD, stroke, or diabetes mellitus have not been systematically evaluated. In the United States alone, 1 700 000 new cases of diabetes mellitus,20 600 000 myocardial infarctions, and 780 000 new or recurrent strokes occur each year.21 Documenting and quantifying the effects of meat consumption on these outcomes, as well as potential differences in effects of red versus processed meat, are of great scientific and public health importance. To address these important questions and elucidate the conflicting results of prior studies, we performed a systematic review and meta-analysis of the evidence for relationships of red meat, processed meat, and red and processed meat combined (referred to hereafter as “total meat”) consumption with risk of CHD, stroke, and diabetes mellitus.

Methods

Search Strategy

We followed Meta-Analysis of Observational Studies in Epidemiology22 protocols throughout the design, implementation, analysis, and reporting. We searched for all prospective or case-control studies or randomized controlled trials that provided effect estimates for potential associations of red, processed, or total meat consumption and incidence of CHD, stroke, total cardiovascular disease (CVD), or diabetes mellitus in adults. Searches were performed with the use of MEDLINE (see Methods in the online-only Data Supplement), EMBASE, AGRIS, AMED, HMIC, PsycINFO, Cochrane Library, Web of Knowledge, CABI, CINAHL, conference abstracts (ZETOC), Faculty of 1000, gray literature sources (SIGLE), related articles, hand-searching of reference lists, and direct author contact. Key words were meat, meat products, beef, ham, other specific unprocessed red and processed meat subtypes, cardiovascular diseases, and diabetes mellitus, including the earliest available online indexing year through March 2009 without language restrictions. “Red meat” was defined as unprocessed meat from beef, hamburgers, lamb, pork, or game and excluding poultry, fish, or eggs23; “processed meat” was defined as any meat preserved by smoking, curing, or salting or addition of chemical preservatives, such as bacon, salami, sausages, hot dogs, or processed deli or luncheon meats, and excluding fish or eggs24; and “total meat” was defined as the total of these 2 categories. Processed meat was primarily processed red meat, although in some studies deli meats, a subcategory of processed meats, may also have included some processed poultry meats that could not be separately excluded. We excluded a priori studies focused on comparing only vegetarians versus nonvegetarians because such comparisons could likely be strongly modified or biased by other differences in diet and lifestyle behaviors in vegetarians. We also recognized that the lowest intake category in each of the included studies would include a subset of individuals (including likely at least some vegetarians) consuming no red or processed meat. Thus, such individuals were captured in the included studies but without the higher potential for bias when analyses were restricted only to special vegetarian populations. We also excluded a priori cross-sectional or ecological studies; commentaries, general reviews, or case reports; and studies reporting only crude risk estimates.

Selection of Articles

Of 1598 identified articles, 1505 were excluded on the basis of review of the title and abstract (Figure 1). Full texts of the 95 remaining manuscripts were independently assessed in duplicate by 2 investigators to determine inclusion/exclusion, with differences resolved by consensus or, if necessary, group consultation among all investigators. Seventy-five studies were excluded because they were reviews (n=16), cross-sectional (n=7), ecological (n=2), conducted in vegetarians (n=10), or repeated publications from the same study (n=6); assessed only overall dietary patterns (n=19), only iron intake (n=2), or only animal protein/fat (n=1); included poultry in the meat definition (n=7); did not assess incident CHD, stroke, or diabetes mellitus (n=3); reported only crude risk estimates (n=1); or included participants with prevalent disease (n=1) (see Methods in the online-only Data Supplement). Initial inclusion/exclusion adjudications were 97% concordant. For 29 studies, authors were contacted to request missing data or clarify meat definitions used; sufficient responses were received for 23 of 29 studies to characterize the exposure or missing data. For example, several articles initially appeared to report findings separately for red meat versus processed meat but on detailed review or direct contact were found to have included processed meat in the red meat category, requiring direct contact to obtain risk estimates for unprocessed red meat alone. Figure 1. Screening and selection process of studies of meat consumption and CHD, stroke, and diabetes mellitus risk.

Data Extraction

For each of the 20 final identified studies, data were extracted independently and in duplicate by 2 investigators, including years the study was performed and reported, study design, sample size, definition(s) of meat intake and disease outcomes, study location, inclusion and exclusion criteria, duration of follow-up, covariates adjusted for, and adjusted risk estimates and confidence intervals (CIs). When >1 multivariable model was reported, risk estimates with the greatest control for potential confounders were extracted. If multivariable models were reported with and without additional adjustment for variables that could be either confounders or intermediates (eg, high cholesterol), the multivariable model without such variables was selected. If the only multivariable model included such variables, this was selected in preference to crude or minimally adjusted models. Accepted standardized quality scores for observational studies are not available. Therefore, quality assessment was performed by evaluating and scoring 5 design criteria on an integer scale (0 or 1, with 1 being better), including appropriateness and reporting of inclusion and exclusion criteria, assessment of exposure, assessment of outcome, control of confounding, and evidence of bias. These scores were summed; quality scores from 0 to 3 were considered lower quality, and scores of 4 to 5 were considered higher quality. Differences in data extracted or quality assessment scores between investigators were unusual and were resolved by consensus. Missing data or definitions were resolved by direct contact with authors as described above. To provide some perspective in regard to why cardiometabolic effects of red versus processed meats might differ, we evaluated nationally representative average nutrient and preservative contents of red and processed meats consumed in the United States. To estimate average nutrient qualities, we analyzed data from the 2005–2006 US National Health and Nutrition Examination Survey (NHANES), accounting for NHANES sampling and weighting strategies to provide nationally representative estimates25,26 (see Methods in the online-only Data Supplement). Foods consumed in this US survey were grouped to match the definitions of our meta-analysis for red and processed meat. Preservative contents were obtained from a recent report of published nitrate, nitrite, and nitrosamine contents of foods commonly consumed in the United States26 and applied directly to meats in the NHANES database with the use of methods similar to those used for nutrients. We recognized that such nutrient data may not be fully generalizable outside the United States, but comparable data were not available from Europe, Asia, or Australia.

Statistical Analysis

All included studies were observational and reported either relative risks (RRs; prospective cohorts) or odds ratios (case-control studies) across several different categories of meat intake. Odds ratios were assumed to approximate RRs24; we also performed analyses limited to prospective cohorts only. The midpoint in each category was used to define median intake in that category, with standardization across studies to a serving size of 100 g (3.5 oz) for red and total meat and 50 g (1.8 oz) for processed meat. For studies with an open-ended highest category that did not report median intake, we assumed that the difference from the lowest range to the median was equivalent to the same difference in the closest adjacent category. To maximize use of the data to calculate pooled dose response, summary estimates of log-linear dose-response regressions were made with the use of random-effects generalized least squares models for trend estimation27 (GLST in STATA [StataCorp, College Station, Tex]). This method is ideal for meta-analyses of studies having multiple risk estimates per study because it accounts for appropriate variance-covariance relationships between and within studies. Covariance was fit with the use of total numbers of cases and of subjects (controls plus cases) for case-control data or person-years for cohort data, at each level of exposure. Evidence for statistical heterogeneity between studies was tested with goodness of fit (χ2). Generalized least squares models for trend take advantage of the multiple data points in all studies simultaneously to provide the best overall pooled estimate of dose response in a single (1-stage) estimation. To construct funnel plots and evaluate the Begg adjusted-rank correlation test for publication bias,28 explore potential sources of heterogeneity, and visually display the individual study results in Forest plots, we also performed 2-stage estimation: Separate generalized least squares models for trend were evaluated for each study to derive study-specific log-linear dose responses (log RR), and then each study-specific log RR was pooled in a second generalized least squares model for trend. Our prespecified primary outcome was based on the 1-stage estimation that better estimates the variance-covariance matrix by using all available β coefficients in each study rather than the 2-stage estimation that first derives a single β coefficient per study and then estimates the variance-covariance matrix. We performed sensitivity analyses, when data were available, for subgroups of specific processed meats. Prespecified potential sources of heterogeneity explored were study location (United States, Asia/Australia, Europe), degree of covariate adjustment (minimal, sociodemographics; adequate, sociodemographics plus either other risk factors or dietary variables; optimal, all 3), overall quality score (0 to 3, 4 to 5), single versus repeated dietary assessment methods, and (to address potential publication bias of “positive” findings) whether the reported analysis was prespecified or post hoc in each article. Analyses were performed with the use of STATA 10.0 (StataCorp, College Station, Tex), with 2-tailed α <0.05.

Results

The 20 identified investigations included 17 prospective cohorts studies and 3 case-control studies conducted in the United States (n=11), Europe (n=6), Asia (n=2), and Australia (n=1) and included 1 218 380 unique individuals in whom 23 889 cases of CHD, 2280 cases of stroke, and 10 797 cases of diabetes mellitus were identified (Table 1). No randomized controlled trials of red, processed, or total meat consumption and incidence of CHD, stroke, or diabetes mellitus were identified. Reported categories of meat consumption typically ranged from never or less than once a month (lowest category of intake) to variable highest categories of intake. Averaged across studies, consumption (mean±SD) levels in the lowest versus highest category of intake were 1.1±1.1 versus 8.3±2.7 servings per week for red, 0.4±0.8 versus 5.7±3.9 servings per week for processed, and 1.8±1.7 versus 10.5±4.2 servings per week for total meat intake, respectively. Most studies used validated multi-item food frequency questionnaires to quantify meat consumption; some used interview-based5,10,29 or fewer-item food frequency2 questionnaires. Total numbers of participants (n=342 to 322 263) and events (n=51 to 14 221) varied widely between studies. Extent of covariate adjustment also varied, especially for dietary variables that were often not controlled for3,4,6,8,13,17 (and J. Kröger, MSc, unpublished data, 2009). Approximately half of the studies included variables that could be confounders or intermediates (eg, lipid levels) in addition to sociodemographic and/or dietary variables.5,7,9,10,13,15,17,29 Four studies reported how red versus processed meat intake was associated with other dietary and lifestyle factors at baseline.7,16,18 Relationships with these other risk factors were similar for red versus processed meat. For example, higher consumption of both red and processed meat tended to be similarly associated with current smoking, higher body mass index, family history of diabetes mellitus, hypertension, higher education and income level, and higher intake of total energy, total fat, saturated, monounsaturated, and polyunsaturated fats, dietary cholesterol, and protein. In addition, red and processed meat consumption levels were similarly associated with less physical activity, multivitamin use, prevalence of high cholesterol, glycemic load, and intake of carbohydrate, fiber, and magnesium. For all but 3 of the studies,4,10,12 the reported exposure-outcome assessment was a prespecified primary or secondary aim.

Table 1. Identified Studies Evaluating the Consumption of Red, Processed, or Total Meat and Incidence of CHD, Stroke, or Diabetes Mellitus First Author (Year) Country Type of Meat* Consumption in Lowest Category, Median Servings/wk Consumption in Highest Category, Median Servings/wk Disease Outcome Disease Ascertainment Study Name Cohort studies Burke (2007)5 Australia Red 3.00 8.00 CHD (total) Regional hospital records and death registry AAC Processed 0.53 2.13 CHD (total) Villegas (2006)18 China Red 1.19 6.00 T2DM Supplementary questionnaire SWHS Processed (and subtypes) 0.00 3.89 T2DM Salonen (1992)10 Finland Total meat 6.07 16.49 CHD (total MI) Regional MI registry KIHD Kröger (unpublished data, 2009)∥ Germany Red Processed 0.67 3.18 4.16 17.61 T2DM T2DM ICD-10 criteria, validated by physician EPIC-Potsdam Sauvaget (2003)11 Japan Red 0.00 5.50 Stroke (fatal) National death registry HNLSS Processed 0.00 5.50 Stroke (fatal) Whiteman (1999)2 UK Red 0.50 5.50 CHD (fatal) National death registry OXCHECK Processed 0.50 5.50 CHD (fatal) Ascherio (1994)4 US Red (and subtypes) 1.11 10.16 CHD (total) Physician review of medical records, autopsy reports, or death certificate HPFS Meyer (2001)19 US Processed 0.00 3.50 T2DM Self-report IWHS Total meat 2.00 13.50 T2DM van Dam (2002)15 US Red (and subtypes) 0.98 9.03 T2DM WHO diabetes criteria, using validated supplementary questionnaire HPFS Processed (and subtypes) 0.00 7.00 T2DM He (2003)13 US Total meat 0.50 8.00 Stroke (hemorrhagic) Physician review of medical records, autopsy reports, or death certificate HPFS Total meat 0.50 8.00 Stroke (ischemic) Liu (2003)7 US Processed 0.08 2.41 CHD (total) Physician review of medical records, autopsy reports, or death certificate NHS1 Total meat 2.21 12.31 CHD (total) Schulze (2003)17 US Red (and subtypes) 0.00 7.49 T2DM National Diabetes Data Group criteria, using validated supplementary questionnaire NHS2 Processed (and subtypes) 0.25 7.00 T2DM Fung (2004)14 US Red 1.47 6.72 T2DM National Diabetes Data Group criteria, using validated supplementary questionnaire NHS1 Processed (and subtypes) 0.28 3.85 T2DM Total meat 2.24 9.87 T2DM (Continued)

Table 1. Continued Population Age, y Sample Size Follow-Up, y No. of Events Person-Years Prespecified Analysis Adjustments† Quality Score‡ Additional Information§ Australian Aborigines 15–88 514 13 118 4381 Yes (primary) +++ 3 Yes Australian Aborigines 15–88 514 13 118 4381 Yes (primary) Women in Shanghai 40–70 70 609 4.6 1969 326 625 Yes (primary) +++ 3 Yes Women in Shanghai 40–70 70 609 4.6 1969 326 625 Yes (primary) Eastern Finnish men 42–60 1931 3 51 5586 No ++ 3 Yes People in Potsdam, Germany 19–70 25 069 7 844 716 277 Yes (primary) +++ 5 Yes People in Potsdam, Germany 19–70 25 069 7 844 716 277 Yes (primary) Atomic bomb survivors 34–103 37 130 16 1224 498 651 Yes (primary) ++ 3 Yes Atomic bomb survivors 34–103 37 130 16 958 473 404 Yes (primary) Patients in Bedfordshire, UK 35–64 10 522 9 94 93 464 Yes (primary) +++ 3 No Patients in Bedfordshire, UK 35–64 10 522 9 91 93 429 Yes (primary) Male health professionals 40–75 44 933 4 386 157 010 No +++ 4 Yes Women in Iowa 55–69 35 988 11 1890 336 204 Yes (secondary) ++ 3 Yes Women in Iowa 55–69 35 988 11 1890 336 204 Yes (secondary) Male health professionals 39–78 42 504 12 1320 466 508 Yes (primary) +++ 5 Yes Male health professionals 39–78 42 504 12 1320 466 508 Yes (primary) Male health professionals 40–75 43 732 14 125 602 693 Yes (secondary) +++ 5 No Male health professionals 40–75 43 732 14 455 609 623 Yes (secondary) Female nurses 30–55 57 031 18 1351 752 353 Yes (primary) +++ 5 Yes Female nurses 30–55 57 031 18 1351 752 353 Yes (primary) Female nurses 26–46 91 246 8 741 716 276 Yes (primary) +++ 5 Yes Female nurses 26–46 91 246 8 741 716 276 Yes (primary) Female nurses 38–63 69 554 14 2475 856 539 Yes (secondary) +++ 4 Yes Female nurses 38–63 69 554 14 2475 856 539 Yes (secondary) Female nurses 38–63 69 554 14 2475 856 539 Yes (secondary) (Continued)

Table 1. Continued First Author (Year) Country Type of Meat* Consumption in Lowest Category, Median Servings/wk Consumption in Highest Category, Median Servings/wk Disease Outcome Disease Ascertainment Study Name T2DM indicates type 2 diabetes mellitus; ICD-10, International Statistical Classification of Diseases, 10th Revision; WHO, World Health Organization; 3ITALCC, 3 Italian case-control studies; AAC, Australian Aboriginal cohort; CARDIO-2000, Greek case-control study; EPIC-Potsdam, European Prospective Investigation Into Cancer and Nutrition–Potsdam Study; HNLSS, Hiroshima/Nagasaki Life Span Study; HPFS, Health Professionals Follow-Up Study; IWHS, Iowa Women’s Health Study; KIHD, Kuopio Ischemic Heart Disease Risk Factor Study; NHS1, Nurses’ Health Study 1; NHS2, Nurses’ Health Study 2; NIH-AARP, National Institutes of Health–AARP Diet and Health Study; OXCHECK, OXford and Collaborators HEalth ChecK; SPAINCC, Spanish case-control study; SWHS, Shanghai Women’s Health Study; and WHS, Women’s Health Study. *Including red meat (unprocessed red meat), processed meat (total processed meat), and total meat (red and processed combined), as well as subtypes (eg, beef, pork, hamburger, ham) within each meat category when available. Fung (2004)12 US Red 0.07 11.90 Stroke (ischemic) Physician review of medical records, autopsy reports, or death certificate NHS1 Processed (and subtypes) 0.07 11.90 Stroke (ischemic) Total meat 0.07 11.90 Stroke (ischemic) Song (2004)16 US Red (only subtypes) T2DM Self-report WHS Processed (and subtypes) 0.00 3.92 T2DM Total meat 0.91 9.94 T2DM Kelemen (2005)8 US Total meat 3.92 16.80 CHD (fatal) National death registry IWHS Sinha (2009)3 US Total meat 1.37 8.75 CVD (fatal) National death registry NIH-AARP Processed 0.45 6.33 CVD (fatal) Total meat 1.37 8.75 CVD (fatal) Processed 0.45 6.33 CVD (fatal) Case-control studies Kontogianni (2008)9 Greece Total meat 0.28 1.25 CHD (nonfatal) Physician diagnosis CARDIO-2000 Tavani (2004)29 Italy Processed (only subtypes) CHD (nonfatal MI) Physician diagnosis 3ITALCC Martinez-Gonzalez (2002)6 Spain Red 3.50 13.30 CHD (nonfatal MI) Physician diagnosis SPAINCC Processed 0.88 5.25 CHD (nonfatal MI)

Table 1. Continued Population Age, y Sample Size Follow-Up, y No. of Events Person-Years Prespecified Analysis Adjustments† Quality Score‡ Additional Information§ †Degree of adjustment for confounders: +, sociodemographics; ++, sociodemographics plus either other risk factors or dietary variables; +++, sociodemographics plus other risk factors and dietary variables. ‡Quality assessment was performed by review of study design, including inclusion and exclusion criteria, assessment of exposure, assessment of outcome, control of confounding, and evidence of bias. Each of the 5 quality criteria was evaluated and scored on an integer scale (0 or 1, with 1 being better) and summed; quality scores from 0 to 3 were considered lower quality and 4 to 5 higher quality. §Authors provided additional information to characterize the exposure or missing data. ∥Includes most recent results from the EPIC-Potsdam Study; Kröger J, Schulze MB, Heidemann C, Schienkiewitz A, Boeing H. Dietary fatty acids and incidence of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Submitted. Female nurses 38–63 71 768 14 476 957 988 No ++ 4 Yes Female nurses 38–63 71 768 14 476 957 988 No Female nurses 38–63 71 768 14 476 478 994 No Female health professionals ≥45 37 309 8.8 1539–1555 326 876 Yes (primary) +++ 4 No Female health professionals ≥45 37 309 8.8 1543 326 876 Yes (primary) Female health professionals ≥45 37 309 8.8 1558 326 876 Yes (primary) Women in Iowa 55–69 29 017 15 739 475 755 Yes (secondary) +++ 4 Yes Male members of AARP 50–71 322 263 10 14 221 236 937 Yes (primary) +++ 3 No Male members of AARP 50–71 322 263 10 14 221 236 937 Yes (primary) Female members of AARP 50–71 223 390 10 5356 191 254 Yes (primary) Female members of AARP 50–71 223 390 10 5356 191 254 Yes (primary) Hospitalized patients, matched controls 26–86 848 cases; 1078 controls … 844 … Yes (primary) ++ 3 Yes Hospitalized patients, matched controls 17–79 558 cases; 1044 controls … 558 … Yes (primary) ++ 2 Yes Hospitalized patients, matched controls <80 171 cases; 171 controls … 171 … Yes (secondary) +++ 4 Yes Hospitalized patients, matched controls <80 171 cases; 171 controls … 171 … Yes (secondary)

Meat Intake and CHD

Nine studies provided 16 separate estimates for relationships of consumption of red, processed, or total meat and incident CHD (Figure 2). Figure 2. Risk of incident CHD associated with servings per day of red meat (top; 3 cohort studies and 1 case-control study, 56 311 participants, and 769 events), processed meat (middle; 4 cohort studies and 1 case-control study, 614 062 participants, and 21 308 events), and total meat (bottom; 4 cohort studies and 1 case-control study, 635 558 participants, and 22 562 events). *Assessed total cardiovascular (CHD+stroke) mortality only. Solid diamonds and lines are study-specific dose-response and 95% CI, respectively. Dashed line and open diamond are pooled dose-response and 95% CI, respectively, combining each study-specific dose-response (two-stage). The overall dose-response and 95% CI from generalized least squares for trend estimation (one-stage) is also shown.

Red Meat

Consumption of red meat was not associated with CHD (RR=1.00 per serving per day; 95% CI, 0.81 to 1.23), with no statistically significant between-study heterogeneity (P=0.36) (Figure 2, top panel). Findings were similar in analyses restricted to cohort studies2,4,5 (RR=0.92; 95% CI, 0.74 to 1.15) or studies for which this exposure-outcome assessment was prespecified2,5,6 (RR=0.95; 95% CI, 0.66 to 1.35).

Processed Meat

Each serving per day of processed meat was associated with 42% higher risk of CHD (RR=1.42; 95% CI, 1.07 to 1.89) (Figure 2, middle panel). Statistical between-study heterogeneity was present (P=0.04), not accounted for by any of our prespecified sources of heterogeneity. For all included studies, this exposure-outcome assessment was prespecified. Restricting the analysis to cohort studies2,3,5,7 resulted in similar findings, with 44% higher CHD risk per serving per day (RR=1.44; 95% CI, 1.07 to 1.95). Restricting the analysis to US studies3,7 resulted in similar findings (RR=1.40; 95% CI, 1.03 to 1.91). With the exclusion of 1 large US study that evaluated only total CVD mortality3 (not CHD alone), each serving per day of processed meat consumption was associated with nearly 2-fold higher risk of CHD (RR=1.90; 95% CI, 1.00 to 3.62), with no evidence for between-study heterogeneity (P=0.29).

Total Meat

Total meat consumption was associated with a trend toward higher CHD risk (RR=1.27; 95% CI, 0.94 to 1.72) (Figure 2, bottom panel). Between-study heterogeneity was present (P=0.002), observed to be due to extreme findings in the smallest study,9 which was also the only case-control study. With the exclusion of this study, total meat consumption was associated with 25% higher CHD risk (RR=1.25; 95% CI, 1.21 to 1.29). These findings were largely driven by 1 study that assessed only total CVD mortality3 (not CHD alone); with the exclusion of this study, a significant association was not confirmed between total meat intake and CHD risk (RR=1.96; 95% CI, 0.67 to 5.70), but CIs were broad. Findings restricted to studies3,7,9 with prespecified aims to assess this exposure-outcome relationship were similar to the overall pooled estimate (RR=1.31; 95% CI, 0.92 to 1.85).

Meat Intake and Diabetes Mellitus

Seven studies provided 15 separate estimates for relationship of red, processed, or total meat consumption and incidence of diabetes mellitus (Figure 3). Figure 3. Risk of incident diabetes mellitus associated with servings per day of red meat (top; 5 cohort studies, 298 982 participants, and 7349 events), processed meat (middle; 7 cohort studies, 372 279 participants, and 10 782 events), and total meat (bottom; 3 cohort studies, 142 851 participants, and 5923 events). *European Prospective Investigation Into Cancer and Nutrition–Potsdam Study, includes most recent results. Solid diamonds and lines are study-specific dose-response and 95% CI, respectively. Dashed line and open diamond are pooled dose-response and 95% CI, respectively, combining each study-specific dose-response (two-stage). The overall dose-response and 95% CI from generalized least squares for trend estimation (one-stage) is also shown.

Red Meat

Consumption of red meat was not significantly associated with incident diabetes mellitus (pooled RR=1.16 per serving per day; 95% CI, 0.92 to 1.46) (Figure 3, top panel). Statistical heterogeneity between studies was not evident (P=0.25). All included studies were cohorts, for which the exposure-outcome assessments were prespecified.

Processed Meat

Seven studies evaluated the relationship of processed meat consumption and incident diabetes mellitus (Figure 3, middle panel). All studies were cohorts for which this exposure-outcome assessment was prespecified. In the overall pooled estimate, each serving per day was associated with 19% higher risk (RR=1.19; 95% CI, 1.11 to 1.27). Significant between-study heterogeneity was present (P<0.001), identified in metaregression as related to study location (P=0.03). With the exclusion of 1 study in Asia/Australia,18 each serving per day was associated with 27% higher risk of diabetes mellitus (RR=1.27; 95% CI, 1.18 to 1.37). When restricted to US studies,14,17,19 each serving per day was associated with 53% higher risk of diabetes mellitus (RR=1.53; 95% CI, 1.37 to 1.71).

Five studies provided estimates for 3 subtypes of processed meat, including (1) bacon (5 estimates, 5 studies)14–18; (2) hot dogs (4 estimates, 4 studies)14–17; and (3) other processed meats (4 estimates, 4 studies).14–17 Each serving (2 slices) per day of bacon was associated with a 2-fold higher incidence of diabetes mellitus (RR=2.07; 95% CI, 1.40 to 3.04); of hot dogs (each 1 per day), with nearly a 2-fold higher incidence (RR=1.92; 95% CI, 1.33 to 2.78); and of other processed meats (each 1 piece per day), with a 66% higher incidence (RR=1.66; 95% CI, 1.13 to 2.42). All of these latter analyses were cohort studies and were reported as prespecified primary or secondary aims.

Total Meat

Each serving per day of total meat was associated with 12% (RR=1.12; 95% CI, 1.05 to 1.19) higher risk of diabetes mellitus (Figure 3, bottom panel). Statistical heterogeneity between studies was not evident (P=0.29). All of these studies were cohorts for which this exposure-outcome assessment was prespecified.

Meat Intake and Stroke

Only 3 identified studies,11–13 all cohorts, evaluated relationships of red, processed, or total meat consumption and incidence of total stroke or stroke subtypes, including 152 630 individuals and 2280 stroke events (Figure 4). Generally, no 2 studies evaluated the same meat and stroke subtype, limiting ability to pool results. Two studies11,12 evaluated red meat intake and either total ischemic stroke (1 study) or total stroke mortality (1 study); when these studies were pooled, the risk estimate was not significant (RR=1.17; 95% CI, 0.40 to 3.43) (Figure 4, top panel). Two studies11,12 evaluated processed meat intake and either total ischemic stroke (1 study) or total stroke mortality (1 study); when these studies were pooled, the risk estimate was not significant (RR=1.14; 95% CI, 0.94 to 1.39) (Figure 4, middle panel). Two studies12,13 evaluated total meat consumption and total ischemic stroke; the pooled risk estimate demonstrated 24% higher risk per daily serving (RR=1.24; 95% CI, 1.08 to 1.43) (Figure 4, bottom panel). Only 1 study13 reported an association for total meat consumption and hemorrhagic stroke (RR per daily serving=1.64; 95% CI, 0.75 to 3.60). Evaluation for between-study heterogeneity was limited by the few studies and estimates. Figure 4. Risk of incident stroke associated with servings per day of red meat (top; 2 cohort studies, 108 898 participants, and 1700 events), processed meat (middle; 2 cohort studies, 108 898 participants, and 1434 events), and total meat (bottom; 2 cohort studies, 115 500 participants, and 931 events). Solid diamonds and lines are study-specific dose-response and 95% CI, respectively. Dashed line and open diamond are pooled dose-response and 95% CI, respectively, combining each study-specific dose-response (two-stage). The overall dose-response and 95% CI from generalized least squares for trend estimation (one-stage) is also shown.

Publication Bias

Evidence for publication bias was not apparent for most of these exposure-outcome relationships on the basis of either visual inspection of the funnel plot or by the Begg test, a statistical analog of the visual funnel plot (Figure I in the online-only Data Supplement), although such tests have limited statistical power in the setting of relatively few studies. The funnel plot suggested possible publication bias in reporting of studies for processed meat intake and risk of CHD; the Begg test did not achieve statistical significance (P=0.57), and excluding the smallest study with the most unbalanced results on the funnel plot5 had little effect on results (RR=1.37; 95% CI, 1.05 to 1.79). The funnel plot also suggested possible publication bias in reporting of studies for red meat intake and diabetes mellitus risk, but the Begg test did not achieve statistical significance (P=0.62); red meat consumption was not significantly associated with diabetes mellitus risk in the overall pooled result (Figure 3, top panel); and excluding the 2 smallest studies with the most unbalanced results on the funnel plot14 (and J. Kröger, MSc, unpublished data, 2009) did not appreciably alter these results (RR=1.05; 95% CI, 0.73 to 1.49).

Nutritional Qualities of Red and Processed Meats

On the basis of nationally representative data on the types and quantities of meats consumed in the United States, both similarities and differences were identified in average nutrient and/or preservative contents of red versus processed meats (Table 2). Per 50-g serving, processed meats contained modestly higher calories and percent energy from fat and lower percent energy from protein compared with 50 g of red meats. Consistent with lower protein content, processed meats also contained less iron. Processed meats contained relatively similar saturated fat and slightly lower cholesterol, the latter perhaps related to some processed meats being derived from pork and/or lower-cholesterol deli meats. Relatively small differences were present in contents of monounsaturated fat, polyunsaturated fat, or potassium. Largest differences were seen in levels of sodium, with processed meats containing 4-fold higher levels (622 versus 155 mg per serving), as well as ≈50% higher nonsalt preservatives including nitrates, nitrites, and nitrosamines.

Table 2. Differences in Average Nutritional and Preservative Contents Between Red Meats and Processed Meats per 50-g Servings, as Consumed in the United States Per 50 g of Meat Red Meats, Mean±SE (Median) Processed Meats, Mean±SE (Median) Based on data from the 2005–2006 US NHANES and a report of published nitrate, nitrite, and nitrosamine contents of foods,26 each analyzed according to actual US consumption levels and accounting for the NHANES sampling and weighting strategies. All mean differences were significant at the 0.05 level. Energy, kcal 123.3±0.7 (124.1) 138.1±2.0 (150.6) Total fat, % energy 49.6±0.3 (54.1) 57.5±0.6 (69.4) Total fat, g 7.1±0.1 (7.7) 10.2±0.2 (12.3) Saturated fat, % energy 18.7±0.1 (20.4) 19.4±0.3 (22.8) Saturated fat, g 2.7±0.0 (2.9) 3.5±0.1 (4.4) Monounsaturated fat, % energy 21.4±0.1 (23.9) 25.3±0.3 (30.7) Monounsaturated fat, g 3.1±0.0 (3.3) 4.5±0.1 (5.3) Polyunsaturated fat, % energy 2.7±0.0 (1.7) 6.4±0.1 (6.1) Polyunsaturated fat, g 0.4±0.0 (0.2) 1.1±0.0 (0.6) Protein, % energy 46.2±0.3 (41.5) 35.4±0.5 (27.4) Protein, g 13.6±0.0 (13.5) 9.8±0.1 (8.8) Sodium, mg 154.8±3.4 (127.1) 621.7±7.6 (575.8) Potassium, mg 161.0±0.8 (152.8) 170.2±1.9 (153.6) Cholesterol, mg 41.9±0.2 (43.8) 34.1±0.3 (28.3) Iron, mg 1.1±0.0 (1.2) 0.6±0.0 (0.6) Nitrates, mg 3.3±0.0 (2.9) 4.6±0.1 (3.0) Nitrites, mg 0.5±0.0 (0.7) 0.8±0.0 (0.6) Nitrosamines, μg 0.1±0.0 (0.2) 0.3±0.0 (0.2)

Discussion

Whereas meat consumption is commonly considered a risk factor for cardiovascular and metabolic diseases, our findings indicate that the effects and magnitudes may vary depending on both the type of meat consumed and the outcome considered. This first systematic review and meta-analysis of these relationships, including 1 218 380 individuals from 10 countries on 4 continents with 23 889 cases of CHD, 2280 cases of stroke, and 10 797 cases of diabetes mellitus, provides the most robust and reliable evidence to date of how unprocessed red and processed meat consumption may influence risk of cardiometabolic diseases. Consumption of processed meats was associated with significantly higher incidence of both CHD and diabetes mellitus, with 42% and 19% higher risk, respectively, per 50-g serving per day. In contrast, consumption of unprocessed red meats was not associated with CHD and was associated with a nonsigificant trend toward higher risk of diabetes mellitus. Associations were intermediate for total meat intake.

Our extensive search of multiple databases and direct contact with authors resulted in the identification of 17 prospective cohorts and 3 case-control studies; no randomized controlled trials were identified that evaluated effects of red, processed, or total meat consumption on CVD or diabetes mellitus events. This is not surprising when it is considered that trials of such effects can be challenging and costly to conduct, with limitations of nonblinding and noncompliance over the long periods of time required to detect clinical end points. In this setting, the best available evidence is derived from long-term prospective cohorts of disease end points such as those identified here, although such studies can be limited by misclassification and residual confounding. Retrospective case-control studies may have additional potential limitations (eg, recall and selection bias).

Thus, each of these individual studies has potential limitations, and our findings should be interpreted in that context. On the other hand, this represents the most complete worldwide evidence to date of the potential effects of red and processed meat consumption on incidence of CHD, stroke, and diabetes mellitus. We also performed multiple sensitivity analyses to evaluate the extent to which our findings might vary depending on underlying study design (cohort versus case-control), presence or absence of prespecified analyses, geographic region (eg, United States versus other), overrepresentation of 1 large study, or other identified sources of heterogeneity. Generally, findings were consistent in each of these sensitivity analyses and similar to the overall pooled results. Thus, although limitations of the individual studies should not be ignored, our results provide the best current evidence for how red, processed, and total meat consumption relate to CHD, stroke, and diabetes mellitus and highlight specific gaps in knowledge that are essential for policy decisions relating to these important diet-disease relationships.

For example, our findings of different relationships of red versus processed meat consumption with incident CHD and diabetes mellitus events support the need to better characterize which particular components of meats may increase cardiometabolic risk. At least in the United States, where most of the studies were performed, processed meats contain, on average, similar saturated fat and lower cholesterol and iron compared with red meats, suggesting that differences in these constituents may not account for different associations with disease risk. Other constituents may be relevant in determining health effects. In particular, the observed substantially higher sodium and nitrate preservative levels in processed meats could plausibly contribute to increased CVD and diabetes mellitus risk and account, at least in part, for the present findings. Dietary sodium significantly increases blood pressure,30–32 and habitual consumption may also worsen arterial compliance and promote vascular stiffness.33 Nitrates and their byproducts (eg, peroxynitrite) experimentally promote atherosclerosis and vascular dysfunction,34 reduce insulin secretion,35,36 and impair glucose tolerance,36 and streptozotocin, a nitrosamine-related compound, is a known diabetogenic compound.37 In observational studies in children, nitrites and nitrous compounds are associated with type 1 diabetes mellitus,38,39 and nitrite concentrations in adults have been used as a biomarker of endothelial dysfunction40 and impaired insulin response.41 Differences in types of foods commonly replaced when individuals consume red versus processed meats could also partly account for their different associations with risk.

Our study had several strengths. We reviewed multiple databases broadly and systematically for all investigations of meat consumption and incidence of CHD, stroke, or diabetes mellitus, making it likely that we identified all major published reports. Multiple authors were contacted directly and clarified findings or provided additional data, minimizing both misclassification and effects of publication bias. Study inclusion/exclusion and data extraction were performed independently and in duplicate by 2 investigators, increasing the validity of results. Studies were identified from the United States, Europe, Asia, and Australia, increasing generalizability. Large numbers of disease end points were identified, providing substantial statistical power to detect clinically meaningful associations. We used generalized least squares models for trend estimation, which explicitly assesses dose response rather than simply categorical comparisons. We carefully identified and separately evaluated red, processed, and total meat consumption; in particular, relatively few prior reports have separately considered unprocessed red meats. Indeed, several key prior reports on red meat consumption included processed meats in this category,3,7,8,19,24 limiting inference on effects of unprocessed red meats alone. For example, a systematic review by the World Cancer Research Fund and American Institute for Cancer Research concluded that both red and processed meat consumption increased colorectal cancer24; however, red meats in several of the included studies were the sum of unprocessed and processed meats. Interestingly, their identified relationship of red (commonly total, ie, unprocessed red plus processed) meat intake with colorectal cancer (22% higher risk per 100 g/d) was approximately half that for processed meat alone (46% higher risk per 100 g/d), consistent with our results that much of the association between total meat intake and CHD and diabetes mellitus may result from effects of processed meats.

Potential limitations should also be considered. As with all meta-analyses, analyses were restricted to available published and unpublished data. Most of these studies did not separately assess extensive details about specific subcategories of deli meats consumed. Processed meats may have included small amounts of processed poultry, which could theoretically have smaller effects and cause underestimation of effects of processed red meats. We did not have data on cooking methods that could alter health effects of red or processed meats.42–44 Both red and processed meats represent somewhat heterogeneous categories, and thus our findings should be interpreted as the average overall association rather than the particular effect of 1 specific subtype of such meats. This interpretation would be similar, for example, to analyses or meta-analyses of effects of other classes of dietary factors, such as fruits, vegetables, fish, whole grains, and alcohol. A recent meta-analysis of relationships between meat consumption and diabetes mellitus has been reported45; this study also found higher risk with processed meat intake but included crude (unadjusted) risk estimates and also did not separately evaluate unprocessed red meats.

All studies were observational, and residual confounding by imprecisely or unmeasured factors cannot be excluded. In particular, several studies did not adjust for other dietary habits or socioeconomic status. Thus, associations of processed meat consumption with diabetes mellitus or CHD could relate to generally less healthy diet or lifestyle rather than causal effects of processed meats. Conversely, most studies adjusted for at least several major demographic and other risk factors; the reported potential confounding factors related to red versus processed meat consumption were similar, yet only the latter was related to risk; and specific ingredients in processed meats (eg, salt, other preservatives) provide biological plausibility for the observed relationships. Several studies adjusted for factors that could be either confounders or intermediates in the causal pathway, which could potentially attenuate the observed risk estimates between meat consumption and disease risk. We standardized all servings to 100 g for red and total meat and 50 g for processed meat, and risks could vary when serving sizes are lower or higher. Representative nutrient and preservative data were available only for the United States, and such values should be considered illustrative rather than definitive for other countries. Too few studies were present to formally exclude publication bias with sufficient statistical power. On the other hand, our extensive direct contact with multiple authors and inclusion of unpublished findings minimizes the potential impact of publication bias. Notably, if publication bias were present, it might cause overestimation of harmful associations between processed meats and diabetes mellitus or CHD (ie, identified harmful associations might more likely be published) but would unlikely contribute to null associations between red meats and CHD or diabetes mellitus or between meats and stroke (ie, publication bias is unlikely to favor reporting of null associations).

Our findings demonstrate that consumption of processed meat in particular is associated with incidence of CHD and diabetes mellitus, highlighting the importance of separate consideration of health effects, underlying mechanisms, and policy implications of different types of processed versus unprocessed meats. Our findings also identify critical gaps in our understanding of how meat consumption influences cardiometabolic risk, including potential effects of red meat consumption on diabetes mellitus or CHD; of any meat consumption on stroke risk; and of specific ingredients that could be underlying these relationships. On the basis of our evaluation of average nutrient and preservative contents of red and processed meats, constituents in meats other than fats may be especially relevant to health effects. On the basis of this systematic review and meta-analysis of all available data, future research should carefully distinguish between different types of meats, and policy measures for improving cardiometabolic health should focus particularly on reducing processed meat consumption, including consideration of recommendations for specific quantitative limits. These findings are particularly timely for current efforts to update the US Dietary Guidelines for Americans, which are also often a reference for other countries around the world.

We thank Eric Ding, Tao Hou, and Jacob Sattelmair for providing statistical advice. We thank the following authors for clarifying definitions in published articles and/or providing additional unpublished data: Alberto Ascherio; Valerie Burke; James Cerhan and Linda Kelemen on behalf of the Iowa Women’s Health Study Investigators; Aaron Folsom; Teresa Fung; Eric Grant; Yoshihide Kinjo; Paul Knekt; Janine Kröger; Carlo La Vecchia; Laurie Lambert; Miguel Martinez-Gonzalez; Katie Meyer; Jun Nagano; Demosthenes Panagiotakos; Catherine Sauvaget; Matthias Schulze; Duc Son Le; Alessandra Tavani; Rob van Dam; Raquel Villegas; Jyrki Virtanen; and Eberhard Windler. Sources of Funding This study was supported by the Bill & Melinda Gates Foundation/World Health Organization Global Burden of Diseases, Risk Factors, and Injuries Study; the National Heart, Lung, and Blood Foundation, National Institutes of Health (R01 HL 085710); and the Searle Scholars Program. Disclosures None.

Footnotes