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KSR Number: KSRA112064

Effect of lower versus higher red meat intake on cardiometabolic and cancer outcomes: a systematic review of randomized trials

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

This systematic review identified low- or very-low certainty evidence suggesting that diets restricted in red meat may have little or no effect on major cardiometabolic outcomes and cancer mortality and incidence. The systematic review used rigorous methods, i.e. the results are likely to be correct. However, it was largely based on a single study conducted in postmenopausal women (70% overweight or obese, 30%-40% with hypertension) which limits the generalisability of these findings.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

No relevant concerns were identified.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Yes
Risk of bias in the review Low

Details of Review

Number of studies 12
Number of participants 54764
Last search date April 2019
Review type Aetiological
Objective To evaluate the effect of lower versus higher red meat intake on the incidence of major cardiometabolic and cancer outcomes.
Population Adults allocated to consume diets that included varying quantities of unprocessed red meat.
Outcome All-cause mortality, cardiovascular mortality, adverse cardiometabolic events and major morbidity, cancer mortality and incidence, quality of life, and surrogate outcomes (weight, body mass index, blood lipid levels, blood pressure, and haemoglobin level).
Study design Randomised controlled trials.
Reference standard NA
Exposure Adults (>18 years of age). Studies were excluded if >20% of the sample was pregnant, or had cancer or a chronic health condition other than cardiometabolic diseases without these conditions being reported separately.
PP factor Consumption of red meat or processed meat.
Comparison of diets lower in red or processed meat and diets higher in red or processed meat, differing by a gradient of at least one serving per week.

Results

The largest of the included randomised controlled trials (RCTs) reported results of 48,835 postmenopausal women included in the the Women's Health Initiative (WHI). Only two RCTs, including the WHI, reported all-cause mortality and other patient-important, major morbid cardiovascular outcomes. As the other trial reported an "implausibly large treatment effect, potentially due to stopping the trial early for benefit" and a much lower number of participants, no pooling was done, i.e. main results are based on the findings of the WHI trial.

The WHI RCT (n=48,835) showed lower estimates for all-cause mortality, cardiovascular mortality, fatal stroke, breast cancer mortality and total cancer mortality, however, in all cases, these included the possibility of no change or an increase:
- all-cause mortality (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.95 to 1.03, risk difference (RD) per 1000 persons -2, 95% CI -12 to 7, follow-up up to 17.05 years, low certainty of evidence)
- cardiovascular mortality (HR 0.98, 95% CI 0.91 to 1.06, RD per 1000 persons -3, 95% CI -11 to 8, follow-up up to 13.8 years, very low certainty of evidence)
- fatal stroke (HR 0.97, 95% CI 0.69 to 1.36, RD per 1000 persons -2, 95% CI -16 to 35, follow-up up to 8 years, very low certainty of evidence)
- breast cancer mortality (HR 0.91, 95% CI 0.72 to 1.15, RD per 1000 persons -5, 95% CI -11 to 10, follow-up up to 16.1 years, very low certainty of evidence)
- total cancer mortality (HR 0.95, 95% CI 0.89 to 1.01, RD per 1000 persons -12, 95% CI -26 to 2, follow-up up to 12.3 years, very low certainty of evidence)

Regarding global quality of life, the WHI RCT reported a mean difference of 0.09, 95% CI 0.07 to 0.12 which was judged to be of "little or no effect" based on the minimal important difference estimates.

Pooling of six trials (n=2,320) showed an effect on high-density lipoprotein (HDL): RD 0.02, 95% CI 0.002 to 0.04, low certainty of evidence. In addition, low- to very low-certainty evidence suggests lower in red meat diets having "little or no effect" on other surrogate outcomes such as cholesterol, weight, blood pressure, and haemoglobin.

Full Risk of Bias Assessment

The research objective was clearly stated. The reported inclusion criteria appear to be appropriate. No language or publication status restrictions were applied.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Yes
Concerns regarding specification of study eligibility criteria Low

MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, CINAHL and ProQuest were searched from inception to July 2018 and update searches were undertaken (MEDLINE only) to April 2019. In addition, trial registries (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform Search Portal), bibliographies of included articles, and relevant literature reviews were screened for additional articles. The search strategies used for each database were published in full (supplementary material) and appeared adequate. No date or language limitations were applied. Two reviewers independently assessed studies for inclusion and any disagreements were resolved through discussion or consultation with a third reviewer.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Yes
2.2 Were methods additional to database searching used to identify relevant reports? Yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Low

Two reviewers independently extracted data from included studies, using a predefined data extraction form, and any disagreements were resolved through discussion or consultation with a third reviewer. The risk of bias of included studies was assessed using a modified version Cochrane risk of bias tool. Risk of bias was assessed independently by two reviewers and any disagreements were resolved through discussion or consultation with a third reviewer; studies were considered to have high risk of bias if two or more of the eight domains were rated as high risk after consensus. Some baseline characteristics are reported for the identified studies.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Low

The main results reported in this systematic review are only based on one trial, however, the authors provided appropriate justification for not pooling these results with another identified trial. Risk of bias was considered as part of the grading of the evidence.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Yes
4.4 Was between-study variation minimal or addressed in the synthesis? Yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Yes
Concerns regarding synthesis and findings Low

Abstract

Background: Few randomized trials have evaluated the effect of reducing red meat intake on clinically important outcomes. Purpose(s): To summarize the effect of lower versus higher red meat intake on the incidence of cardiometabolic and cancer outcomes in adults. Data Sources: EMBASE, CENTRAL, CINAHL, Web of Science, and ProQuest from inception to July 2018 and MEDLINE from inception to April 2019, without language restrictions. Study Selection: Randomized trials (published in any language) comparing diets lower in red meat with diets higher in red meat that differed by a gradient of at least 1 serving per week for 6 months or more. Data Extraction: Teams of 2 reviewers independently extracted data and assessed the risk of bias and the certainty of the evidence. Data Synthesis: Of 12 eligible trials, a single trial enrolling 48 835 women provided the most credible, though still low-certainty, evidence that diets lower in red meat may have little or no effect on all-cause mortality (hazard ratio [HR], 0.99 [95% CI, 0.95 to 1.03], cardiovascular mortality (HR, 0.98 [CI, 0.91 to 1.06]), and cardiovascular disease (HR, 0.99 [CI, 0.94 to 1.05]). That trial also provided low- to very-low-certainty evidence that diets lower in red meat may have little or no effect on total cancer mortality (HR, 0.95 [CI, 0.89 to 1.01]) and the incidence of cancer, including colorectal cancer (HR, 1.04 [CI, 0.90 to 1.20]) and breast cancer (HR, 0.97 [0.90 to 1.04]). Limitation(s): There were few trials, most addressing only surrogate outcomes, with heterogeneous comparators and small gradients in red meat consumption between lower versus higher intake groups. Conclusion(s): Low- to very-low-certainty evidence suggests that diets restricted in red meat may have little or no effect on major cardiometabolic outcomes and cancer mortality and incidence. Primary Funding Source: None (PROSPERO: CRD42017074074).