Reduced or modified dietary fat for preventing cardiovascular disease

Lee Hooper; Carolyn D Summerbell; Rachel Thompson; Deirdre Sills; Felicia G Roberts; Helen Moore; George Davey Smith

doi:10.1002/14651858.CD002137.pub2

. Author manuscript; available in PMC: 2014 Sep 15.

Published in final edited form as: Cochrane Database Syst Rev. 2011 Jul 6;(7):CD002137. doi: 10.1002/14651858.CD002137.pub2

Reduced or modified dietary fat for preventing cardiovascular disease

Lee Hooper ¹, Carolyn D Summerbell ², Rachel Thompson ³, Deirdre Sills ⁴, Felicia G Roberts ⁵, Helen Moore ², George Davey Smith ⁶

PMCID: PMC4163969 EMSID: EMS58572 PMID: 21735388

Abstract

Background

Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol), but their effects on important health outcomes are less clear.

Objectives

To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration.

Search methods

For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, were searched through to June 2010. References of Included studies and reviews were also checked.

Selection criteria

Trials fulfilled the following criteria: 1) randomised with appropriate control group, 2) intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions), 3) not multi factorial, 4) adult humans with or without cardiovascular disease, 5) intervention at least six months, 6) mortality or cardiovascular morbidity data available.

Data collection and analysis

Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed.

Main results

This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I² 50%). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides), of at least two years duration and in studies of men (not of women). There were no clear effects of dietary fat changes on total mortality (RR 0.98, 95% CI 0.93 to 1.04, 71,790 participants) or cardiovascular mortality (RR 0.94, 95% CI 0.85 to 1.04, 65,978 participants). This did not alter with sub-grouping or sensitivity analysis.

Few studies compared reduced with modified fat diets, so direct comparison was not possible.

Authors’ conclusions

The findings are suggestive of a small but potentially important reduction in cardiovascular risk on modification of dietary fat, but not reduction of total fat, in longer trials. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups, should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturates. The ideal type of unsaturated fat is unclear.

Medical Subject Headings (MeSH): *Diet, Fat-Restricted; Cardiovascular Diseases [epidemiology; *prevention & control]; Dietary Fats [administration & dosage]; Randomized Controlled Trials as Topic; Risk Factors

MeSH check words: Adult, Aged, Humans, Middle Aged

BACKGROUND

In 1949 Ryle and Russell in Oxford documented a dramatic increase in coronary heart disease, and the Registrar General’s Statistical Tables of 1920 to 1955 showed that there had been a 70-fold increase in coronary deaths during this 35 year period (Oliver 2000; Ryle 1949). This sudden surge in coronary heart disease sparked research into its causes. A case control study published in 1953 of 200 post-myocardial infarction patients and age-matched controls established that those with disease had higher LDL cholesterol levels (Oliver 1953).

Meanwhile in 1949 in the US Gofman had separated lipids into lipoprotein classes through ultra centrifugation, describing the low density lipoproteins (LDL) as ‘atherosclerogenic’ (Gofman 1949). The following year Keys proposed that the concentration of plasma cholesterol was proportional to dietary saturated fat intake (Keys 1950), and this relationship was confirmed in work by Hegsted (Hegsted 1965; Hegsted 2000) who published an equation explaining the relationship in 1965 and subsequently in 2000, suggesting that dietary saturated fat increases serum cholesterol and so increases cardiovascular risk, while polyunsaturated fats reduce both (this has since been further refined):

Δ serum cholesterol (in mg/dl) = 2.16 * Δ dietary saturated fat intake (as percentage of energy) − 1.65 * Δ dietary polyunsaturated intake (as percentage of energy) + 6.77 * Δ dietary cholesterol intake (in units of 100mg/day) − 0.53

The Seven Countries Study compared CHD mortality in 12000 men aged 40-59 in seven countries and found positive correlations between CHD mortality and total fat intake in 1970, then in 1986 between CHD mortality and saturated fat intake (Keys 1986, Thorogood 1996). A migrant study of Japanese men confirmed in 1974 that men in California had the diet richest in saturated fat and cholesterol, and the highest CHD rates, those in Hawaii had intermediate diet and CHD rates, and those in Japan had a diet lowest in saturated fat and cholesterol, and the least CHD (Kagan 1974, Robertson 1977). However, recent systematic reviews of the observational data have not confirmed these early studies. Skeaff 2009 included 28 US and European cohorts (including 6600 coronary heart disease deaths among 280,000 participants) investigating the effects of total, saturated, monounsaturated, trans and omega-3 fats on coronary heart disease deaths and events. They found no clear relationship between total, saturated or monounsaturated fat intake and coronary heart disease events or deaths. There was evidence that trans fats increased both coronary heart disease events and deaths, and that total polyunsaturated fats and omega-3 fats decreased them. Siri-Tarino 2010 included 21 prospective epidemiologic studies assessing the relationship between saturated fats and coronary heart disease, stroke and cardiovascular disease, finding that saturated fat intake was not associated with risk of coronary heart disease, stroke or cardiovascular disease. Observational studies are potentially powerful at providing associations between dietary factors and cardiovascular risk, but the scale of measurement error is such that detecting such effects may be difficult. Thus intervention studies are needed to clarify cause and effect, to ensure that confounding is not either hiding or generating true relationships. Trials also directly address the issue of whether altering dietary fat in adults is helpful in reducing the risk of cardiovascular diseases in the general population and in those at high risk. It is essential that intervention trials form the basis of evidence based practice in this area.

Most intervention studies have assessed the effect of dietary interventions on risk factors for heart disease, and separate work ties the effect of altering these risk factors to changes in disease incidence and mortality. Systematic review in this area follows the same pattern, so that there are systematic reviews of the effect of dietary fat advice on serum lipid levels (Brunner 1997; Brunner 2009; Clarke 1997; Denke 1995; Kodama 2009; Mensink 1992; Shafiq 2010; Weggemans 2001; Yu-Poth 1999) suggesting that dietary changes cause changes in serum lipids and reviews on the effect of lipid level alterations on cardiovascular morbidity and mortality (Briel 2009; De Caterina 2010; Law 1994; Robinson 2009; Rubins 1995; Walsh 1995), suggesting that changes in lipids do affect cardiovascular risk. Other risk factors dealt with in a similar way are blood pressure (Bucher 1996; Law 1991; Shah 2007), body weight or fatness (Astrup 2000; Hession 2009; SIGN 1996), angiographic measurements (Marchioli 1994), antioxidant intake (Ness 1997), metabolic profile (Kodama 2009) and alcohol intake (Rimm 1996).

A problem with this two-level approach is that any single dietary alteration may have effects over a wide range of risk factors for cardiovascular disease. An example of this is the choice of substitution of saturated fats by carbohydrate, polyunsaturated fats or monounsaturated fats in the diet. This choice may alter lipid profile, and may also affect blood pressure, body weight, oxidative state, rate of cholesterol efflux from fibroblasts, insulin resistance, post-prandial triacylglycerol response, blood clotting factors, and platelet aggregation. There may also be further risk factors of which we are not yet aware. Evidence of beneficial effect on one risk factor does not rule out an opposite effect on another unstudied risk factor, and therefore an overall null (or harmful) effect of intervention. While understanding the effects of dietary advice on intermediate risk factors helps to ensure diets are truly altered by advice, and illuminates mechanisms, the best way of combining the effects on all of these risk factors is to not study risk factors, but to study the effects of dietary change on important outcomes, on cardiovascular morbidity and mortality, and on total mortality.

Substantial randomised controlled trial data on the effects of dietary fat on mortality and morbidity does exist - the first version of this systematic review included over 18,000 participants in trials of at least six months duration, reporting on over 1400 deaths, over 800 cardiovascular deaths, and over 1200 cardiovascular events (Hooper 2000, Hooper 2001). The review found no clear relationship between fat modification (reduction of saturated fats, including studies that replaced the missing calories with carbohydrates - low fat diets - and studies that replaced the missing calories with other fats - modified fat diets) and total or cardiovascular mortality, but did find that such modification reduced the rate of cardiovascular events by around 16% (rate ratio 0.84, 95% CI 0.72 to 0.99 compared with usual diet). Since 2000 several important new studies have been published. These include some very large studies that have modified dietary fat intake in women over several years (including the Women’s Health Initiative that included over 2000 women with, and over 48,000 women without, cardiovascular disease at baseline for over eight years (WHI with CVD 2006; WHI without CVD 2006) and the Women’s Healthy Eating and Living Study including over 3000 women for 11 years (WHEL 2007)) allowing us to add a substantial body of new research on low fat diets (many of the large studies included in the first version of the review were of modified fat diets rather than reduced fat diets), as well as information on the effects of these changes in women (as previous large studies were mainly in men). The results of WHI in particular have raised many questions about both the effects of fat on health and on how we best conduct research to understand the relationship (Michels 2009; Prentice 2007; Stein 2006; Yngve 2006).

Public health dietary advice on prevention of cardiovascular disease has changed a little over time, with a focus on fat modification during the 1960s and fat reduction during the 1990s. Recent recommendations by the American Heart Association suggest that, among other dietary measures, Americans should “limit intake of saturated fat to 7% of energy, trans fat to 1% of energy, and cholesterol to 300 mg/day by choosing lean meats and vegetable alternatives, fat-free (skim) or low-fat (1% fat) dairy products and minimize intake of partially hydrogenated fats” (Lichtenstein 2006).

How effective are these alterations in dietary fat at reducing cardiovascular morbidity and mortality? Should we replace the energy from saturated and trans fats with carbohydrates, polyunsaturated or monounsaturated fats?

This systematic review aimed to assess the effects of reducing or modifying dietary fat on mortality, cardiovascular mortality and cardiovascular events, as well as on individual cardiovascular outcomes and total cancers, and cardiovascular risk factors. Additionally we used the whole database of studies to use meta-regression to explore effects of changes in total, saturated, polyunsaturated, monounsaturated, trans, weight and study duration on the primary outcomes. Finally we included studies that directly compare reduced with modified dietary fats.

OBJECTIVES

The aim of this systematic review was to assess the effect of change in dietary fats, which would be expected to result in lipid lowering, on mortality and cardiovascular morbidity, using all available randomised clinical trials. For this update interventions were classified as low fat, modified fat or combined low and modified fat diets and effects of each type of dietary intervention were assessed.

Specific questions included:

Does reducing saturated fat intake, by reducing and/or modifying dietary fat, in the longer term (at least six months) reduce mortality, cardiovascular mortality or cardiovascular morbidity (or individual health events such as myocardial infarction, stroke, diabetes or cancer)?
Does a long term reduced fat diet, compared with usual diet, reduce mortality, cardiovascular mortality or cardiovascular morbidity (or individual health events such as myocardial infarction, stroke, diabetes or cancer)?
Does a long term reduced fat diet alter classic cardiovascular risk factors (weight, body mass index, systolic or diastolic blood pressure, serum total, LDL or HDL cholesterol and triglyceride)?
Does a long term modified fat diet, compared with usual diet, reduce mortality, cardiovascular mortality or cardiovascular morbidity (or individual health events such as myocardial infarction, stroke, diabetes or cancer)?
Does a long term modified fat diet alter classic cardiovascular risk factors (weight, body mass index, systolic or diastolic blood pressure, serum total, LDL or HDL cholesterol and triglyceride)?
Does reducing and modifying dietary fat (as a combined intervention) in the longer term reduce mortality, cardiovascular mortality or cardiovascular morbidity (or individual health events such as myocardial infarction, stroke, diabetes or cancer)?
Does a long term reduced and modified fat diet (as a combined intervention) alter classic cardiovascular risk factors (weight, body mass index, systolic or diastolic blood pressure, serum total, LDL or HDL cholesterol and triglyceride)?
Are effects on mortality, cardiovascular mortality or cardiovascular morbidity moderated by differences in baseline cardiovascular risk, mode of intervention, control group total fat intake, control group saturated fat intake, gender, setting or decade of publication, or changes in total fat intake, saturated fat intake, polyunsaturated fat intake, monounsaturated fat intake, trans fat intake, dietary cholesterol, weight, serum LDL cholesterol, or study duration?
Is a long term reduced fat diet or a modified fat diet more effective in reducing mortality, cardiovascular mortality or cardiovascular morbidity (or individual effects such as myocardial infarction, stroke or cancer diagnoses)?
Is a long term reduced fat diet or a modified fat diet more acceptable to people trying to adhere to these diets?
Is a long term reduced fat diet or a modified fat diet more effective in altering classic cardiovascular risk factors (weight, body mass index, systolic or diastolic blood pressure, serum total, LDL or HDL cholesterol and triglyceride)?

METHODS

Criteria for considering studies for this review

Types of studies

Randomized controlled trials only. Randomization of individuals was accepted, or of larger groups where there were at least six of these groups randomized. Studies where allocation was not truly randomised (e.g. divisions based on days of the week or first letter of the family name were excluded) or where allocation was not stated as randomised (and no further information was available from the authors) were excluded.

Types of participants

Studies of adults (18 years or older, no upper age limit) at any risk of cardiovascular disease (with or without existing cardiovascular disease) were accepted. Participants could be of either gender, but those who were acutely ill, pregnant or lactating were excluded.

Types of interventions

All randomised controlled trials of interventions stating an intention to reduce or modify dietary fat or cholesterol, such as would be expected to result in improvement of serum lipid profile, were considered. These included an intention to reduce total fat intake, modify fat intake (while maintaining total fat intake), and reduction and modification of fat intake, all compared to a usual diet type control or modification of dietary fat compared to reduced total fat. The intervention had to be dietary advice, supplementation (of fats, oils or modified or low fat foods) or a provided diet, and the control group usual diet, placebo or a control diet.

A low fat diet was considered to be one that aimed to reduce fat intake to < 30%E from fat, and at least partially replace the energy lost with carbohydrates (simple or complex), protein or fruit and vegetables. A modified fat diet was considered to be one that aimed to include 30% or more energy from total fats, and included higher levels of mono-unsaturated or poly-unsaturated fats than a ‘usual’ diet.

Interventions excluded (unless they were present in addition to those above) were addition of alpha-linolenic acid, omega-3 fats or fish oils (as the effect of these is dealt with in a separate review), high fibre diets and garlic (as pulses, fruits and vegetables may have various effects other than lipid lowering) or exploration of varying forms of carbohydrate (unless also specifically low in fat or fat modified). Also excluded were all multiple risk factor interventions other than diet or supplementation (unless the effects of diet or supplementation could be separated, as in a factorial design, so the additional intervention was consistent or randomised between the intervention and control groups), and studies that aimed for weight loss in one arm but not the other. Atkins-type diet aiming to increase protein and fat intake were excluded, as were studies where fat was reduced by means of a fat-substitute (like Olestra). Enteral and parenteral feeds were excluded, as were formula weight reducing diets.

Examples: studies that reduced or modified fats and encouraged physical activity in one arm and compared with encouraging physical activity in the control were included; studies that reduced or modified fats and encouraged physical activity in one arm and compared with no intervention in the control were excluded; studies that reduced or modified fats and encouraged fruit and vegetables in one arm and compared with no intervention in the control were included.

Types of outcome measures

Primary outcomes

The main outcomes were total and cardiovascular mortality and combined cardiovascular events. Combined cardiovascular events included any of the following data available from a trial: cardiovascular deaths, cardiovascular morbidity (non-fatal myocardial infarction, angina, stroke, heart failure, peripheral vascular events, atrial fibrillation) and unplanned cardiovascular interventions (coronary artery bypass surgery or angioplasty).

Secondary outcomes

Secondary outcomes included individual types of cardiovascular events, including total myocardial infarction, non-fatal myocardial infarction, stroke (fatal and non-fatal), diabetes diagnosis, cancer deaths and cancer diagnoses, and quality of life measures (including informal outcomes such as feelings of health, time off work).

Tertiary outcomes

Tertiary outcomes were process outcomes, and included changes in saturated and total fat intakes, and classic cardiovascular risk factors (weight, body mass index, systolic or diastolic blood pressure, serum total, LDL or HDL cholesterol and triglyceride). Trials were only included where primary outcome data (mortality or cardiovascular morbidity) could be collected (by communication with authors if necessary). Studies where it was known that no events occurred were included, and their data used to assess tertiary outcomes.

Search methods for identification of studies

Electronic searches

The initial searches were run in March to June 1998 and included The Cochrane Library, MEDLINE, EMBASE, CAB Abstracts, CVRCT Registry, SIGLE, bibliographies and experts. A comprehensive search strategy was developed to search for nutrition based randomised controlled trials with morbidity or mortality outcomes.

MEDLINE on SilverPlatter was searched for randomised controlled trials on diet and cardiovascular disease or mortality from 1966 to May 1998. An additional MEDLINE (SilverPlatter 1966 to June 1998) search strategy was run to collect papers where only lipid outcomes were mentioned (see Appendix 1 for details of both searches). These search strategies were adapted for use on The Cochrane Library (Issue 2, 1998), EMBASE (Ovid online to May 1998), the CVRCT Registry (May 1998), CAB Abstracts (Ovid online, 1973 to March 1998) and SIGLE (to January 1999). Published systematic reviews addressing diet and heart health were sought as a source of RCTs using similar strategies on MEDLINE (Silver Platter, 1966-March 1998) and The Cochrane Library (Issue 1, 1998).

Cochrane Review Groups in areas related to this review include the Diabetes Group (now the Endocrine and Metabolic Disorders Group), Stroke Group, Renal Group, Hypertension Group and Peripheral Vascular Disease Group. The groups were contacted and asked to search their trial registers for relevant trials.

The review authors updated the searches in June 2010, and modified searches were run on Cochrane Central Register of Controlled Trials (CENTRAL on The Cochrane Library), Ovid MEDLINE and EMBASE. Modification was due to altered database accessibility as well as altered recommended RCT filters. The searches for the earlier review were run as a wider search for studies for several reviews (including a variety of dietary factors), the recent searches were focused on dietary fat interventions only. As databases other than these three had not provided any included studies during the first version of the review, and the numbers of titles and abstracts were not feasible to handle for the update, these were the only databases used for this update. The search strategies used for the update search are shown in Appendix 2.

No language restrictions were applied to the searches.

Searching other resources

Bibliographies of all identified systematic reviews, major non-systematic reviews and included trials were searched for further trials for the first review and the update. Experts in the field were contacted for references to studies not yet identified by the search process. Attempts were made to obtain translations of relevant non-English articles, or contact with the author was established to enable assessment of eligibility.

Data collection and analysis

Selection of studies

Articles were only rejected on initial screen if the reviewer could determine from the title and abstract that the article was not a report of a randomized controlled trial; the trial did not address a low or modified fat diet; the trial was exclusively in children less than 18 years old, pregnant women or the critically ill; the trial was of less than 6 months duration; or the intervention was multifactorial. When a title/abstract could not be rejected with certainty, the full text of the article was obtained for further evaluation.

The inclusion of studies was assessed independently by two assessors (LH and one of RLT, DS, FR, HM, Indra Tumur and Dorotheé Fagard) and differences between reviewers’ results resolved by discussion and, when necessary, in consultation with a third reviewer (Rudolph Reimersma, see acknowledgements). Trials were categorised as “possible” (where all inclusion criteria appeared to be met or where the ascertainment, or otherwise, of outcome events was uncertain, to be resolved by writing to the author) or “excluded”. Attempts were made to contact all authors of “possible” trials in order to confirm or ascertain whether inclusion criteria were met.

Data extraction and management

A data extraction form was designed for this review. Data concerning participants, interventions and outcomes, trial quality characteristics (Chalmers 1990), data on potential effect modifiers including participants baseline risk of cardiovascular disease, trial duration, intensity of intervention (dietary advice, diet provided, dietary advice plus supplementation, supplementation alone), medications used (particularly lipid lowering medication) and smoking status, numbers of events and total patient years in trial were extracted. Where provided, data on risk factors for cardiovascular disease including blood pressure, lipids and weight were collected. Baseline risk of cardiovascular disease was defined as follows: high risk are participants with existing vascular disease including a history of myocardial infarction, stroke, peripheral vascular disease, angina, heart failure or previous coronary artery bypass grafting or angioplasty; moderate risk are participants with a familial risk, dyslipidaemia, diabetes mellitus, hypertension, chronic renal failure; low risk are other participants or mixed population groups. Original reports of trial results were independently extracted by two reviewers (LH and one of CDS, RLT, DS, FR, HM, Indra Tumur, Dorotheé Fagard, Rudolph Reimersma), differences were resolved by discussion.

Assessment of risk of bias in included studies

Trial quality characteristics were assessed using the Cochane Collaboration’s tool for assessment of risk of bias; studies already included were re-assessed using this tool (Higgins 2011). All validity data were extracted by two reviewers independently (LH and one of CDS, RLT, DS, FR, HM, Indra Tumur, Dorotheé Fagard, Rudolph Reimersma), and differences resolved by discussion.

Measures of treatment effect

Primary measures of interest were the effect of intervention on:

total and cardiovascular mortality
combined cardiovascular events (including cardiovascular deaths, non-fatal myocardial infarction, stroke, angina, heart failure, peripheral vascular disease, angioplasty and coronary artery bypass grafting)
quality of life measures.

Unit of analysis issues

We did not include any cluster randomised trials in this review, and cross-over studies (such as the Finnish Mental Hospital study, Finnish Mental Hosp 1972) were excluded as this design would be inappropriate for assessing effects on cardiovascular events or mortality.

Where there was more than one relevant intervention arm but only one control arm the relevant intervention arms were either pooled to create a single pair-wise comparison (where the intervention arms were equivalently appropriate for this review) as described in the Cochrane Handbook (Higgins 2011). Intervention arms that were not appropriate for this review, or less appropriate than another arm, were excluded. When two arms were appropriate for different subgroups then the control group was used once with each intervention arm, but the subgroups were not pooled overall. When assessing event data we aimed to avoid counting more than one outcome event for any one individual within any one comparison. Where we were unclear (for example, where a paper reported numbers of heart attacks, but did not report the number of people who experienced a heart attack, in each arm) we asked authors for further information.

Dealing with missing data

As the outcomes of our review were often not the planned outcomes of relevant trials (many studies with relevant methods, participants, intervention, control and duration had other primary and secondary outcomes, so mortality and morbidity were reported in many studies only as reasons for dropout, or not reported at all), we tried to contact the authors of all identified studies that were appropriate for inclusion on the basis of participants, intervention, comparison and methodology, to ask about mortality and morbidity, the review’s primary and secondary outcomes. This allowed inclusion of many studies that would otherwise have had to be omitted. Studies which were otherwise relevant but where presence or absence of primary outcomes could not be established were retained in the section of studies awaiting classification.

It was often unclear where data on primary or secondary outcome events may still have been missing, and so data were not imputed for this review.

Assessment of heterogeneity

Heterogeneity was examined using the I² test, and considered important where > 50% (Higgins 2003; Higgins 2011).

Assessment of reporting biases

Funnel plots were drawn to examine the possibility of small study bias, including publication bias (Egger 1997), for the primary outcomes total mortality and combined cardiovascular events.

Data synthesis

The data within the original review were in the form of rates. Treatment effect was measured as a rate ratio and meta-analysis performed as a weighted average of (ln) rate ratios (as described by Hasselblad 1995). For trials with a zero in one arm of the data a small number (0.5) was added to the number of events in both groups. Meta-analysis was performed using random effects methodology (DerSimonian 1986) within S-PLUS (Higgins 1999). For the update of the review we checked that using event data gave similar results to rate data as described above - using the same studies the outcomes of the meta-analysis using Mantel-Haenszel random effects methods were almost identical (presence or absence of statistical significance was never different, and scale of effect size was always similar). For this reason, within the update, numbers of events in each study arm, and total number of participants randomised, were extracted, and Mantel-Haenszel random effects meta-analysis carried out in Review Manager software. Event and continuous outcome data were extracted for the latest time point available within the trial (and always at least six months from inception).

Trials where it was known that there were no events in either intervention group were included in the review for completeness, but were not included in the meta-analysis (where it was stated that no events of particular type occurred this was detailed in Characteristics of included studies). These studies inclusion or otherwise would not influence the results of the review. Where trials ran one control group and more than one included intervention group, data from the intervention group providing the comparison that best assessed the effect of altering dietary fat was used. Where the intervention groups appeared equal in this respect the intervention groups were merged (simply added for dichotomous data, and using the techniques described in the Higgins 2011 for continuous data). It was planned that if trials randomized by cluster were identified the patient numbers would be reduced to an “effective sample size” (as described by Hauck 1991), however none were identified that were both included and had cardiovascular events or deaths.

Subgroup analysis and investigation of heterogeneity

For this update dietary interventions were classified as low fat, modified fat or combined low and modified fat diets. Pre-specified analyses included:

Effects of low, modified, and combined low and modified fat diets compared with usual or standard diet on the following outcomes:

total mortality
cardiovascular mortality
combined cardiovascular events

Pre-specified subgroups for primary outcomes included:

mean follow-up time of up to and including, or over, 2 years
initial level of cardiovascular risk (low, medium, high)
mode of intervention (advice, supplementation or provision of diet).

Further subgroups, added into the updating of the systematic review, included:

control group total fat intake,
control group saturated fat intake,
year of first publication of results
gender, and
setting (workplace, community, outpatient), at the request of the Cochrane Occupational Health Field.

We explored the effects of different levels of dietary fats achieved in trials (all difference between the intervention and control groups, as a percentage of energy) using meta-regression on total mortality, cardiovascular mortality and total cardiovascular events by:

total fat intake
saturated fat intake
monounsaturated fat intake
polyunsaturated fat intake
trans fat intake
body weight
LDL cholesterol

The effects of low fat, modified fat and low and modified fat diets (all compared with control or usual diet), and low fat vs modified fat diets on secondary and tertiary outcomes were assessed.

Random effects meta-regression (Berkley 1995) was performed using the STATA command metareg (Sharp 1998, Sterne, Bradburn and Egger 2001, Sterne 2009).

Sensitivity analysis

Sensitivity analyses were carried out for primary outcomes, subgrouping by type of dietary fat intervention (reduced fat, modified fat or both) assessing the effect of

running Mantel-Haenszel fixed effects relative risk meta-analyses (rather than random effects), as events could be considered to be rare (percentages of participants experiencing events was 6% for mortality, 2% for cardiovascular mortality and 7% for cardiovascular events) (Higgins 2011),
running Peto fixed effects odds ratio meta-analysis, which may be more useful than Mantel-Haenszel when events are rare but works better when studies have similar numbers of participants in each arm (not the case with several included studies such as WHI)
excluding the largest study (WHI with CVD 2006, WHI without CVD 2006),
excluding studies which were not free of systematic difference in care (or unclear)
excluding studies that were not free of dietary differences other than fat (or unclear).

RESULTS

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

Results of the search

The initial search strategy resulted in 16,821 potential titles and abstracts, which were scanned for relevant studies. The 2010 update search found an additional 5,191 titles and abstracts to assess for inclusion, making 22,012 titles and abstracts screened in total. Two hundred and seventy six papers were collected as full text in the first review, and a further 254 were collected in the review update, and all 530 were assessed for inclusion in duplicate. The papers were then amalgamated into studies. Of these a total of 48 randomised controlled trials were included in the review. For all included studies we searched for additional publications to ensure that we did not miss any relevant methodology or outcome data from that dataset. This full set of published papers (along with any additional information provided by authors) was data extracted (along with assessment of validity) in duplicate for each included trial. A further 15 studies (17 papers) were allocated to Studies awaiting classification as it could not be established whether they had collected data on mortality or morbidity, the outcomes of this review (Characteristics of studies awaiting classification).

Included studies

Forty eight studies were included in the review (Included studies) and were described in Characteristics of included studies. Some included studies included several comparison arms (e.g. the Kuopio study includes four comparisons: Sarkkinen Fat Mod 1995; Sarkkinen Red & Mod 1995; Sarkkinen Red Fat 1995; Sarkkinen Red vs Mod 1995 and the Monounsaturated fat Obesity study includes three comparisons: Due Low fat 2008; Due Mod fat 2008; Due Low vs Mod 2008); and some studies were reported in several sections for ease of analysing subgroup data (e.g. the Minnesota Coronary Study was reported separately for men (Minnesota Coron men 1989) and women (Minnesota Coron women 1989); the National Diet-Heart Study was reported in its various sub-studies (NDHS Faribault 1968; NDHS Open 1st L&M 1968; NDHS Open 1st mod 1968, NDHS Open 2nd L&M 1968, NDHS Open 2nd Mod 1968); and the Women’s Health Initiative was reported by cardiovascular risk (WHI with CVD 2006, WHI without CVD 2006). In total there were 60 comparisons included in the review.

The main study papers ranged in publication date from 1965 to 2009, and the comparisons were conducted in North America (30), Europe (26), Australia/ New Zealand (3) and the Middle East (1). Ten of the comparisons included only people at high risk of cardiovascular disease, 17 at moderate risk, and 33 at low risk. Sixteen comparisons included only men, 14 only women, and 30 both men and women.

Dietary interventions varied from trials which provided dietary advice (in varying degrees of intensity and duration, 35 studies), provided advice plus some dietary supplementation (such as oils or margarines, nine studies), to studies that provided most food eaten by participants (via institutional provision, meals provided for those living independently or study shops, 16 studies). The setting for most studies was the community (in that participants were living in the community - the actual setting for provision of advice, group work etc was usually unclear, although interventional advice was occasionally clearly in a home or community setting, and occasionally in a primary or secondary healthcare setting), but three studies took place in institutions (Minnesota Coron men 1989; Minnesota Coron women 1989; NDHS Faribault 1968; Veterans Admin 1969), and no studies appeared to have been carried out in occupational settings.

Twenty five comparisons, including 61,958 participants and first published between 1965 and 2007, compared a reduced fat diet with usual or control diet (Ley 2004; BDIT Pilot Studies 1996; BRIDGES 2001; CARMEN 2000; CARMEN MS sub-study 2002; DO IT 2006; Seppelt 1996; Lean 1997; Anderson 1990; Sarkkinen Red Fat 1995; Ball 1965; Boyd 1988; Moy 2001; MSFAT 1997; Due Low fat 2008; Nutrition & Breast Health; Ole Study 2002; Polyp Prevention 1996; Simon 1997; McKeown-Eyssen 1994; Black 1994; WHEL 2007; WHI with CVD 2006; WHI without CVD 2006; WINS 2006).

Fifteen comparisons, including 13,004 participants and published between 1965 and 2007, compared a modified fat diet with control or usual diet (Frenkiel 1986, Houtsmuller 1979, Sarkkinen Fat Mod 1995, Dullaart 1992, Rose 1965, Minnesota Coron men 1989, Minnesota Coron women 1989, MRC 1968, Due Mod fat 2008, NDHS Faribault 1968, NDHS Open 1st mod 1968, NDHS Open 2nd Mod 1968, Oslo Diet-Heart 1966, Sydney Diet-Heart 1978, Veterans Admin 1969). Ten interventions, including 4,931 participants and published between 1968 and 2006, compared a reduced and modified fat diet with usual or control diet (beFIT 1997; DART 1989; Sarkkinen Red & Mod 1995; MeDiet 2002; NDHS Open 1st L&M 1968; NDHS Open 2nd L&M 1968; Oxford Retinopathy 1978; PREMIER 2003; Sondergaard 2003; STARS 1992). Nine interventions, including 1,290 participants and published between 1994 and 2009, compared a low fat diet with a modified fat diet (Sarkkinen Red vs Mod 1995; Due Low vs Mod 2008; McAuley 2005; Rivellese 1994; Azadbakht 2007; THIS DIET 2008; Sacks high protein 2009; Sacks low protein 2009; Strychar 2009). One intervention (144 participants) was not classifiable (Curzio 1989).

Of these comparisons 12 stated that an intended outcome was to assess mortality or cardiovascular morbidity of some sort (DART 1989; DO IT 2006; Rose 1965; Ball 1965; Minnesota Coron men 1989; Minnesota Coron women 1989; MRC 1968; Oslo Diet-Heart 1966; Sydney Diet-Heart 1978; THIS DIET 2008; Veterans Admin 1969; WHEL 2007). A further 36 intended to monitor lipids, blood pressure, weight or other cardiovascular risk factor outcomes, seven aimed to assess effects on cancers or cancer related outcomes such as polyps, two the feasibility of dietary intake, and the remaining three studies aimed to assess bile acid kinetics or diabetic retinopathy. Of the 48 included studies, nine recruited participants with cardiovascular disease (were secondary prevention studies), 12 recruited those at increased risk of CVD (including those recruited on the basis of raised lipids, blood pressure or weight), and 25 recruited people from the general population or without specific CVD risk (primary prevention). A further two studies recruited a mix of participants (at high and lower CVD risk).

Of the 51 comparisons of a modified and/or low fat diet with a control or usual diet, four measured the total fat intake in the control arm as less than 30% of energy (30%E), 18 30% - 34.9%E, 19 35% - 39.9%E, six had a control arm with at least 40%E, and it was unclear what the total fat intake in the control arm was in the remaining four comparisons. Three of the included comparisons had a saturated fat intake in the control group of less than 10% of energy (10%E), 19 10% - 14.9%E, 14 15% - 19.9%E and one comparison 20+%E, while saturated fat intake in the control group was unclear in a further 14 comparisons.

Of the 60 intervention arms only 21 provided data on mortality (including 71,790 participants and 4292 deaths), 16 on cardiovascular mortality (65,978 participants and 1407 cardiovascular deaths), and 23 on combined cardiovascular events (65,508 participants and 4887 events). In 25 of the included arms none of the participants experienced any deaths or cardiovascular events, and in three further studies it was clear that events had occurred, but it was not clear in which arm(s) the events had occurred (BDIT Pilot Studies 1996; Oxford Retinopathy 1978; Simon 1997), so that data could not be included in the meta-analyses.

Excluded studies

Two hundred and eighty eight trials have been excluded (Excluded studies, the full texts assessed in duplicate for inclusion), and the reasons for these exclusions were described in Characteristics of excluded studies.

One more trial was ongoing (Ongoing studies) and described in Characteristics of ongoing studies.

Risk of bias in included studies

To understand the risk of bias in the individual included studies in a visual way, see Figure 1, and the summary of studies included in the review, see Figure 2.

Allocation

All trials included were randomised controlled trials, those with detected pseudo random allocation (for example where participants are randomised according to birth date or alphabetically from their name) were excluded. Allocation concealment was judged well done in 26 comparisons (Ley 2004; BRIDGES 2001; CARMEN 2000; CARMEN MS sub-study 2002; Dullaart 1992; MSFAT 1997; NDHS Faribault 1968; NDHS Open 1st L&M 1968; NDHS Open 1st mod 1968; NDHS Open 2nd L&M 1968; NDHS Open 2nd Mod 1968; Nutrition & Breast Health; Ole Study 2002; Oslo Diet-Heart 1966; Oxford Retinopathy 1978; Polyp Prevention 1996; PREMIER 2003; Sacks low protein 2009; Sacks high protein 2009; STARS 1992; THIS DIET 2008; McKeown-Eyssen 1994; WHEL 2007; WHI with CVD 2006; WHI without CVD 2006; WINS 2006), not done in one (Sondergaard 2003) and unclear in the remainder.

Blinding

Blinding of participants is not easy in dietary studies, as the participants usually have to follow instructions to attain the specific dietary goals. However, it is feasible in some circumstances, including when food is provided via an institutional setting, or meals provided at a central setting and remaining meals packed to take away, through use of a trial shop, where very specific food-based dietary advice is provided for all participants, or where the same dietary advice is provided to both groups but a different supplement (e.g. dietary advice to reduce fats, then provision of different oils or fats) is provided. Where participants are not blinded it is difficult to ensure that study staff, health care providers and outcome assessors are blinded. The 11 comparisons that appear to have had adequate participant and study personnel blinding were Minnesota Coron men 1989, Minnesota Coron women 1989, NDHS Faribault 1968, NDHS Open 1st L&M 1968, NDHS Open 1st mod 1968, half the participants in NDHS Open 2nd L&M 1968, half the participants in NDHS Open 2nd Mod 1968, Sacks low protein 2009, Sacks high protein 2009, the Ole Study 2002 and Veterans Admin 1969), and blinding was inadequate or unclear in the remaining studies.

Incomplete outcome data

Assessing whether incomplete outcome data have been addressed was difficult as the primary outcomes for this review were often seen as dropouts and exclusions from the original studies. When mortality and/or cardiovascular events were noted in any one study it is still feasible that some participants left that study feeling unwell or because the diet was inconvenient (so were simply lost to follow up from the perspective of the study) and later died or experienced a cardiovascular event. However, in some cases studies checked medical records or death registers to ensure that such events were all collected (these 10 studies included DART 1989, NDHS Faribault 1968, Oslo Diet-Heart 1966, PREMIER 2003, Sydney Diet-Heart 1978, THIS DIET 2008, Veterans Admin 1969, Black 1994, WHEL 2007, WINS 2006). In the other studies it is not possible to know whether additional deaths or cardiovascular events occurred, that were not counted or ascertained within this review.

Selective reporting

Assessment of selective reporting is difficult when the outcome of interest is simply a cause of dropouts in most included studies. We tried to contact all of the trialists to ask about deaths and outcome events, but it is possible that some trialists did not reply as they felt that their data did not reflect the expected or hoped for pattern of events. All of the included studies have either reported that the participants did not experience any of our primary outcomes, published their outcome data or have provided the data they did possess. For this reason all the included studies have been graded as ‘Free of selective reporting’.

Other potential sources of bias

The studies were assessed for risk of bias in relation to ‘systematic difference in care’ and ‘dietary differences other than fat’. The 29 comparisons free of systematic differences in care between the study arms included CARMEN 2000, CARMEN MS sub-study 2002, Frenkiel 1986, Seppelt 1996, Lean 1997, Sarkkinen Fat Mod 1995, Sarkkinen Red Fat 1995, Sarkkinen Red & Mod 1995, Sarkkinen Red vs Mod 1995 Rose 1965, Minnesota Coron men 1989, Minnesota Coron women 1989, MSFAT 1997, Due Low fat 2008, NDHS Faribault 1968, NDHS Open 1st L&M 1968, NDHS Open 1st mod 1968, NDHS Open 2nd L&M 1968, NDHS Open 2nd Mod 1968, Ole Study 2002, Oxford Retinopathy 1978, PREMIER 2003, Rivellese 1994, Sacks low protein 2009, Sacks high protein 2009, Strychar 2009, Azadbakht 2007, THIS DIET 2008, Veterans Admin 1969), while 27 comparisons clearly did have differences in care (such as differential time provided for those on the intervention to learn a new diet, and/or differential medical follow-up), and four were unclear.

Some comparisons were partially confounded by dietary changes other than those directly related to dietary fat intakes (for example, some studies encouraged intervention participants to make changes to their fat intake as well as changes to fruit and vegetable or fibre or salt intakes). The 39 comparisons that appeared free of such differences included Ley 2004, BDIT Pilot Studies 1996, beFIT 1997, CARMEN 2000, CARMEN MS sub-study 2002, DART 1989, Houtsmuller 1979, Seppelt 1996, Lean 1997, Anderson 1990, Sarkkinen Fat Mod 1995, Sarkkinen Red Fat 1995, Sarkkinen Red & Mod 1995, Sarkkinen Red vs Mod 1995, Dullaart 1992, Rose 1965, Ball 1965, Boyd 1988, Minnesota Coron men 1989, Minnesota Coron women 1989, MRC 1968, MSFAT 1997, NDHS Faribault 1968, NDHS Open 1st L&M 1968, NDHS Open 1st mod 1968, NDHS Open 2nd L&M 1968, NDHS Open 2nd Mod 1968, Nutrition & Breast Health, Oxford Retinopathy 1978, Sacks low protein 2009, Sacks high protein 2009, Simon 1997, Strychar 2009, Sydney Diet-Heart 1978, Azadbakht 2007, THIS DIET 2008, Veterans Admin 1969, Black 1994, WINS 2006. A further three comparisons were unclear, and the remainder, 18 comparisons, were confounded as to the effects of changes in fat.

Effects of interventions

Reduced, modified or reduced and modified dietary fat vs. usual or control diet

Primary outcomes

Total mortality

There was no clear effect of any dietary fat intervention compared to usual or control diet on mortality (RR 0.98, 95% CI 0.93 to 1.04, I² 0%, 71,790 participants, 4292 deaths, p_effect 0.53, Analysis 1.1). Similarly there was no effect of modified fat vs usual diet (RR 1.02, 95% CI 0.88 to 1.18, I² 34%, 11,441 participants, 1120 deaths, p_effect 0.81), reduced fat vs usual diet (RR 0.97, 95% CI 0.90 to 1.04, I² 0%, 58,130 participants, 2936 deaths, p_effect 0.42), or reduced and modified fat vs usual diet (RR 0.97, 95% CI 0.76 to 1.23, I² 0%, 2219 participants, 236 deaths, p_effect 0.78).

Sensitivity analyses (using Mantel-Haenszel fixed effects relative risk meta-analysis, Peto odds ratio (fixed effects), removing the largest single study (WHI), removing studies with a systematic difference in care between the intervention and control arms, and removing studies with dietary differences between arms other than in dietary fat intake) did not alter the lack of statistically significant effect overall or for modified fat intake, reduced fat intake or reduced and modified fat intake compared with usual or control diet (Table 1). The funnel plot does not suggest severe small study bias, although there may be some smaller studies missing suggesting increased total mortality in the intervention group (so addition of any such studies would further lessen the likelihood of a protective effect of dietary fat modification or reduction on mortality). The funnel plot is shown in Figure 3.

Table 1. Sensitivity analyses of primary outcomes.

Outcome	Sensitivity Analysis	Subgroup	Risk ratio (95% CI)	Number of studies / participants/ events	I²
Total mortality	Mantel-Haenszel, Fixed effects	Overall analysis	0.98 (0.93 to 1.04)	21/ 71795 / 4292	0%
Total mortality	Mantel-Haenszel, Fixed effects	Modified fat intake	1.03 (0.92 to 1.14)	8/11441/ 1120	34%
Total mortality	Mantel-Haenszel, Fixed effects	Reduced fat intake	0.97 (0.90 to 1.04)	10/ 58130/ 2936	0%
Total mortality	Mantel-Haenszel, Fixed effects	Reduced&modified fat intake	0.96 (0.76 to 1.22)	2/ 2224/ 236	0%
Total mortality	Peto Odds Ratio (fixed effects)	Overall analysis	OR0.98 (0.92 to 1. 05)	21/ 71795 / 4292	0%
Total mortality	Peto Odds Ratio (fixed effects)	Modified fat intake	OR 1.03 (0.91 to 1. 18)	8/11441/ 1120	39%
Total mortality	Peto Odds Ratio (fixed effects)	Reduced fat intake	OR 0.97 (0.90 to 1. 04)	10/ 58130/ 2936	0%
Total mortality	Peto Odds Ratio (fixed effects)	Reduced and modified fat intake	OR 0.96 (0.73 to 1. 25)	2/ 2224/ 236	0%
Total mortality	Excluding WHI	Overall analysis	0.98 (0.91 to 1.07)	20/ 22960/ 1888	0%
Total mortality	Excluding WHI	Reduced fat intake	0.94 (0.80 to 1.10)	9/ 9295/ 532	0%
Total mortality	Excluding studies with systematic difference in care	Overall analysis	1.03 (0.92 to 1.16)	6/ 10715/ 882	0%
Total mortality	Excluding studies with systematic difference in care	Modified fat intake	1.03 (0.92 to 1.16)	5/ 10178/ 881	0%
Total mortality	Excluding studies with systematic difference in care	Reduced fat intake	0.33 (0.01 to 8.12)	1/ 537/ 1	NR
Total mortality	Excluding studies with systematic difference in care	Reduced&modified fat intake	NR	0/ 0/ 0	NR
Total mortality	Excluding studies with systematic differences in diet other than fat	Overall analysis	1.03 (0.93 to 1.13)	12/ 16060/ 1320	0%
Total mortality	Excluding studies with systematic differences in diet other than fat	Modified fat intake	1.05 (0.93 to 1.18)	7/ 11029/ 1005	7%
Total mortality	Excluding studies with systematic differences in diet other than fat	Reduced fat intake	0.90 (0.60 to 1.34)	4/ 2998/ 89	0%
Total mortality	Excluding studies with systematic differences in diet other than fat	Reduced&modified fat intake	0.98 (0.76 to 1.25)	1/ 2033/ 224	NR
Cardiovascular mortality	Mantel-Haenszel, Fixed effects	Overall analysis	0.95 (0.85 to 1.05)	16/ 65983/ 1407	0%
Cardiovascular mortality	Mantel-Haenszel, Fixed effects	Modified fat intake	0.92 (0.79 to 1.08)	6/ 10788/ 593	45%
Cardiovascular mortality	Mantel-Haenszel, Fixed effects	Reduced fat intake	0.96 (0.82 to 1.12)	7/ 52971/ 602	0%
Cardiovascular mortality	Mantel-Haenszel, Fixed effects	Reduced&modified fat intake	0.98 (0.76 to 1.26)	3/ 2224/ 212	0%
Cardiovascular mortality	Peto Odds Ratio (fixed effects)	Overall analysis	OR 0.94 (0.84 to 1. 05)	16/ 65983/ 1407	11%
Cardiovascular mortality	Peto Odds Ratio (fixed effects)	Modified fat intake	OR0.91 (0.77 to 1. 08)	6/ 10788/ 593	51%
Cardiovascular mortality	Peto Odds Ratio (fixed effects)	Reduced fat intake	OR0.96 (0.81 to 1. 13)	7/ 52971/ 602	0%
Cardiovascular mortality	Peto Odds Ratio (fixed effects)	Reduced&Modified fat intake	OR 0.97 (0.73 to 1. 29)	3/ 2224/ 212	0%
Cardiovascular mortality	Excluding WHI	5Overall analysis	0.91 (0.79 to 1.04)	14/ 17148/ 874	7%
Cardiovascular mortality	Excluding WHI	Reduced fat intake	0.74 (0.47 to 1.17)	5/4136/ 69	0%
Cardiovascular mortality	Excluding studies with systematic difference in care	Overall analysis	0.97 (0.70 to 1.33)	4/ 9983/ 451	59%
Cardiovascular mortality	Excluding studies with systematic difference in care	Modified fat intake	0.97 (0.70 to 1.33)	4/ 9983/ 451	59%
Cardiovascular mortality	Excluding studies with systematic difference in care	Reduced fat intake	NR	0/ 0/ 0	NR
Cardiovascular mortality	Excluding studies with systematic difference in care	Reduced&modified fat intake	NR	0/ 0/ 0	NR
Cardiovascular mortality	Excluding studies with systematic differences in diet other than fat	Overall analysis	0.95 (0.80 to 1.13)	9/ 12970/ 748	22%
Cardiovascular mortality	Excluding studies with systematic differences in diet other than fat	Modified fat intake	0.97 (0.75 to 1.26)	5/ 10376/ 503	47%
Cardiovascular mortality	Excluding studies with systematic differences in diet other than fat	Reduced fat intake	0.75 (0.40 to 1.42)	3/561/44	3%
Cardiovascular mortality	Excluding studies with systematic differences in diet other than fat	Reduced&modified fat intake	1.01 (0.77 to 1.31)	1/ 2033/ 201	NR
Combined cardiovascular events	Mantel-Haenszel, Fixed effects	Overall analysis	0.93 (0.88 to 0.98)	23/ 65508/ 4887	50%
Combined cardiovascular events	Mantel-Haenszel, Fixed effects	Modified fat intake	0.83 (0.73 to 0.93)	9/ 11660/ 855	61%
Combined cardiovascular events	Mantel-Haenszel, Fixed effects	Reduced fat intake	0.96 (0.91 to 1.03)	8/ 50655/ 3632	17%
Combined cardiovascular events	Mantel-Haenszel, Fixed effects	Reduced&modified fat intake	0.84 (0.71 to 1.00)	6/ 3193/ 400	40%
Combined cardiovascular events	Peto Odds Ratio (fixed effects)	Overall analysis	OR 0.92 (0.86 to 0. 97)	23/ 65508/ 4887	61%
Combined cardiovascular events	Peto Odds Ratio (fixed effects)	Modified fat intake	OR 0.78 (0.67 to 0. 91)	9/ 11660/ 855	70%
Combined cardiovascular events	Peto Odds Ratio (fixed effects)	Reduced fat intake	OR0.96 (0.90 to 1. 03)	8/ 50655/ 3632	30%
Combined cardiovascular events	Peto Odds Ratio (fixed effects)	Reduced&modified fat intake	OR 0.79 (0.63 to 1. 00)	6/ 3193/ 400	60%
Combined cardiovascular events	Excluding WHI	Overall analysis	0.81 (0.70 to 0.93)	21/ 16673/ 1442	39%
Combined cardiovascular events	Excluding WHI	Reduced fat intake	0.82 (0.63 to 1.05)	6/ 1820/ 187	0%
Combined cardiovascular events	Excluding studies with systematic difference in care	Overall analysis	0.93 (0.77 to 1.12)	9/ 12158/ 533	12%
Combined cardiovascular events	Excluding studies with systematic difference in care	Modified fat intake	0.95 (0.77 to 1.17)	6/ 10753/ 527	24%
Combined cardiovascular events	Excluding studies with systematic difference in care	Reduced fat intake	0.20 (0.01 to 4.13)	1/ 537/ 2	NR
Combined cardiovascular events	Excluding studies with systematic difference in care	Reduced&modified fat intake	0.28 (0.04 to 2.15)	2/ 868/ 4	0%
Combined cardiovascular events	Excluding studies with systematic differences in diet other than fat	Overall analysis	0.85 (0.72 to 1.01)	14/ 14710/ 1097	42%
Combined cardiovascular events	Excluding studies with systematic differences in diet other than fat	Modified fat intake	0.84 (0.65 to 1.09)	8/ 11248/ 701	63%
Combined cardiovascular events	Excluding studies with systematic differences in diet other than fat	Reduced fat intake	0.87 (0.63 to 1.20)	3/ 561/ 109	0%
Combined cardiovascular events	Excluding studies with systematic differences in diet other than fat	Reduced&modified fat intake	0.91 (0.73 to 1.13)	3/ 2901/ 287	0%

Analysis described	Total mortality: Number of studies, participants, events	Total mortality: Relative Risk (95% CI), Heterogeneity - I², %	CVD mortality: Number of studies, participants, events	CVD mortality: Relative Risk (95% CI), Heterogeneity - I², %	CVD events: Number of studies, participants, events	CVD events: Relative Risk (95% CI), Heterogeneity - I², %
Main meta-analysis	21, 71790, 4292	0.98 (0.93 to 1.04), 0	16, 65978, 1407	0.94 (0.85 to 1.04), 0	23, 65508, 4887	0.86 (0.77 to 0.96), 50
Subgroup ‘mean follow-up ≤2 years’	9, 12272, 767	1.05 (0.91 to 1.20), 0	6, 11434, 523	1.04 (0.88 to 1.23), 0	12, 13844, 689	0.95 (0.84 to 1.09), 0
Subgroup ‘mean follow-up >2 years’	12, 59518, 3525	0.97 (0.91 to 1.03), 0	10, 54544, 884	0.89 (0.78 to 1.01), 0	11, 51664, 4198	0.78 (0.67 to 0.92), 72
Sub-group ‘low CVD risk’	10, 66776, 3717	0.99 (0.93 to 1.05), 0	6, 59682, 879	0.93 (0.77 to 1.13), 35	10, 58338, 3408	0.93 (0.82 to 1.05), 13
Subgroup ‘moderate CVD risk’	3, 1200, 47	0.69 (0.39 to 1.21), 0	2, 663, 23	0.66 (0.28 to 1.53), 0	5, 1537, 143	0.57 (0.33 to 0.99), 53
Sub-group ‘high CVD risk’	8, 3814, 528	0.95 (0.78 to 1.17), 24	8, 5633, 505	0.95 (0.80 to 1.12), 0	8, 5633, 1336	0.88 (0.75 to 1.02), 58
Sub-group ‘Dietary advice’	13, 60320, 3201	0.98 (0.92 to 1.05), 0	9, 54703, 796	0.97 (0.85 to 1.12), 0	12, 52595, 3998	0.85 (0.72 to 1.00), 62
Sub-group ‘dietary advice plus supplementation’	4, 1372, 219	0.80 (0.63 to 1.02), 0	4, 1372, 169	0.87 (0.62 to 1.21), 15	4, 1372, 395	0.78 (0.66 to 0.92), 0
Sub-group ‘diet provided’	4, 10098, 872	1.03 (0.92 to 1.15), 0	3, 9903, 442	0.93 (0.69 to 1.26), 63	7, 11541, 494	0.91 (0.73 to 1.14), 19
Subgroup ‘total fat in control <30%E’	4, 3592, 81	0.93 (0.61 to 1.43), 0	2, 618, 25	0.76 (0.35 to 1.64), 0	3, 1155, 152	0.82 (0.65 to 1.03), 1
Sub-group ‘total fat in control 30-34.9%E’	4, 3450, 333	0.91 (0.46 to 1.81), 23	3, 3344, 21	0.72 (0.15 to 3.53), 51	5, 1429, 74	0.93 (0.62 to 1.39), 0
Sub-group ‘total fat in control 35-39.9%E’	8, 62820, 3311	1.00 (0.94 to 1.07), 0	6, 60088, 1054	1.00 (0.88 to 1.12), 0	10, 60919, 4034	0.96 (0.84 to 1.10), 44
Subgroup ‘total fat in control 40+%E’	3, 1491, 454	0.96 (0.83 to 1.11), 0	3, 1491, 227	0.80 (0.63 to 1.02), 0	3, 1491, 435	0.83 (0.71 to 0.97), 0
Sub-group ‘saturated fat in control <10%E’	2, 3625, 316	0.97 (0.79 to 1.20), 0	1, 3088, 7	0.40 (0.08 to 2.08), -	1, 537, 2	0.20 (0.01 to 4.13), -
Sub-group ‘saturated fat in control 10-14.9%E’	5, 50089, 2520	1.01 (0.77 to 1.32), 32	5, 49631, 558	0.98 (0.83 to 1.16), 0	11, 51610, 3565	0.97 (0.87 to 1.07), 10
Sub-group ‘saturated fat in control 15-19.9%E’	6, 14598, 1134	1.02 (0.92 to 1.13), 0	4, 11966, 657	0.90 (0.74 to 1.11), 37	5, 11991, 793	0.86 (0.68 to 1.09), 64
Sub-group ‘saturated fat in control 20+%E’	0, 0, 0	-	0, 0, 0	-	0, 0, 0	-
Sub-group ‘studies of men’	11, 9604, 1224	0.97 (0.87 to 1.08), 7	9, 8951, 735	0.89 (0.77 to 1.02), 0	13, 10589, 1162	0.82 (0.74 to 0.90), 0
Sub-group ‘studies of women’	5, 59130, 2960	0.99 (0.92 to 1.07), 0	4, 56587, 658	1.03 (0.88 to 1.20), 0	4, 53605, 3566	1.04 (0.89 to 1.21), 53
Sub-group ‘studies of men and women’	5, 3056, 108	0.84 (0.58 to 1.22), 0	3, 440, 14	0.45 (0.15 to 1.37), 0	6, 1314, 159	0.60 (0.32 to 1.13), 66
Sub-group ‘community setting’	17, 61692, 3420	0.97 (0.91 to 1.03), 0	13, 56077, 965	0.95 (0.84 to 1.07), 0	20, 55605, 4405	0.84 (0.73 to 0.95), 51
Sub-group ‘residential setting’	4, 10098, 872	1.03 (0.92 to 1.15), 0	3, 9903, 442	0.93 (0.69 to 1.26), 63	3, 9903, 482	0.94 (0.71 to 1.24), 63
Sub-group ‘published in 1960s’	6, 2178, 580	0.92 (0.80 to 1.06), 2	5, 1983, 326	0.80, 0.64 to 1.00), 11	9, 3621, 638	0.81 (0.71 to 0.92), 0
Sub-group ‘published in 1970s’	3, 9515, 584	1.13 (0.95 to 1.33), 9	2, 9057, 304	1.06 (0.85 to 1.33), 0	3, 9159, 301	0.71 (0.35 to 1.43), 88
Sub-group ‘published in 1980s’	1, 2033, 224	0.98 (0.76 to 1.25), -	1, 2033, 201	1.01 (0.77 to 1.31), -	1, 2033, 283	0.92 (0.74 to 1.15), -
Sub-group ‘published in 1990s’	5, 4880, 137	0.90 (0.65 to 1.26), 0	3, 364, 11	0.27 (0.07 to 1.08), 0	3, 364, 57	0.51 (0.32 to 0.81), 0
Sub-group ‘published since 2000’	6, 53184, 2767	0.98 (0.91 to 1.05), 0	5, 52541, 565	0.98 (0.83 to 1.15), 0	7, 50331, 3608	0.96 (0.85 to 1.>08), 29

Outcome / Variable	Total mortality, coefficient (95% CI), number of studies, I²	Cardiovascular mortality, coefficient (95% CI), number of studies, I²	Cardiovascular events, coefficient (95% CI), number of studies, I²	CVD events (co-regression with duration) coefficient (95% CI), number of studies, I²,
Difference in total fat intake, %E	−0.010 (−0.030 to 0.010), 20, 0%*	−0.023 (−0.074 to 0.029), 14, 4%	−0.012 (−0.037 to 0.012), 21, 25%	−0.016 (−0.045 to 0.013), 21, 23%
Difference in SFA intake, %E	0.005 (−0.016 to 0.026), 18, 0%	−0.006 (−0.050 to 0.037), 14, 3%	−.013 (−0.043 to 0.017), 21, 19%	−0.008 (−0.048 to 0.032), 21, 22%
Difference in MUFA intake, %E	−0.036 (−0.112 to 0.040), 15, 0%	−0.073 (−0.203 to 0.056), 13, 3%	−0.023 (−0.067 to 0.021), 14, 41%	−0.024 (−0.071 to 0.022), 14, 36%
Difference in PUFA intake, %E	−0.004 (−0.016 to 0.008), 17, 0%	−0.000 (−0.027 to 0.026), 14, 4%	−0.002 (−0.022 to 0.019), 19, 24%	−0.006 (−0.032 to 0.021), 19, 27%
Difference in trans fat intake, %E	Insufficient data, 2 studies	Insufficient data, 2 studies	Insufficient data, 2 studies	Insufficient data, 2 studies
Difference in weight, kg	−0.035 (−0.138 to 0.068), 14, 0%	−0.067 (−0.240 to 0.106), 9, 17%	−0.038 (−0.154 to 0.078), 14, 47%	−0.033 (−0.118 to 0.052), 14, 15%**
Difference in LDL cholesterol, mmol/L	−0.948 (−5.752 to 3.856), 6, 0%	−2.909 (−10.529 to 4.710), 6, 0%	−1.600 (−3.815 to 0.616), 7, 28%	−1.465 (−4.094 to 1.164), 7, 25%
Difference in serum total cholesterol, mmol/L	0.024 (−0.168 to 0.217), 18, 0%	−0.187 (−0.505 to 0.131), 15, 0%	−0.155 (−0.554 to 0.244), 17, 49%	−0.155 (−0.635 to 0.325), 17, 53%
Study duration, years	−0.004 (−0.024 to 0.016), 22, 0%	−0.014 (−0.072 to 0.044), 16, 4%	−0.037 (−0.106to0.032), 24, 45%

Methods	RCT
Participants	Moderately hypercholesterolaemic, non-obese Caucasian men and women aged 30-50 (USA) CVD risk: moderate Control: randomised 62, analysed 51 Intervention: randomised 56, analysed 47 Mean years in trial: control 0.91, intervention 0.92 % male: control 61, intervention 66 Age: mean control 40.3 (sd 5.4), intervention 40.7 (sd 5.2) (all 30-50)
Interventions	Reduced fat diet vs usual diet Control aims: no diet intervention Intervention aims: 25%E from fats, 20%E from protein, 55%E from CHO, <200mg chol /day (Also an intervention arm with similar aims plus increased fibre intake) Control methods: no intervention Intervention methods: seminars and individual eating patterns taught, 10 weeks teaching and 40 weeks maintenance Total fat intake (at 1 year): low fat 30 (sd 7.5), cont 31 (sd 5.7)%E Saturated fat intake (at 1 year): low fat 9 (sd 2.7), cont 10 (sd 2.9)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: diet composition, lipids Data available on total mortality? yes (none) Cardiovascular mortality? yes (none) Events available for combined cardiovascular events: cardiovascular deaths, fatal and non-fatal MI, stroke (none) Secondary outcomes: total and non-fatal MI, stroke Tertiary outcomes: total, LDL and HDL cholesterol
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“matched on age, gender & cholesterol level, randomly assigned to intervention group using systematic random procedure”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were aware of their dietary advice, researchers were not
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Deaths, cancer and CV events are drop-outs, trialists asked for data
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	(As the high fibre arm has not been used in the data set). See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Overweight and obese people (Iran) CVD risk: low Modified fat diet: 50 randomised, 45 analysed Low fat diet: 50 randomised, 44 analysed Mean years in trial: both groups 1.1 % male: modified fat diet 32%, low fat diet 25% Age: mean modified fat 45 (sd 5), low fat diet 46 (sd 6)
Interventions	Reduced fat diet vs modified fat diet Modified fat aims: 30%E from fat, SFA 5%E, MUFA 15%E, PUFA 10%E, protein 15%E, CHO 55%E, cholesterol <200mg/d, fibre 25g/d, 500kcal below energy needs Low fat aims: 20%E from fat, SFA 5-6%E, MUFA 7%E, PUFA 7%E, protein 15%E, CHO 65%E, cholesterol <200mg/d, fibre 25g/d, 500kcal below energy needs Modified fat methods: monthly appointments, oral and written information on healthy food choices, individual programmes Low fat methods: monthly appointments, oral and written information on healthy food choices, individual programmes Total fat intake (at 14 months): low fat 20 (sd 10)%E, mod fat 30 (sd 7.2)%E Saturated fat intake (at 14 months): low fat 6.8 (sd 4.2)%E, mod fat 7.0 (sd 3.6)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: weight, metabolic risk Data available on total mortality? yes (none) Cardiovascular mortality? yes (none) Events available for combined cardiovascular events: MI, stroke (no events) Secondary outcomes: total MI, stroke, cancer diagnoses, cancer deaths (no events) Tertiary outcomes: weight, total, LDL and HDL cholesterol, TGs, BP
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Program generated by a random number table (?)
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants and nutritionist were not blinded, lab staff were
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Both groups given equivalent intervention intensity and duration. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	Focus on fat and types of fat. See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Men who have recently recovered from their first MI (UK) CVD risk: high Control: unclear how many randomised, 129 analysed Intervention: unclear how many randomised, 123 analysed Mean years in trial: 3.0 % male: 100 Age: unclear (all <65)
Interventions	Reduced fat intake vs. usual diet Control aims: usual diet, overweight subjects given weight reduction advice (mainly CHO reduction) Intervention aims: reduce fat intake to 40g daily, overweight subjects given weight reducing advice Control methods: continued with normal diet, unclear if follow up for control group was as for intervention group Intervention methods: unclear who gave dietary advice or how often, patient and wife saw doctor and dietitian 2 weeks after hospital discharge, then every 2 weeks for 3 months, every 3 months for two years and six-monthly thereafter. Diet diaries checked by dietitian at each visit and problems discussed Total fat intake (at 4 years): low fat 21.8 (sd unclear), cont 44.3 (sd unclear)%E Saturated fat intake: unclear Style: diet advice Setting: community
Outcomes	Stated trial outcomes: reinfarction, death Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: cardiovascular deaths, non-fatal MI Secondary outcomes: total MI Tertiary outcomes: none (weight and total cholesterol reported but no variance info)
Notes	At 3 years weight: control −3.6kg n=67, intervention −5.4kg n=68 total cholesterol: control −0.85mmol/L n=52, intervention −1.14mmol/L n=54
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“allocated at random to one of two groups at each hospital”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were not blinded, the researcher who assessed outcomes was blinded to treatment arm
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear if any lost to follow up
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Unclear risk	See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Women with mammographic dysplasia (Canada) CVD risk: low Control: 147 randomised, 110 analysed at over 8 years Intervention: 148 randomised, 104 analysed at over 8 years Mean years in trial: control 7.5, intervention 6.8 % male: 0 Age: mean control 45, intervention 44 (all >30)
Interventions	Reduced fat intake vs usual diet Control aims: healthy diet advice, no alteration in dietary fat advised, aim to maintain weight Intervention aims: total fat 15%E, replace fat by complex CHO, aim to maintain weight Control methods: seen for advice once every 4 months for 12 months Intervention methods: seen for advice once a month for 12 months Total fat intake (at 9.2 years): low fat 31.7 (sd 7.3)%E, cont 35.3 (sd 5.6)%E Saturated fat intake (at 9.2 years): low fat 10.6 (sd 4.6), cont 12.3 (sd 4.6)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: dietary fat, serum cholesterol Data available on total mortality? yes, but not clear from which groups Cardiovascular mortality? no Events available for combined cardiovascular events: none Secondary outcomes: none Tertiary outcomes: weight, BMI, total and HDL cholesterol
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“randomly allocated”
Allocation concealment (selection bias)	Unclear risk	Randomisation not described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants not blinded, but outcome assessors blinded to intervention
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Minor, women in intervention group seen more frequently. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Women and men with mild hypercholesterolemia (USA) CVD risk: moderate Control: unclear how many randomised, 192 analysed Intervention: unclear how many randomised, 217 analysed Mean years in trial: unclear (max duration 0.5 years) % male: 52 (not divided by intervention group) Age: mean 43.2 (not divided by intervention group) (all >30)
Interventions	Reduced and modified fat vs usual diet Control aims:asked to delay dietary changes (provided intervention after the randomised trial) Intervention aims: total fat <30%E, SFA <7%E, dietary chol<200mg/d Control methods: usual intake Intervention methods: 8 weekly classes with nutrition info and behaviour modification with spouses, plus individual appointments at 3 and 6 months Total fat intake (at 6 months): int 25.2 (sd unclear)%E, cont unclear - no significant difference from baseline 34 (sd unclear)%E Saturated fat intake (at 6 months): int 7.6% (sd unclear)%E, cont unclear - no significant difference from baseline 12 (sd unclear)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: lipids Data available on total mortality? yes (no events) Cardiovascular mortality? no Events available for combined cardiovascular events: unclear but authors stated that there were no CVD events Secondary outcomes: none Tertiary outcomes: weight, total, LDL and HDL cholesterol, TGs (but variance data only provided for the randomised comparison for LDL cholesterol)
Notes	Weight: control ‘no change’, intervention −2.7kg at 6 months
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified random sampling scheme
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants knew their allocation, unclear for outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Intensive intervention for intervention group, but no intervention during the 6 months of the randomised part of the study for the control group. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	People with non-melanoma skin cancer (USA) CVD risk: low Control: randomised 67, analysed 58 Intervention: randomised 66, analysed 57 Mean years in trial: 1.9 % male: control 67%, intervention 54% Age: mean control 52.3 (sd 13.2), intervention 50.6 (sd 9.7)
Interventions	Reduced fat vs. usual diet Control aims: no dietary advice Intervention aims: total fat 20%E, protein 15%E, CHO 65%E Control methods: no dietary change, 4 monthly clinic visits Intervention methods: 8 weekly classes, with behavioural techniques, plus 4 monthly clinic visits Total fat intake (“during study” months 4-24): low fat 20.7 (sd 5.5), cont 37.8 (sd 4.1) %E Saturated fat intake (“during study, months 4-24): low fat 6.6 (sd 1.8), cont 12.8 (sd 2.0)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: incidence of actinic keratosis and non-melanoma skin cancer Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: cardiovascular deaths Secondary outcomes: cancer deaths (none) Tertiary outcomes: none (weight data provided, but no variance info)
Notes	At 2 years control −1.5kg n=50?, intervention −1kg n=51?
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“list of randomly generated numbers”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Physician blinding: adequate Participant blinding: inadequate
Incomplete outcome data (attrition bias) All outcomes	Low risk	For mortality. Unclear for other outcomes
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Minor, all have 4 monthly clinic visits, the intervention group had 8 behavioural technique classes that the control group did not have
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Women with severe cyclical mastopathy for at least 5 years (Canada) CVD risk: low Control: randomised 10, analysed 9 Intervention: randomised 11, analysed 10 Mean years in trial: control 0.45, intervention 0.45 % male: 0% Age: mean control 36, intervention 38 (variances unclear)
Interventions	Reduced fat vs usual diet Control aims: given principles of healthy diet, not counselled to alter fat content Intervention aims: total fat 15%E, CHO 65%E Control methods: seen every 2 months to monitor symptoms, nutrition and biochemistry Intervention methods: seen monthly to monitor symptoms, nutrition and biochemistry, teaching materials included food guide, recipes, product information and advice on eating out Total fat intake (at 6 months): low fat 22.8 (sd unclear), cont 33.4 (sd unclear)%E Saturated fat intake (at 6 months): low fat 8.8 (sd unclear), cont 12.3 (sd unclear)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: mastopathy symptoms, plasma hormone and lipids Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: none Secondary outcomes: cancer deaths (none) Tertiary outcomes: total cholesterol (but variance data not provided)
Notes	Total cholesterol rose by 0.09mmol/L in control group (from 4.5 to 4.59) and fell by 0. 15mmol/L in intervention group (4.84 to 4.69)
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“randomly allocated”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were not blinded, those assessing physical outcomes were blinded, those assessing symptoms were not
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Minor differences in follow up frequency. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Women diagnosed with stage I or II breast cancer over the past 2 years (USA) CVD risk: low Control: randomised unclear (at least 56), analysed 56 Intervention: randomised unclear (at least 50), analysed 50 Mean years in trial: unclear (1 year max follow up) % male: 0 Age: mean control unclear (71% postmenopausal), intervention unclear (56% post-menopausal) (all 20-65)
Interventions	Reduced fat vs usual diet Control aims: no formal intervention Intervention diet aims: total fat 20%E, high fibre, plant based micronutrients Intervention stress: separate parallel arm, stress reduction programme (data not used here) Control methods: no formal intervention Intervention methods: nutrition intervention programme, 15 sessions (42 hours) over 15 weeks, group-based, dietitian led, 2 individual sessions using social cognitive theory and patient centred counselling to increase self efficacy and confidence Total fat intake (at 12 months): low fat 29.9 (sd unclear), cont 33.6 (sd unclear)%E Saturated fat intake: unclear Style: diet advice Setting: community
Outcomes	Stated trial outcomes: diet and BMI Data available on total mortality? yes Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: cardiovascular deaths, non fatal MI, stroke (no events) Secondary outcomes: total and non-fatal MI, stroke, cancer deaths (events only for cancer deaths) Tertiary outcomes: weight
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“randomised”, stratified by medical centre, cancer stage and age, randomised number/envelope method by project coordinator
Allocation concealment (selection bias)	Low risk	The project coordinator had contact with those from the University of Massachussets, but not those from the other 3 centres, and allocation could not be altered later
Blinding (performance bias and detection bias) All outcomes	High risk	Participants not blinded, unclear about researchers
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	High intensity programme for intervention group, nothing for control group. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	High risk	Intervention also focused on fibre and plant based micronutrients. See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Healthy overweight people, BMI 26-34 (Europe, 5 centres) CVD risk: low Control: unclear how many randomised, 77 analysed (290 randomised over all 3 arms) Intervention with simple CHO: unclear how many randomised, 76 analysed Intervention with complex CHO: unclear how many randomised, 83 analysed Mean years in trial: unclear (max duration 0.5 years) % male: control 48%, simple CHO intervention 47%, complex CHO intervention 52% Age: mean control 38 (sd 9), simple CHO intervention 41 (sd 9), complex CHO intervention 38 (sd 9)
Interventions	Reduced fat vs usual diet Control aims: to attain national “normal” intake Intervention aims: total fat reduced by 10%E with increases in simple or complex CHO Control methods: trial shop provided local selection of a specific set of national “normal” intake foods Intervention methods: trial shop provided local selection of a specific set of low fat and high simple or complex CHO foods Total fat intake (at 6 months): low fat complex CHO 27.8 (sd unclear)%E, low fat simple CHO 25.5 (sd unclear)%E, cont 36.5 (sd unclear)%E Saturated fat intake (at 6 months): low fat complex CHO 9.9 (sd unclear)%E, low fat simple CHO 8.6 (sd unclear)%E, cont 12.7 (sd unclear)%E Style: food provided Setting: community
Outcomes	Stated trial outcomes: weight, body composition, lipids Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: CVD deaths, non-fatal MI, stroke, heart failure, PVD (no events) Secondary outcomes: cancer deaths and diagnoses (no events) Tertiary outcomes: weight, total, LDL and HDL cholesterol, TGs
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer randomisation
Allocation concealment (selection bias)	Low risk	Randomisation by 3rd party, independent of research centres. Blind data were sent to him for computer randomisation
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were clear about whether they were in the control or an intervention group
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Trial shop used by both groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT (data for this study excludes the 13 participants that were included in the main CARMEN data set)
Participants	People with at least 3 risk factors for metabolic syndrome (Europe, 5 centres) CVD risk: moderate Control: 12 randomised, 8 analysed Intervention with simple CHO: 10 randomised, 9 analysed Intervention with complex CHO: 11 randomised, 9 analysed Mean years in trial: control 0.4, simple CHO 0.5, complex CHO 0.5 % male: control 0%, simple CHO 33%, complex CHO 22% Age: mean control 47.5 (sd 3.9), simple CHO intervention 44.7 (sd 4.7), complex CHO intervention 43.4 (sd 4.5)
Interventions	Reduced fat vs usual diet Control aims: to attain national “normal” intake Intervention aims: total fat reduced by 10%E with increases in simple or complex CHO Control methods: trial shop provided local selection of a specific set of national “normal” intake foods Intervention methods: trial shop provided local selection of a specific set of low fat and high simple or complex CHO foods Total fat intake (at 6 months): low fat complex CHO 27.1 (sd 4.8), low fat simple CHO 20.6 (sd 6.6), cont 30.4 (sd 2.3)%E Saturated fat intake: unclear Style: food provided Setting: community
Outcomes	Stated trial outcomes: weight, body composition, lipids Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: CVD deaths, non-fatal MI, stroke, heart failure, PVD (no events) Secondary outcomes: cancer deaths and diagnoses (no events) Tertiary outcomes: BMI, total, LDL and HDL cholesterol, TGs, diastolic BP
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer randomisation
Allocation concealment (selection bias)	Low risk	Randomisation by 3rd party, independent of research centres. Blind data were sent to him for computer randomisation
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were clear about whether they were in the control or an intervention group
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Trial shop used by both groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Hypertensives with cholesterol >6.5mmol/L (UK) CVD risk: moderate Control: randomised 72, analysed 63 Intervention: randomised 72, analysed 61 Mean years in trial: control 0.47, intervention 0.46 % male: control 54%, intervention 44% Age: mean control 56, intervention 57
Interventions	Unclear Control aims: no dietary advice Intervention aims: advice to reduce serum cholesterol (?) Control methods: no advice at any visit (0, 1, 3 and 6 months) Intervention methods: intensive and specific dietary advice, by dietitian at each visit (0, 1, 3 and 6 months) Total fat intake: unclear Saturated fat intake: unclear Style: diet advice Setting: community
Outcomes	Stated trial outcomes: blood pressure, weight, lipids Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: cardiovascular deaths (no events) Secondary outcomes: cancer deaths (no events) Tertiary outcomes: total, HDL and LDL cholesterol, TG (not used in analysis as unclear whether reduced and/or modified fat intervention)
Notes	Changes in lipid parameters from baseline to 6 months (control n=63, intervention n= 61), all mmol/L Total cholesterol control −0.3 (sd 0.7), intervention −0.3 (sd 0.6) LDL cholesterol control −0.1 (sd 0.7), intervention −0.3 (sd 0.7) HDL cholesterol control −0.0 (sd 0.1), intervention 0.2 (sd 0.2) TGs control −0.2 (sd 0.6), intervention −0.2 (sd 0.7)
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“stratified by antihypertensive treatment, randomly allocated”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants not blinded, researchers unclear
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Dietetic time for those on intervention only. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Unclear risk	Dietary goals unclear.

Methods	RCT
Participants	Men recovering from an MI (UK) CVD risk: high Control: randomised 1015, analysed unclear Intervention: randomised 1018, analysed unclear Mean years in trial: control 1.9, randomised 1.9 % male: 100% Age: mean control 56.8, intervention 56.4 (all <70)
Interventions	Reduced and modified fat vs usual diet Control aims: no dietary advice on fat, weight reducing advice if BMI>30 Intervention aims: reduce fat intake to 30%E, increase P/S to 1.0, weight reducing advice if BMI>30 Note: This was a factorial trial, and so some in each group were randomised to increased fatty fish and/or increased cereal fibre Control methods: dietitians provided ‘sensible eating’ advice without specific information on fats Intervention methods: dietitians provided the participants and their wives with initial individual advice and a diet information sheet, participants were revisited for further advice, recipes, encouragement at 1, 3, 6, 9, 12, 15, 18 and 21 months Total fat intake (through study): int 31 (sd 7), cont 35 (sd 6)%E Saturated fat intake (through study): int 11 (sd 3), cont 15 (sd 3)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: mortality, reinfarction Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: cardiovascular deaths (including stroke deaths) plus non-fatal MI Secondary outcomes: cancer deaths, total MI, non-fatal MI Tertiary outcomes: total and HDL cholesterol
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	randomised using sealed envelopes
Allocation concealment (selection bias)	Unclear risk	Unclear if envelopes were opaque
Blinding (performance bias and detection bias) All outcomes	High risk	Physician blinding: yes Participant blinding: unclear
Incomplete outcome data (attrition bias) All outcomes	Low risk	GPs contacted for information on mortality and morbidity when patients did not attend
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Different levels of advice appear to have been provided. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	There were also other arms, testing fish and fibre interventions (in a factorial design). See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Survivors of Oslo Diet Study who had hyperlipidaemia and high risk of CVD in the 1970s (Norway) CVD risk: moderate (although 25% have CVD) control: No n-3 control, 142 randomised, 117 analysed With n-3 control, 140 randomised, 124 analysed intervention: No n-3 intervention, 139 randomised, 122 analysed With n-3 intervention, 142 randomised, 124 analysed Mean years in trial: 3 % male: 100 Age: control groups median 70 years, intervention groups median 70
Interventions	Reduced fat intake vs usual diet Control aims: usual care (with n-3 capsules or corn oil capsules) Intervention aims: 27-30%E from fat, protein 15-18%, CHO 50-55%E, increase fruit, vegetables, fish, decrease meat, polyunsaturated margarine provided free (with n-3 capsules or corn oil capsules) Control methods: usual care, with either corn oil or omega-3 capsules Intervention methods: dietary advice (30-45 mins initially plus 30 mins follow up at 3 months, then 6 monthly), polyunsaturated margarines provided free, plus either corn oil or omega-3 capsules Total fat intake (at 36 months): low fat 27.6 (sd 5.5), cont 29.5 (sd 5.4)%E Saturated fat intake (at 36 months): low fat 9.2 (sd 3.6), cont 10.5 (sd 3.7)%E Style: diet advice and supplement Setting: community
Outcomes	Stated trial outcomes: CVD Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: total MI, verified cardiovascular events Secondary outcomes: cancer deaths and diagnoses, diabetes, total MI Tertiary outcomes: BMI, total, HDL, LDL cholesterol, TG, systolic BP
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	‘randomly assigned’
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Not for dietary intervention.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Additional dietary appointments in the intervention groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	High risk	Also fruit, veg, fish and meat advice. See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Young overweight adults who had lost at least 8% of body weight (Denmark) CVD risk: low control: 25 randomised, 25 analysed (24 completed) Intervention low fat: 48 randomised, 48 analysed (43 completed) Mean years in trial: control 0.49, low fat 0.47 % male: control 42%, low fat 43% Age: control group 27.6 (sd 5.1), low fat 27.3 (sd 4.9)
Interventions	Reduced fat intake vs usual diet Control aims: 30-40%E from fat, SFA >15%E, MUFA 5-15%E, PUFA 0-10%E, protein 10-20%E, CHO45-55%E, added sugars 5-15%E, alcohol <5%E, glycaemic index high, energy density high, energy intake ad libitum Low fat aims: 20-30%E from fat, SFA <10%E, MUFA 5-15%E, PUFA 5-10%E, protein 10-20%E, CHO 55-65%E, added sugars <10%E, alcohol <5%E, glycaemic index medium, energy density low, energy intake ad libitum Control and intervention methods: supermarket model, all foods provided free, personal shoppers helped participants collect appropriate foods, not allowed to leave shop until dietary composition was correct, waste and leftovers returned to shop, minimum of 2 dietetic counselling sessions over 2 months Total fat intake (at 6 months): low fat 23.6 (sd 1.67)%E, cont 32.1 (sd 1.62)%E Saturated fat intake (at 6 months): low fat 7.9 (sd 1.17)%E, cont 15.1 (sd 1.0)%E Style: food provided Setting: community
Outcomes	Stated trial outcomes: CVD risk, diabetes risk, weight Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: total MI, stroke (no events) Secondary outcomes: cancer deaths and diagnoses, total and non-fatal MI, stroke (no events in any group) Tertiary outcomes: weight, BMI, total, HDL, LDL cholesterol, TG
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Independently randomised by 2 study personnel, stratified by sex and initial BMI
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were aware of their own allocated diet, those assessing outcomes unclear
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Reasons for dropouts provided, ITT analysis used for continuous outcomes
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Yes, advice and shop system was the same across all groups
Free of dietary differences other than fat?	High risk	No, there were also differences in sugary foods, legumes, dietary glycaemic index etc

Methods	RCT
Participants	Type I diabetics with elevated urinary albumin (Netherlands) Risk: moderate Control: randomised 20, analysed 20 Intervention: randomised 18, analysed 16 Mean years in trial: control 2.0, intervention 1.9 % male: control 75%, intervention 81% Age: mean control 41 (sd 14), intervention 44 (sd 12) (all 21-65)
Interventions	Modified fat vs usual fat Control aims: usual diet (urged not to alter fat or protein intake) Intervention aims: replace SFA by linoleic acid to achieve P/S of 1.0, total fat and protein intake to remain unchanged Control methods: unclear Intervention methods: counselling by a dietitian (unclear how often, but at least annually) Total fat intake (at 2 years):mod fat 37 (sd 4), cont 40 (sd 7)%E Saturated fat intake (at 2 years): mod fat 13 (sd 2), cont 16 (sd 3)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: albuminuria and serum lipoproteins Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: cardiovascular deaths, non-fatal MI, stroke (no events) Secondary outcomes: stroke (no events), MI (no events), cancer deaths (no events) Tertiary outcomes: weight, total, HDL and LDL cholesterol (data read off graph as data files no longer exist, total and LDL cholesterol data not used as very different in control and intervention arms at baseline)
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“stratified according to gender, randomised in blocks of 6 using opaque sealed envelopes” by independent statistical investigator with no contact with participants
Allocation concealment (selection bias)	Low risk
Blinding (performance bias and detection bias) All outcomes	High risk	Participants could not be blinded, research blinding was unclear
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Unclear risk	Probably not, appears that the intervention group had more time with dietitian. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	People with radiolucent gallstones taking ursodeoxycholic acid, UDCA (USA) CVD risk: low Control: randomised 17, analysed 16 Intervention: randomised 19, analysed 16 Mean years in trial: control 0.6, intervention 0.6 % male: control 35%, intervention 58% Age: mean control 52.4, intervention 53.1
Interventions	Modified fat vs average diet Control aims: dietary advice for total fat 38-42%E, dietary cholesterol 500mg/day, protein 18-22%E, CHO 38-42%E, weight maintaining, low fibre Intervention aims: as above but limit dietary cholesterol to 250mg/day, weight maintaining, low fibre Control methods: dietary advice from dietitian every 3 months Intervention methods: dietary advice from dietitian every 3 months Total fat intake (at 6 or 9 months): mod fat 32.5 (sd 6.2), cont 36.0 (sd 5.1)%E Saturated fat intake: unclear Style: diet advice Setting: community
Outcomes	Stated trial outcomes: bile acid kinetics Data available on total mortality? yes (no events) Cardiovascular mortality? no Events available for combined cardiovascular events: none Secondary outcomes: none Tertiary outcomes: none
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“randomly allocated”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants knew their allocation, unclear for researchers
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Similar level and duration of advice. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Unclear risk	Intervention unclear, aim was to maintain total fat intake in both groups but reduce cholesterol intake - so fat modification must have occurred. See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Adults with newly diagnosed diabetes (The Netherlands) CVD risk: moderate Control: 51 randomised, unclear how many analysed (all analysed re deaths) Intervention: 51 randomised, unclear how many analysed (all re deaths) Mean years in trial: unclear (max duration 6 years) % male: 56% overall Age: mean unclear Baseline total fat intake: int cont Baseline saturated fat intake: int cont
Interventions	Modified fat vs usual diet Control aims: SFA 35%E, CHO 50%E, protein 15%E Intervention aims: total fat 40%E, 1/3 linoleic acid, CHO 45%E, protein 15%E Control methods: unclear, surveyed by dietitian Intervention methods: unclear, surveyed by dietitian Total fat intake: mod fat unclear, cont unclear Saturated fat intake: mod fat unclear, cont unclear Style: diet advice? Setting: community
Outcomes	Stated trial outcomes: progression of diabetic retinopathy Data available on total mortality? no Cardiovascular mortality? no Events available for combined cardiovascular events: total MI and angina Secondary outcomes: none Tertiary outcomes: total cholesterol, TGs (data read off graph)
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants matched in pairs then randomised
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Neither participants nor physicians appear blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Unclear risk	Level and type of intervention unclear. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	State that fibre and dietary cholesterol were similar in control and intervention. See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Healthy women, BMI >25 (UK) CVD risk: low Control: randomised 53, analysed 40 Intervention: randomised 57, analysed 42 Mean years in trial: control 0.42, intervention 0.43 % male: 0 Age: mean control 50, intervention 51
Interventions	Reduced fat vs usual diet Control aims: advice - total fat 35%E, CHO 34.5%E, 1200kcal per day encouraged but not prescribed Intervention aims: total fat 20%E, CHO 58%E, 1200kcal/day encouraged but not prescribed Control methods: dietary advice supported by exchanges and recipes Intervention methods: dietary advice supported by exchanges and recipes Total fat intake: unclear Saturated fat intake: unclear Style: diet advice Setting: community
Outcomes	Stated trial outcomes: weight loss and cardiovascular risk factors Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: cardiovascular deaths, non fatal MI, stroke (no events) Secondary outcomes: total and non-fatal MI, stroke, cancer deaths (no events) Tertiary outcomes: BMI, total, LDL and HDL cholesterol, TG, BP
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“medical officer drew coloured straws from a box”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were not blinded, unclear about researchers
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Deaths, cancer and CV events are drop-outs, trialists asked for data
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Similar intervention in both groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

PERMALINK

Reduced or modified dietary fat for preventing cardiovascular disease

Lee Hooper

Carolyn D Summerbell

Rachel Thompson

Deirdre Sills

Felicia G Roberts

Helen Moore

George Davey Smith

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

BACKGROUND

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Tertiary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

RESULTS

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study.

Figure 2. Methodological quality graph: review authors’ judgements about each methodological quality item presented as percentages across all included studies.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Reduced, modified or reduced and modified dietary fat vs. usual or control diet

Primary outcomes

Total mortality

Table 1. Sensitivity analyses of primary outcomes.

Figure 3. Funnel plot of comparison: fat modification or reduction vs usual diet - total mortality.

Table 2. Subgrouping data for primary outcomes.

Table 3. Meta-regression, exploring effects of dietary changes on the primary outcomes.

Cardiovascular mortality

Cardiovascular events

Figure 4. Funnel plot of comparison: fat modification or reduction vs usual diet - combined cardiovascular events.

Secondary outcomes

Total myocardial infarction

Stroke

Cancer deaths

Cancer diagnoses

Diabetes diagnoses

Non-fatal myocardial infarction

Quality of life

Tertiary outcomes

Weight and Body Mass Index (BMI)

Low density lipoprotein (LDL) cholesterol

High density lipoprotein (HDL) cholesterol

Total cholesterol

Methods	RCT
Participants	People with impaired glucose intolerance or high normal blood glucose (New Zealand) CVD risk: moderate Control: unclear how many randomised (176 between both groups), unclear how many analysed (112 between both groups at 5 years) Intervention: as above Mean years in trial: 4.1 over whole trial % male: control 80%, intervention 68% Age: mean control 52.0 (SE 0.8), intervention 52.5 (SE 0.8)
Interventions	Reduced fat vs usual diet Control aims: usual diet Intervention aims: reduced fat diet (no specific goal stated) Control methods: usual intake Intervention methods: monthly meetings to follow a 1 year structured programme aimed at reducing fat in the diet, includes education, personal goal setting, self-monitoring Total fat intake (at 1 year): low fat 26.1 (sd 7.7), cont 33.6 (sd 7.8)%E Saturated fat intake (at 1 year): low fat 10.0 (sd 4.2), cont 13.4 (sd 4.7)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: lipids, glucose, blood pressure Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: MI, angina, stroke, heart failure Secondary outcomes: total MI, stroke, cancer diagnoses, cancer deaths Tertiary outcomes: weight, total, LDL and HDL cholesterol, TGs, BP
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Unmarked opaque envelopes were opened by the person recruiting, unable to alter allocation later
Allocation concealment (selection bias)	Low risk
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were not blinded, outcome assessors were
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Overweight and insulin-resistant women (New Zealand) CVD risk: low Low fat: randomised 32, analysed 24 (at 1 year) Modified fat: randomised 30, analysed 28 (at 1 year) Mean years in trial: low fat 0.88, modified fat 0.97 % male: 0 Age: mean low fat 45 (sd 7.5), modified fat 47 (sd 7.9)
Interventions	Reduced fat vs Modified fat diet Modified fat aims: 30%E from fat, predominantly MUFA, protein 30%E, CHO low glycaemic index 40%E, 5 meals/d, less than 5 hours between meals, ad libitum consumption, 30mins activity 5 days/week advised Low fat aims: total fat <30%E, SFA <8%, protein 15%E, CHO >55%E, advised to reduce dietary fat, salt and sugar, national healthy eating guidelines plus at least 6 servings of bread and whole-grains /d, at least 3 of vegetables, 2 of fruit, 2 of low fat dairy/d, ad libitum consumption, 30mins activity 5 days/week advised (Also a high fat Atkins-type arm Low fat methods: unclear how much dietary advice, or who delivered Modified fat methods: unclear how much dietary advice or who delivered it Total fat intake (at 6 months): low fat 28 (sd 7)%E, mod fat 35 (sd 7)%E Saturated fat intake (at 6 months): low fat 10 (sd 4)%E, mod fat 11 (sd 3)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: weight loss, lipids Data available on total mortality? yes (none) Cardiovascular mortality? yes (none) Events available for combined cardiovascular events: total MI, stroke (no CVD events) Secondary outcomes: non-fatal and total MI, stroke, cancer deaths and diagnoses (no events for any outcome) Tertiary outcomes: weight, BMI, total, LDL and HDL cholesterol, TG, systolic and diastolic BP
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	‘randomised’
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants knew allocation, unclear whether researchers did also
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Unclear risk	Probably, as both groups were taught their diets. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	High risk	Differences in meal frequency, salt and sugar advice.

Methods	RCT
Participants	People after adenomatous colorectal polypectomy (Canada) CVD risk: low Control: randomised 102, unclear how many analysed Intervention: randomised 99, unclear how many analysed Mean years in trial: 2.0 % male: control 55%, intervention 57% age: mean control 58, intervention 58 (all <85)
Interventions	Reduced fat vs usual diet Control aims: advice for nutritionally balanced diet (optional low fibre supplement with added calcium and iron) Intervention aims: total fat <20%E (or less than 50g fat/d), at least 50g fibre daily (optional fibre supplement with added calcium and iron) Control methods: 4-monthly counselling to encourage a nutritionally balanced diet Intervention methods: monthly counselling on diet to achieve fat goals Total fat intake (at 24 months): low fat men 24.3 (sd 5.2), women 24.4 (sd 8.2), cont men 31.6 (sd 5.9), women 31.3 (sd 6.5)%E Saturated fat intake: unclear Style: dietary advice & supplement (food) Setting: community
Outcomes	Stated trial outcomes: recurrence of neoplastic polyps Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: none Secondary outcomes: cancer diagnoses, cancer deaths (no deaths) Tertiary outcomes: total cholesterol (but no variance data presented and graph too small to read)
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk
Allocation concealment (selection bias)	Low risk	“stratification by physician, gender, age, randomisation by research associate, centrally, using random numbers generated by computer”
Blinding (performance bias and detection bias) All outcomes	High risk	Participants not blinded, physicians were
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs - unclear if any data missing. ITT analysis performed
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	More frequent visits for intervention group. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	High risk	Dietary fibre advice also in intervention group

Methods	RCT
Participants	Healthy postmenopausal women with above median serum testosterone (Italy) CVD risk: low Control: randomised 57, analysed at 6 months 55 Intervention: randomised 58, analysed at 6 months 51 Mean years in trial: control 4.38, intervention 4.28 % male: 0 Age: mean unclear (age range 48-69)
Interventions	Reduced and modified fat vs usual diet Control aims: advised to increase fruit and vegetable intake Intervention aims: taught Sicilian diet including reduced total, saturated and omega–6 fats, increased blue fish (high in omega 3), increased whole cereals, legumes, seeds, fruit and vegetables Control methods: advice Intervention methods: taught Sicilian diet and cooking by professional chefs, with a weekly cooking course including social dinners Total fat intake (at 6 months): low & mod fat 30.9 (sd 11.4), cont 34.0 (sd 11.8)%E Saturated fat intake (at 6 months): low & mod fat 8.4 (sd 3.0), cont 11.2 (sd 5.0)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: breast cancer, weight, lipids, wellbeing Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: cardiovascular deaths, non fatal MI, stroke, ventricular fibrillation, ventricular overload Secondary outcomes: total and non-fatal MI, stroke, cancer diagnoses and deaths (events only for stroke and cancer diagnoses) Tertiary outcomes: none
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“individually randomised”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants were aware of assignment, researchers unclear
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Intensive cookery course with social element compared with briefadvice. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	High risk	Both groups encouraged to increase fruit and vegetables, but intervention group also encouraged to increase fish, pulses, seeds, whole grains

Methods	RCT
Participants	Institutionalised men living in a mental hospital (USA) CVD risk: low Control: randomised 2196, analysed unclear Intervention: randomised 2197, analysed unclear Mean years in trial: control 1.0, intervention 1.1 % male: 100 Age: unclear, ranges from <30 to >70
Interventions	Modified fat diet vs. usual diet Control aims: usual institutional diet provided Intervention aims: institutional diet modified to total fat 45%E, PUFA 18-20%E, P/S 2.5, less than 150mg/day dietary chol Control methods: whole diet provided Intervention methods: whole diet provided Total fat intake (over 4 years): mod fat 37.8 (sd unclear)%E, cont 39.1 (sd unclear)%E Saturated fat intake (over 4 years): mod fat 9.2 (sd unclear)%E, cont 18.3 (sd unclear) %E Style: diet provided Setting: residential institution
Outcomes	Stated trial outcomes: MI, mortality, sudden deaths Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: total MI plus sudden death plus stroke Secondary outcomes: stroke, cancer deaths, total MI Tertiary outcomes: none (data provided on total cholesterol and TGs but no variance info)
Notes	This was a 4.5 year institutional study, but as turnover of participants was very high average time in trial per participant was actually around one year. Participants were replaced as they left, and often left the institution and later returned
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“stratified randomisation”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	Low risk	Physician blinding: adequate Participant blinding: adequate
Incomplete outcome data (attrition bias) All outcomes	High risk	No, participants appear to have been lost on leaving the institution
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Whole diet provided for both groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods
Participants	Institutionalised women living in a mental hospital (USA) CVD risk: low Control: randomised 2320, analysed unclear Intervention: randomised 2344, analysed unclear Mean years in trial: control 1.0, intervention 1.1 % male: 0 Age: unclear, ranges from <30 to >70
Interventions	Modified fat diet vs. usual diet Control aims: usual institutional diet provided Intervention aims: institutional diet modified to total fat 45%E, PUFA 18-20%E, P/S 2.5, less than 150mg/day dietary chol Control methods: whole diet provided Intervention methods: whole diet provided Total fat intake (over 4 years): mod fat 37.8 (sd unclear)%E, cont 39.1 (sd unclear)%E Saturated fat intake (over 4 years): mod fat 9.2 (sd unclear)%E, cont 18.3 (sd unclear) %E Style: diet provided Setting: residential institution
Outcomes	Stated trial outcomes: MI, mortality, sudden deaths Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: total MI plus sudden death plus stroke Secondary outcomes: stroke, cancer deaths, total MI Tertiary outcomes: none (data provided on total cholesterol and TGs but no variance info)
Notes	This was a 4.5 year institutional study, but as turnover of participants was very high average time in trial per participant was actually around one year. Participants were replaced as they left, and often left the institution and later returned
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“stratified randomisation”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	Low risk	Physician blinding: adequate Participant blinding: adequate
Incomplete outcome data (attrition bias) All outcomes	High risk	No, participants appear to have been lost on leaving the institution
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Whole diet provided for both groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Middle-aged siblings of people with early CHD, with at least one CVD risk factor (USA) CVD risk: moderate Control: randomised 132, analysed 118 Intervention: randomised 135, analysed 117 Mean years in trial: 1.9 % male: control 49%, intervention 55% Age: control mean 45.7 (sd 7), intervention 46.2 (sd 7)
Interventions	Reduced fat intake vs. usual diet Control: physician management (physicians informed on risk factor management) Intervention: nurse management, aim total fat 40g/d or less Control methods: physician management with risk factor management at 0, 1 and 2 years Intervention methods: nurse management, appointments 6-8 weekly for 2 years Total fat intake (at 2 years): low fat 34.1 (sd unclear), cont 38.0 (sd unclear)%E Saturated fat intake (at 2 years): low fat 11.5 (sd unclear), cont 14.4 (sd unclear)%E Style: diet advice Setting: community
Outcomes	Stated trial outcomes: dietary intake Data available on total mortality? yes, no deaths Cardiovascular mortality? yes, no deaths Events available for combined cardiovascular events: total MI, stroke, unstable angina, PVD and PTCA Secondary outcomes: cancer diagnoses (no events), cancer deaths (none), stroke, total and non-fatal MI Tertiary outcomes: BMI, HDL and LDL cholesterol, TG
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned via computerised schema after all eligible siblings from a family had been screened
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Participants and trialists clear about their allocation
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Differences in frequency of follow up, but unclear what differences in care occurred between the physician and nurse-led care. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Unclear risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Free-living men who have survived a first MI (UK) CVD risk: high Control: randomised 194, analysed 181 at 2 years Intervention: randomised 199, analysed 172 at 2 years Mean years in trial: control 3.7, intervention 3.8 % male: 100 Age: unclear (all <60)
Interventions	Modified fat vs usual diet Control aims: usual diet Intervention aims: reduce dietary fat to 35g fat per day, add 84g soya oil per day Control methods: usual diet Intervention methods: unclear who gave dietary advice or how often Total fat intake (at 3.5 years): mod fat 46 (sd unclear), cont 43 (sd unclear)%E Saturated fat intake: unclear Style: diet advice & supplement (soy oil) Setting: community
Outcomes	Stated trial outcomes: MI or sudden death Data available on total mortality? yes Cardiovascular mortality? yes Events available for combined cardiovascular events: cardiovascular deaths and fatal or non-fatal MI Secondary outcomes: total and non-fatal MI Tertiary outcomes: none (data for weight, total cholesterol and BP, but no variance info)
Notes	For all, data at 4 years, control n=89, intervention n=88 Weight change: control −3kg, intervention 0kg Total cholesterol change: control −0.47mmol/L, intervention −1.11mmol/L Systolic BP change: control 0mmHg, intervention +2mmHg Diastolic BP change: control +3mmHg, intervention −1mmHg
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	“using random numbers, by blocks within hospitals”
Allocation concealment (selection bias)	Unclear risk	Randomisation method not clearly described
Blinding (performance bias and detection bias) All outcomes	High risk	Physician blinding: adequate Participant blinding: inadequate
Incomplete outcome data (attrition bias) All outcomes	High risk	Data collection was thorough, but some participants dropped out and contact was lost
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	High risk	Unlikely as control group continued diet as usual, intervention group were likely to have had additional contact. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Healthy people aged 20-55 (Netherlands) CVD risk: low Control: randomised unclear (120?), analysed 103 Intervention: randomised unclear (120?), analysed 117 Mean years in trial: control 0.46, intervention 0.49 % male: control 50%, intervention 50% Age: mean control men 35.6 (sd 10), control women 36.0 (sd 11), intervention men 35. 5 (sd 11), intervention women 36.0 (sd 12) (all 19-55)
Interventions	Reduced fat vs usual diet Control aims: advised to use products from trial shop ad lib. (usual fat products provided) Intervention aims: advised to use products from trial shop ad lib. (low fat products provided) Control methods: participants obtained foods in a study shop at least once a week Intervention methods: participants obtained foods in a study shop at least once a week Total fat intake (at 6 months): low fat 34.7 (sd unclear), cont 42.7 (sd unclear)%E Saturated fat intake (at 6 months): low fat 14.2 (sd unclear), cont 18.2 (sd unclear)%E Style: food provided Setting: community
Outcomes	Stated trial outcomes: weight, vitamin and fatty acid intake, anti-oxidative capacity Data available on total mortality? yes (no events) Cardiovascular mortality? yes (no events) Events available for combined cardiovascular events: MI, stroke and CVD deaths (no events) Secondary outcomes: stroke, MI, cancer diagnoses and deaths (no events for any outcome) Tertiary outcomes: weight (for subgroup), weight and lipids provided for larger group, but without variance data
Notes	Change from baseline to 6 months for whole group (control 103, intervention 117): Weight, kg: 1.1, 0.4 total cholesterol, mmol/L: 0.07, −0.09 HDL cholesterol, mmol/L: −0.03, −0.06 LDL cholesterol, mmol/L: 0.15, 0.16 TGs, mmol/L: 0.04, −0.04
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“stratified randomisation (according to sex, age, QI index and eating behaviour) by co-ordinating centre”, a statistician at Unilever Research, SAS software, and allocation could not be altered later
Allocation concealment (selection bias)	Low risk
Blinding (performance bias and detection bias) All outcomes	High risk	Participants aware of allocation, those analysing biochemistry were not
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear, deaths, cancer and CV events are drop-outs, trialists asked for data - unclear if any data missing
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Both groups used study shop. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies

Methods	RCT
Participants	Men living in a mental health institute (USA) CVD risk: low Control: randomised 57, analysed 52 Interventions B, C, E combined: randomised 167, analysed 143 Mean years in trial: control 1.0, Interventions 0.9 % male: 100 Age: unclear (all 45-54)
Interventions	Modified fat vs. usual diet Control aims: total fat 40%E, SFA 16-18%E, dietary chol 650-750mg/d, P/S 0.4 Intervention aims: B (C, E) total fat 30%E (40%E, 40%E), SFA <9%E (<9%E, not stated), dietary chol 350-450mg/d (350-450mg/d, not stated), PUFA 15%E (18-20%E, not stated), P/S 1.5 (2.0, 4.4) Control methods: whole diet provided Intervention methods: whole diet provided Total fat intake (at 28 & 44 weeks combined): B (C, E) mod fat 29.2 (38.5, 37.1) (sds unclear)%E, cont 39.4 (sd unclear)%E Saturated fat intake (at 28 & 44 weeks combined): B (C, E) mod fat 6.6 (7.4, 4.9) (sds unclear)%E, cont 15.6 (sd unclear)%E Style: diet provided Setting: residential institution
Outcomes	Stated trial outcomes: lipid levels and dietary assessment Data available on total mortality? yes Cardiovascular mortality? no Events available for combined cardiovascular events: none Secondary outcomes: no cancer deaths or diagnoses occurred Tertiary outcomes: total cholesterol
Notes
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified randomisation by the statistical centre
Allocation concealment (selection bias)	Low risk
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, facilitated by provision of the whole diet
Incomplete outcome data (attrition bias) All outcomes	Low risk	Institution so able to follow up all participants through study
Selective reporting (reporting bias)	Low risk	Not relevant for primary and secondary outcomes as all trialists asked for data
Other bias	Low risk
Free of systematic difference in care?	Low risk	Whole diet provided for both groups. See Control and Intervention Methods in Interventions section of the Table of Characteristics of Included Studies
Free of dietary differences other than fat?	Low risk	See Control and Intervention Aims in Interventions section of the Table of Characteristics of Included Studies