Background

There has been a longstanding interest in assessing the role of nutrition in human health. Diet is not merely the sum or combination of individual micronutrients and macronutrients. Indeed, the ancient Greek word ‘diaita’ means ‘way of living’, not just dietary needs, thus referring to the whole spectrum of life conditions: work, sleep, social environment and interactions, as well as daily activities. Over the last several decades, there has been increasing attention to investigate the potential benefits of whole dietary patterns in chronic disease prevention and management. Originating from Southern Europe, the traditional Mediterranean diet represents one of the most popular dietary patterns, with scientific investigations starting in the 1960s with the landmark Seven Countries study1 showing that populations in countries of the Mediterranean region, such as Greece and Italy, experienced lower cardiovascular mortality compared with northern European populations or the US population, likely as a result of different lifestyles including eating habits.

Subsequently, a large body of observational data and meta-analyses of longitudinal prospective studies around the world have corroborated potential cardiometabolic benefits of the Mediterranean-style diet, with reduced rates of cardiovascular disease (CVD) and diabetes with increasing adherence to this dietary pattern. Experimental evidence also suggests potential mechanisms to explain the beneficial effect of the Mediterranean diet on cardiometabolic health.

Key components of a Mediterranean dietary pattern are a high monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in monounsaturated fats such as tree nuts) and a high intake of plant-based foods, including fruits, vegetables and legumes.2 Despite the consistent observational data, the trial evidence on the effectiveness of a Mediterranean-style diet in the prevention and management of major CVD is relatively limited or of questionable quality. This is a critical issue, as several scientific organisations and guidelines for the prevention of major chronic diseases include dietary recommendations, which call for holistic approaches to food choices, in line with the traditional Mediterranean-style diet. Given the clinical and public health relevance of CVD and the potential impact of dietary interventions, we examined the available data from randomised controlled trials (RCTs) assessing the effects of providing dietary advice to follow a Mediterranean-style diet, provision of relevant foods or both, in primary or secondary prevention of major CVD and underlying risk factors. Specifically, we wanted to examine the potential effect of a Mediterranean-style diet among healthy individuals, high-risk people and those with established CVD, to assess the impact of this intervention at different stages of the natural history of CVD.

Review methods

Searching up to September 2018 was conducted across several databases including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science Core Collection, DARE, HTA, NHS EED (Cochrane Library). Definitions of a Mediterranean dietary pattern vary, hence we included only RCTs of interventions that reported at least both of the following key components: a high monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in monounsaturated fats such as tree nuts) and a high intake of plant-based foods, including fruits, vegetables and legumes.2 The control group received no intervention or minimal intervention, usual care or another dietary intervention. Populations of interest were the following: healthy adults and adults at high risk of CVD (primary prevention) and those with established CVD (secondary prevention). Outcomes included both clinical events and CVD risk factors. We only included studies with follow-up periods of 3 months or more.

There was a high degree of heterogeneity across trials in terms of participants recruited and the range of dietary interventions. Therefore, we grouped studies into the following four categories to facilitate our interpretation of the results: (1) Mediterranean dietary intervention compared with no intervention or a minimal intervention for primary prevention; (2) Mediterranean dietary intervention compared with another dietary intervention for primary prevention; (3) Mediterranean dietary intervention compared with usual care for secondary prevention and (4) Mediterranean dietary intervention compared with another dietary intervention for secondary prevention.

We assessed the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, summarising evidence as high, moderate, low or very low quality. Reasons for downgrading included limitations in study design, inconsistency in reporting and imprecision due to small sample size and wide confidence intervals.

Review findings

Overall, 30 completed RCTs (12 461 participants randomised) and 7 ongoing trials met our inclusion criteria.3 We analysed 22 primary prevention trials and 6 secondary prevention trials (2/8 excluded from main analysis due to published concerns regarding the reliability of the data).

Only one primary prevention trial reported mortality or CVD outcomes. The PREDIMED trial (7747 randomised) was retracted and re-analysed following concerns regarding randomisation at 2 of 11 sites.4 Low-quality evidence showed little or no effect of the PREDIMED intervention (advice to follow a Mediterranean diet plus supplemental extra virgin olive oil or tree nuts) compared with a low fat diet on CVD mortality (HR 0.81 (95% CI 0.50 to 1.32)) or total mortality (HR 1.00 (95% CI 0.81 to 1.24)) over 4.8 years. There was, however, a reduction in the number of strokes with the PREDIMED intervention (HR 0.60 (95% CI 0.45 to 0.80), moderate-quality evidence) (Table 1).

For secondary prevention, only one trial, The Lyon Diet Heart Study, examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared with usual care in 605 CVD patients over 46 months. There was low-quality evidence of a reduction in CVD mortality (RR 0.35 (95% CI 0.15 to 0.82)) and total mortality (RR 0.44 (95% CI 0.21 to 0.92)) with the intervention.5 Another small trial reported very low-quality evidence of unadjusted combined clinical endpoints compared with another diet (Table 1).

For CVD risk factors, low-quality evidence from five primary prevention trials showed a small reduction in total cholesterol (−0.16 mmol/L (95% CI −0.32 to 0.00)). Moderate-quality evidence from two primary prevention trials found a reduction in systolic (−2.99 mmHg (95% CI -3.45 to 2.53)) and diastolic (−2.0 mmHg (95% CI -2.29 to 1.71)) blood pressure, with low or very low-quality evidence of little or no effect on low density lipoprotein or high density lipoprotein cholesterol or triglycerides. Only one or two small secondary prevention trials reported lipid levels or blood pressure, with evidence rated as low or very low quality, so there was generally not enough data to detect any difference in these outcomes. (Table 2).

Limitations of the evidence

Overall, there were limited high-quality data on clinical endpoints, our primary outcome. Two studies were excluded from all main analyses in sensitivity analyses due to published concerns regarding the reliability of the data.3 Only the PREDIMED trial reported clinical endpoints for primary prevention. However, this study experienced methodological issues regarding randomisation for two sites, and the inclusion of non-randomised second household members, with the report subsequently being retracted and re-analysed. The new publication controlled for these in the analyses and conducted a series of sensitivity analyses excluding these sites.4 Overall, we should treat findings from the PREDIMED trial with extreme caution, given the number of methodological issues flagged. The findings in secondary prevention are based on one older trial reporting very large effect estimates using a modified Zelan design.5 In addition, both the PREDIMED trial and The Lyon Diet Heart Study supplied supplemental foods as well as dietary advice to follow a Mediterranean-style diet, so the policy implications of the findings of these trials are unclear. The majority of studies included in this review were at unclear risk of bias for many of the risk of bias domains, so results should be interpreted cautiously. High risk of bias was noted for differential attrition rates between the intervention and control groups in two trials and high risk of other bias in two trials where there are published concerns regarding the reliability of the data.

Implications

At the present time, there is no definitive trial evidence regarding the effects of a Mediterranean-style diet on clinical endpoints for both the primary and secondary prevention of major CVD. Overall, the available trial evidence is promising (though not conclusive) and generally supportive of favourable effects of the Mediterranean-style diet on individual cardiometabolic risk factors in primary prevention studies, and potentially also on clinical endpoints such as stroke. Several ongoing trials, particularly those reporting clinical endpoints in secondary prevention, will add to the evidence base. Further adequately powered primary prevention trials are needed to confirm findings on clinical endpoints to date. With the accrual of further evidence, the heterogeneity observed between trials in terms of both the nature and duration of the intervention, comparators and the range of participants recruited can be explored further and its impact on outcomes examined. The ongoing studies may help reduce the uncertainty. Given the lack of evidence on potential harmful effects of a Mediterranean-style diet, health professionals and scientific organisations may refer to this dietary pattern as a potential non-pharmacological option to reduce cardiovascular risk, in conjunction with other established lifestyle interventions.