Abstract: In this substantive review update, 30 RCTs (49 papers) (12,461 participants randomised) and seven ongoing trials met our inclusion criteria. The majority of trials contributed to primary prevention: comparisons 1 (nine trials) and 2 (13 trials). Secondary prevention trials were included for comparison 3 (two trials) and comparison 4 (four trials plus an additional two trials that were excluded from the main analyses due to published concerns regarding the reliability of the data). Two trials reported on adverse events where these were absent or minor (low- to moderate-quality evidence). No trials reported on costs or health-related quality of life. Primary prevention The included studies for comparison 1 did not report on clinical endpoints (CVD mortality, total mortality or non-fatal endpoints such as myocardial infarction or stroke). The PREDIMED trial (included in comparison 2) was retracted and re-analysed following concerns regarding randomisation at two of 11 sites. Low-quality evidence shows little or no effect of the PREDIMED (7747 randomised) intervention (advice to follow a Mediterranean diet plus supplemental extra-virgin olive oil or tree nuts) compared to a low-fat diet on CVD mortality (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.50 to 1.32) or total mortality (HR 1.0, 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), a decrease from 24/1000 to 14/1000 (95% CI 11 to 19), moderate-quality evidence). For CVD risk factors for comparison 1 there was low-quality evidence for a possible small reduction in total cholesterol (-0.16 mmol/L, 95% CI -0.32 to 0.00) and moderate-quality evidence for a reduction in systolic (-2.99 mmHg (95% CI -3.45 to -2.53) and diastolic blood pressure (-2.0 mmHg, 95% CI -2.29 to -1.71), with low or very low-quality evidence of little or no effect on LDL or HDL cholesterol or triglycerides. For comparison 2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol (-0.15 mmol/L, 95% CI -0.27 to -0.02) and triglycerides (-0.09 mmol/L, 95% CI -0.16 to -0.01) with moderate or low-quality evidence of little or no effect on total or HDL cholesterol or blood pressure. Secondary prevention For secondary prevention, the Lyon Diet Heart Study (comparison 3) examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality (HR 0.35, 95% CI 0.15 to 0.82) and total mortality (HR 0.44, 95% CI 0.21 to 0.92) with the intervention. Only one small trial (101 participants) provided unadjusted estimates for composite clinical endpoints for comparison 4 (very low-quality evidence of uncertain effect). For comparison 3 there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure. Similarly, for comparison 4 where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure. Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The quality of evidence for the modest benefits on CVD risk factors in primary prevention is low or moderate, with a small number of studies reporting minimal harms. There is a paucity of evidence for secondary prevention. The ongoing studies may provide more certainty in the future.

Plain-language summary: This review assessed the effects of providing dietary advice to follow a Mediterranean-style diet or provision of foods relevant to the diet (or both) to healthy adults, people at increased risk of cardiovascular disease and those with cardiovascular disease, in order to prevent the occurrence or recurrence of cardiovascular disease and reduce the risk factors associated with it. Definitions of a Mediterranean dietary pattern vary and we included only randomised controlled trials (RCTs) of interventions that reported 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. Additional components included: low to moderate red wine consumption; high consumption of whole grains and cereals; low consumption of meat and meat products and increased consumption of fish; moderate consumption of milk and dairy products. The control group was no intervention or minimal intervention, usual care or another dietary intervention. We found 30 RCTs (49 papers) that met these criteria. The trials varied enormously in the participants recruited and the different dietary interventions. We grouped studies to look at the effects of following a Mediterranean-style diet into the following four categories to help us with our interpretation of the results: 1. Mediterranean dietary intervention compared to no intervention or a minimal intervention to prevent the onset of cardiovascular disease; 2. Mediterranean dietary intervention compared to another dietary intervention to prevent the onset of cardiovascular disease; 3. Mediterranean dietary intervention compared to usual care for people with cardiovascular disease to prevent recurrence; 4. Mediterranean dietary intervention compared to another dietary intervention for people with cardiovascular disease to prevent recurrence. Few trials reported on the occurrence of cardiovascular disease either in those with or without disease to begin with. A large trial in people at high risk of cardiovascular disease found a benefit of the Mediterranean dietary intervention compared to a low-fat diet on the risk of having a stroke, but not on heart attacks, death from heart disease or other causes. A further study in people with cardiovascular disease found a benefit of the Mediterranean dietary intervention on death from heart disease or other causes. We rated these two studies as providing low to moderate-quality evidence. We had to exclude two studies from our analyses as concerns had been raised that the data were unreliable. The other trials in the review measured risk factors for cardiovascular disease. There was low to moderate-quality evidence for some beneficial changes in lipid levels and blood pressure with a Mediterranean-style diet in people without disease. In people with cardiovascular disease already there was very low to low-quality evidence that there was no effect of a Mediterranean-style diet on risk factors. Two trials reported side effects of the diet that were either absent or minor. The review concludes that, despite the large number of included trials, there is still uncertainty regarding the effects of a Mediterranean-style diet on cardiovascular disease occurrence and risk factors in people both with and without cardiovascular disease already. We did find seven studies that are still ongoing and when we have the results from these we will incorporate them into the review to help reduce the uncertainty.