Primary cardiovascular prevention by Mediterranean diet – The PREDIMED trial

Traditionally, the Mediterranean diet is composed of olive oil, fruit, nuts, vegetables, and cereals. Fish and poultry intake is moderate and consumption of dairy products, red meat, processed meats, and sweets is low. Further, wine consumption with meals is moderate (Serra-Majem et al. 2006). In observational cohort studies (Sofi et al. 2010) and the secondary preventive Lyon Diet Heart Study, (De Lorgeril et al. 1999) increasing adherence to the Mediterranean diet has been consistently beneficial in lowering cardiovascular (CV) risk (Serra-Majem et al. 2006).

In the recently published PREDIMED trial (Prevención con Dieta Mediterránea) (Estruch et al. 2013), patients at high CV risk, but with no CV disease at enrollment, were randomly assigned to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet.

PREDIMED was a parallel-group, randomized multi-centre trial conducted in Spain that enrolled men (55 to 80 years of age) and women (60 to 80 years of age) with no CV disease at baseline, but who had either type 2 diabetes mellitus or at least three of the following major risk factors: smoking, hypertension, elevated low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, overweight or obesity, or a family history of premature coronary heart disease. The primary end point was a composite of myocardial infarction, stroke, and death from CV causes. Secondary end points included stroke, myocardial infarction, death from CV causes, and death from any cause. End point registration in PREDIMED was carried out according to the PROBE technique (Hansson et al. 1992), i.e. all medical records related to end points were examined by a special end point adjudication committee, whose members were unaware of the individual patient's treatment allocations. The initial intention in PREDIMED was to recruit 9000 participants, which was judged to be necessary to provide statistical power of 80% to detect a relative risk reduction of 20% in each Mediterranean-diet group versus the control-diet group during a 4-year follow-up period. The event rate in the control group was of 12%, and the sample size was recalculated in April 2008 to 7400 participants based on the advice of the data and safety monitoring board. Drug-treatment regimens were well balanced between the three groups throughout the study period. No diet-related adverse effects were reported during follow-up.

The major finding in the trial was that an energy-unrestricted Mediterranean diet supplemented with either extra-virgin olive oil or nuts resulted in an absolute risk reduction of approximately 3 major CV events per 1000 person-years. The relative risk reduction was approximately 30% among high- risk persons who were initially free of CV disease. A total of 288 primary-outcome events occurred in the trial during the median follow-up period of 4.8 years. There were 96 primary events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), and 83 events in the group assigned to a Mediterranean diet with nuts (3.4%). In comparison, there were 109 primary events in the control group (4.4%). The absolute reductions in the primary end point rates in the respective groups were 8.1, 8.0, and 11.2 per 1000 person-years. Notably, regarding components of the primary end point, only stroke risk reached statistical significance.

The Spanish PREDIMED trial clearly demonstrates that among persons at high CV risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts may reduce the incidence of major CV events. Two previous Mediterranean-diet studies support the conclusion of the PREDIMED trial in that there was reduction of stroke risk (Sofi et al. 2010, Kastorini et al. 2011). Also, an inverse association between the Mediterranean diet (Sofi et al. 2010, Kastorini et al. 2011) or olive oil consumption (Samieri et al. 2011) and incident stroke has been demonstrated in other studies. Importantly, the results of the PREDIMED trial might explain, in part, the lower CV mortality seen in Mediterranean countries compared to northern European countries and the United States (Muller-Nordhorn et al. 2008). An earlier study by Esposito and co-workers (2004) demonstrated that switching patients with the metabolic syndrome to a Mediterranean-style diet resulted in improvement in endothelial function and a significant reduction in markers of systemic vascular inflammation. In participants who followed the Mediterranean-style diet, the prevalence of the metabolic syndrome was reduced by approximately one half.

Previous research has demonstrated that the components of the Mediterranean diet that are associated with better survival include moderate consumption of ethanol (mostly from wine), low consumption of meat and meat products, and high consumption of vegetables, fruits, nuts, legumes, fish, and olive oil (Trichopoulou et al. 2009; Buckland et al. 2012). The Mediterranean diet may have favourable effects on intermediate pathways of cardio-metabolic risk, such as blood lipids and insulin sensitivity, as well as markers of oxidative stress, inflammation, and vasoreactivity (Jacobs et al. 2009). However, the mechanisms by which a Mediterranean-style diet may reduce the low-grade inflammatory state that is associated with the metabolic syndrome are unclear. The olive and nut enriched diets could have an impact on both traditional risk factors and emerging risk markers. Given that there is a linear increase in hs-CRP levels with increasing numbers of metabolic syndrome components, it is not surprising that targeted dietary interventions result in a reduction in hs-CRP in such patients (see Esposito et al. 2004).

The PREDIMED trial is clearly a landmark study for primary dietary prevention of CV disease in high-risk patients. Now it is up to the medical community to incorporate the findings of this trial into nutritional recommendations for primary prevention of CV events in their patients. Taken together, available evidence strongly suggests that Mediterranean-style diets are effective for primary and secondary CV disease prevention in patients with the metabolic syndrome.

Last, but not least, it is important to note that 82% of PREDIMED participants had hypertension and the Mediterranean diet was highly effective in this subgroup.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.