New from the PREDIMED study: Mediterranean diet for primary prevention of cardiovascular disease

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2 May 2013

In high-risk individuals without cardiovascular disease, a Mediterranean diet including either extra virgin olive oil or nuts reduced the incidence of first major cardiovascular events by up to 30% over 5 years. The effects of diet were enhanced in individuals with dyslipidemia. While the findings reaffirm the role of the Mediterranean diet as a first step in managing cardiovascular risk, it is also clear that pharmacotherapy beyond current best treatment, including statins, is also needed.

Estruch R, Ros E, Salas-Salvado J; PREDIMED Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;Epub ahead of print 25 February, 2013.

STUDY SUMMARY

Objective

To evaluate the effects of two Mediterranean diets (one supplemented with extra-virgin olive oil and one supplemented with nuts) on primary prevention of cardiovascular (CV) events.

Study design

Parallel-group, multicentre, randomised trial

Study population

In total, 7,447 subjects aged 55-80 years with at least 3 major CV risk factors (smoking, hypertension, elevated low-density lipoprotein cholesterol [LDL-C], low high-density lipoprotein cholesterol [HDL-C], overweight or obese or family history of premature coronary heart disease) were enrolled and allocated (1:1:1) to a Mediterranean diet supplemented with extra-virgin olive oil (~1 litre per week), a Mediterranean diet supplemented with nuts (15 g of walnuts, 7.5 g of hazelnuts and 7.5 g of almonds) or a control diet. No restriction on total calorie intake was advised, and physical activity was not promoted. The characteristics of the patient population are summarised below.

Baseline characteristics of the groups

Variable	Med. Diet + olive oil	Med. Diet + nuts	Control
Total N	2543	2454	2450
Mean age, yr	67.0	66.7	67.3
% Female	59	54	60
% BMI >30 kg/m2	47	44	49
% Type 2 diabetes	50	47	49
% Hypertension	82	83	84
% Dyslipidemia*	72	73	72
% Statins	41	39	40
*Defined as high LDL-C (>160 mg/dL or 4.1 mmol/L), low HDL-C (<40 mg/dL or 1.0 mmol/L in men and <50 mg/dL or 1.3 mmol/L in women), or on lipid-modifying therapy

Primary variable

CV events, a composite of myocardial infarction (MI), stroke and CVD death

Secondary variables

The individual components of the primary endpoint, plus all-cause mortality

Methods

Patients in the two Mediterranean diet groups were followed-up by dieticians in individual and group dietary training sessions every 3 months, In each session, adherence to the diet was assessed by a self-report 14-item food frequency dietary questionnaire. It was originally planned that patients in the control group would also be followed in the same way to 3 years and thereafter would receive a leaflet explaining the low-fat diet every year. However, to avoid issues with compliance, the protocol was subsequently amended to allow for follow-up of the control group with the same frequency and intensity as the Mediterranean diet groups, using a 9-point questionnaire. A general medical questionnaire, a 137-point food frequency questionnaire and The Minnesota Leisure Time Physical Activity Questionnaire were also completed by all individuals every year. Urine and blood samples were also taken in the two diet groups as independent markers of compliance (urinary hydroxytyrosol levels for the group receiving extra-virgin olive oil, and plasma alpha-linolenic acid for the group receiving nuts).

Main results

The key findings are summarized below.

In both groups there was good adherence to the intervention according to self-reported intake and biomarker analyses. There were no differences in physical activity between the groups.

Over a median of 4.8 years follow-up, the use of a Mediterranean diet supplemented with extra-virgin olive oil or nuts was associated with relative reductions of risk of 30% and 28%, respectively (see Table).This benefit was attributed to significant reduction in stroke; there was no significant impact on the other endpoints.

Subgroup analyses showed that the benefit of a Mediterranean diet was enhanced in individuals with dyslipidemia versus those without (hazard ratio 0.60, 95% CI 0.44-0.80 versus 0.95, 95% CI 0.64-1.42).

Key outcomes in the PREDIMED study

Endpoint	Med. Diet + olive oil (OO)	Med. Diet + nuts (N)	Control	P-value*
Primary				00	N
No. of events	96	83	109	0.009	0.02
Adjusted HR (95% CI)*	0.70 (0.54-0.92)	0.72 (0.54-0.96)		0.01	0.03

Stroke
No. of events	49	32	58	0.03	0.003
Adjusted HR (95% CI)	0.67 (0.46-0.98)	0.54 (0.35-0.84)		0.04	0.006

* versus control

Author's conclusion

Among individuals at high CV risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major CV events.
The results support the benefits of the Mediterranean diet for primary prevention of CVD.

COMMENT

The Residual Risk Initiative (R3i) highlighted the importance of a healthy diet, in particular diet quality, in their position paper.1 Evidence supports the benefits of a Mediterranean diet on cardiometabolic risk factors, including dyslipidemia, blood pressure, insulin resistance and type 2 diabetes.2,3 Furthermore, the recent European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for management of dyslipidemia emphasised the importance of diet and lifestyle interventions as the first step in management of dyslipidemia to prevent CVD.4

However, the key issue with lifestyle intervention is to ensure adherence. It is therefore notable that the current study showed good adherence associated with each dietary intervention, according to the self-report dietary questionnaire and corroborated by biomarkers analysis. This in turn strengthens the finding of significant reduction in CV events in this high-risk patient population with a Mediterranean diet. Indeed, with the rising pandemic of obesity and cardiometabolic disease, now extending to Asia,5 the study reaffirms the importance of this lifestyle intervention for preventing cardiovascular disease.

However, closer inspection of the data also indicates the limitations of such dietary lifestyle intervention. About 45% of patients were already receiving a statin or other lipid-modifying therapy, 82%-83% were receiving treatment for hypertension, and about 30% were receiving oral hypoglycaemic therapy. Thus, against this background of evidence-based treatment of cardiometabolic disease, the incorporation of a Mediterranean diet reduced but did not prevent the majority of incident CV events. About 8 major CV events per 1000 person-years still occurred in this high-risk group, indicating the need to target additional risk factors.

Atherogenic dyslipidemia is an important driver of CV risk in individuals with cardiometabolic disease.1,6 Given the prevalence of atherogenic dyslipidemia typically seen in this population, this would be an appropriate target for additional intervention.

In line with the position paper of the R3i, this paper highlights the importance of diet quality in preventing CVD. However, additional interventions, including those targeting atherogenic dyslipidemia may provide further benefit in high-risk individuals with cardiometabolic disease.

References

1. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
2. Trichopoulou A, Bamia C, Trichopoulous D. Mediterranean diet and survival among patients with coronary heart disease in Greece. Arch Intern Med 2005; 165: 929-35.
3. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, D’Armiento M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome. JAMA 2004; 292: 1440-6.
4. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
5. Creeping epidemic of obesity hits Asia Pacific region. Available at http://www.escardio.org/about/press/press-releases/pr-13/Pages/epidemic-obesity-hits-asia.aspx. Accessed 21 February, 2013.
6. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.