The Mediterranean Diet in the Primary Prevention of CVD

Niki Katsiki, MSc, PhD, MD, FRSPH, and

Dimitri P. Mikhailidis, BSc, MSc, MD,

FRSPH, FCP, FFPM, FRCP, FRCPath

Review

The beneficial effects of the Mediterranean diet for secondary prevention of cardiovascular (CV) risk are well known and have been well publicized.^1,2 In this study, Estruch et al set about to investigate whether the Mediterranean diet was effective for primary prevention of cardiovascular disease.³ They compared 3 diets — a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, and a low-fat diet (control group) — with regard to CV morbidity and mortality in patients at high CV risk (but without CV disease at baseline).

Study Details

Estruch et al³ conducted a parallel-group, multicenter, randomized study. The PREDIMED (Prevención con Dieta Mediterránea) trial investigated the impact on primary CV prevention of the Mediterranean diet. Participants were men 55 to 80 years of age and women 60 to 80 years of age with a history of type 2 diabetes mellitus (T2DM) or at least 3 CV risk factors (smoking, hypertension, elevated low-density lipoprotein [LDL] cholesterol levels, low high-density lipoprotein [HDL] cholesterol levels, overweight-obesity, or a family history of premature coronary heart disease) but without a history of CV disease (CVD).

A total of 7,447 individuals were randomly assigned in a 1:1:1 ratio to the 3 dietary interventions: Mediterranean diet supplemented with extra-virgin olive oil (approximately 1 L/week; n = 2,543), Mediterranean diet supplemented with 30 g of nuts (walnuts, almonds, and hazelnuts; n = 2,454) or a control low-fat diet (n = 2,450).

Follow-up was for a median of 4.8 years. The 2 Mediterranean groups participated in individual and group dietary-training sessions at baseline and every 3 months (adherence to the Mediterranean diet was assessed and personalized advice was provided). After the first visit, which included dietary consultation, subjects in the control group received only a low-fat diet leaflet on a yearly basis. However, during the study the authors included group sessions and personalized dietary advice as frequently as for the 2 other groups. Compliance was assessed with biochemical markers in random samples at 1, 3, and 5 years. Calorie restriction and physical activity were not encouraged.

A total of 523 participants were lost to follow-up (3.6%, 6.3%, and 11.3% for olive oil, nuts, and control group, respectively). These “dropouts” were younger, more obese, and with a lower adherence to the Mediterranean diet compared with those who completed the study.

Compliance in both Mediterranean diet groups was good throughout the study, as assessed by biomarkers. No differences were recorded with regard to physical activity.

The rates of the primary outcome (myocardial infarction [MI], stroke, and CV death) were 3.8%, 3.4%, and 4.4% in olive oil, nuts, and control groups, respectively (unadjusted hazard ratios [HRs] were 0.70, 95% confidence interval [CI], 0.53-0.91 for Mediterranean diet with olive oil; P = 0.009; and HR, 0.70; 95% CI, 0.53-0.94; P = 0.02 for Mediterranean diet with nuts versus control diet, respectively). In multivariate analysis, similar benefits were found for the 2 Mediterranean groups compared with controls with regard to the primary outcome (HR, 0.70; 95% CI, 0.56-0.90; P ≤0.005).

In the secondary analysis only stroke reduction was significant (adjusted HR, 0.61; 95% CI, 0.44-0.86; P = 0.005 for the 2 Mediterranean groups versus controls). Subgroup analyses showed no differences in CV risk reduction between the 2 Mediterranean groups versus controls, except for obese patients (BMI >30 kg/m²), who marginally benefited more from Mediterranean diets (HR for primary end point: 0.51; 95% CI, 0.37-0.71; P = 0.05).

To avoid a possible effect of the protocol change on the dietary intervention in the control group, HRs for the Mediterranean groups versus control group were calculated before and after this change; no differences were found in terms of interaction. Diet-related adverse events were not reported throughout the study.

Commentary Beneficial Effects for Mediterranean Diet, But More Study Needed

The PREDIMED study³ does not provide data on individual CV risk factors such as weight, BMI, waist circumference, blood pressure (BP), and lipids. Furthermore, several PREDIMED participants had T2DM (50.4%, 46.6%, and 48.5% for Mediterranean-olive oil, Mediterranean-nuts, and control group, respectively). There is no report on diabetes duration and complications, or on glucose and glycated hemoglobin (A1C) levels at baseline and at the end of the study. However, in an earlier analysis the PREDIMED investigators reported no significant associations between glucose control and adherence to a Mediterranean diet4 based on baseline A1C from 262 cases. In contrast, plasma glucose levels, systolic BP, and total cholesterol/HDL cholesterol ratio were significantly decreased in both Mediterranean diet groups versus controls at 3 months.⁵ All the above cardiometabolic parameters are associated with CV risk and should be further analyzed.

Metabolic syndrome (MetS), a cluster of dyslipidemia, central obesity, hypertension, and insulin resistance, is a predictor of CVD.⁶ Apart from its diagnostic criteria,⁶ MetS is associated with other CV risk factors including HDL dysfunction; increased small, dense LDL levels; postprandial hypertriglyceridemia; and liver and renal dysfunction.⁷ Lifestyle interventions can beneficially affect MetS components and even resolve MetS, as shown in a recent meta-analysis.⁸ Of note, the PREDIMED investigators reported in an earlier study⁹ that MetS prevalence at 1 year was significantly reduced (by 13.7%) only in the nuts-supplemented diet group. More recently, the same investigators published a cross-sectional assessment that showed an inverse association between nut consumption and MetS incidence, as well as central obesity and T2DM.10 Statins may also improve MetS^11,12; approximately 40% of the PREDIMED trial participants were taking statins.³ However, drug treatment (including lipid-reducing, antihypertensive, antiplatelet, and hypoglycemic agents as well as hormone-replacement therapy) remained similar in the 3 groups.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, is associated with increased CV risk.^13,14 Weight reduction is recommended in NAFLD patients as it can improve liver histology and biochemical risk factors.15 Statins have also been reported to beneficially affect both histological and cardiometabolic markers.^16-19 Insulin sensitizers and antioxidants may also be used to treat NAFLD, but more evidence is needed.²⁰ These findings were supported by a recent meta-analysis by Musso et al.¹⁵ Elevated serum uric acid (SUA) levels represent another potential CV risk factor.^21,22 Diet as well as lipid-lowering, antihypertensive, and hypoglycemic drugs can reduce hyperuricemia.23-25 The European Society of Cardiology/European Atherosclerosis Society and Canadian Cardiovascular Society^26,27 defined an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² as a CVD risk factor. The PREDIMED investigators previously reported²⁸ that renal function significantly improved to a similar extent in the 3 diet groups after 1 year. Multifactorial treatment, including a statin, was also shown to increase eGFR.^23,24,29 Therefore, alterations in SUA levels as well as kidney and liver function should be reported throughout the PREDIMED trial.³

The PREDIMED authors do not discuss the cost of Mediterranean diets, a factor that can influence long-term implementation in the general population, especially in low-income countries. Furthermore, culture, religion, and tradition play a role in the dietary patterns. In this context, Appel et al³⁰ mention in their accompanying editorial that the control group actually “consumed a variant of the Mediterranean diet.” Whether Mediterranean diets can be properly applied in countries with different cultural and economic background remains unanswered. Furthermore, Appel et al³⁰ also highlight the fact that the observed CV benefits in the PREDIMED trial were mainly attributed to the supplemental foods (and the subsequent increased consumption of fish and legumes) and not to the Mediterranean diet per se. The PREDIMED results should be interpreted accordingly.

Other dietary products with beneficial effect on CV risk factors may be useful (eg, spreads containing plant stanol-esters).³¹ The PREDIMED investigators also previously showed³² that plasma total antioxidant capacity was significantly increased only in the 2 Mediterranean diet groups at 1-year follow up.

Apart from culture, the higher dropout rate in the control group may indirectly reflect low motivation derived from the “small nonfood gifts” given to them. What were these gifts? The change in the protocol during the trial, although required, is another limitation of this study.

In conclusion, Estruch et al³ reported beneficial effects of 2 Mediterranean diets (supplemented with olive oil or nuts) on CV risk reduction and particularly on stroke. However, further randomized clinical trials are needed to clarify the role of the Mediterranean diet on primary CV prevention, especially in non-Mediterranean countries. Multifactorial therapy, including lifestyle modifications and administration of a statin, has been repeatedly shown to significantly improve several cardiometabolic risk factors such as MetS, hyperuricemia, and liver and kidney function. Treatment strategies should address multiple vascular risk factors.

References

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About the Author

Niki Katsiki, MSC, PhD, MD, FRSPH, is a specialist in internal medicine and a researcher at the Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece. Her PhD is based on obesityrelated peptides in diabetic patients. Dr. Katsiki’s clinical and research interests involve cardiovascular disease prevention and treatment. She has participated in obesity, lipid, diabetes, and smoking cessation outpatient clinics with a special focus on dyslipidemias. Dr. Katsiki was an Honorary Clinical Research Fellow at the Department of Clinical Biochemistry (Academic Head, DP Mikhailidis), Royal Free Hospital campus, University College London Medical School, University College London (UCL), UK. She is also a SCOPE member of the International Association for the Study of Obesity. Dr. Katsiki serves as a reviewer for several cardiovascular journals and is the Editorial Manager of Angiology and Section Editor of Archives of Medical Science. She was assisted in the writing of this article by Dimitri P. Mikhailidis, BSc, MSc, MD, FRSPH, FCP, FFPM, FRCP, FRCPath, Academic Head of the Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), and Department of Surgery, Royal Free Campus, University College London Medical School, UCL, London, UK. He is Editor-in-Chief of several journals including Current Medical Research and Opinion, Current Vascular Pharmacology, and Expert Opinion on Pharmacotherapy.

Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279-1290.