The Mediterranean Diet in the Primary Prevention of CVD

Cardiology Review® OnlineAugust 2013
Volume 29
Issue 4

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

Dimitri P. Mikhailidis, BSc, MSc, MD,



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 MetS11,12; 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 Society26,27 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.


1. Mead A, Atkinson G, Albin D, et al; UK Heart Health Group; Thoracic Dietitians Interest Group (Specialist group of the British Dietetic Association). Dietetic guidelines on food and nutrition in the secondary prevention of cardiovascular disease—evidence from systematic reviews of randomized controlled trials (second update, January 2006). J Hum Nutr Diet. 2006;19:401-419.

2. de Lorgeril M, Salen P. Mediterranean diet in secondary prevention of CHD. Public Health Nutr. 2011;14:2333-2337.

3. 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.

4. Díez-Espino J, Buil-Cosiales P, Serrano-Martínez M, Toledo E, Salas- Salvadó J, Martínez-González MÁ. Adherence to the Mediterranean diet in patients with type 2 diabetes mellitus and HbA1c level. Ann Nutr Metab. 2011;58:74-78.

5. Estruch R, Martínez-González MA, Corella D, et al; PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145:1-11.

6. Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640-1645.

7. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Characteristics other than the diagnostic criteria associated with metabolic syndrome: an overview [published online April 25, 2013]. Curr Vasc Pharmacol.

8. Yamaoka K, Tango T. Effects of lifestyle modification on metabolic syndrome: a systematic review and meta-analysis. BMC Med. 2012;10:138.

9. Salas-Salvadó J, Fernández-Ballart J, Ros E, et al; PREDIMED Study Investigators. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med. 2008;168:2449-2458.

10. Ibarrola-Jurado N, Bulló M, Guasch-Ferré M, et al; PREDIMED Study Investigators. Cross-sectional assessment of nut consumption and obesity, metabolic syndrome and other cardiometabolic risk factors: the PREDIMED study. PLoS One. 2013;8:e57367.

11. Athyros VG, Ganotakis E, Kolovou GD, et al; Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) Collaborative. Assessing the treatment effect in metabolic syndrome without perceptible diabetes (ATTEMPT): a prospective-randomized study in middle aged men and women. Curr Vasc Pharmacol. 2011;9:647-657.

12. Athyros VG, Kakafika AI, Papageorgiou AA, et al. Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study. Curr Med Res Opin. 2008;24:1593-1599.

13. Lioudaki E, Ganotakis ES, Mikhailidis DP. Liver enzymes: potential cardiovascular risk markers? Curr Pharm Des. 2011;17:3632-3643.

14. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk? Curr Vasc Pharmacol. 2011;9:698-705.

15. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and metaanalysis of randomised trials. Diabetologia. 2012;55:885-904.

16. Athyros VG, Tziomalos K, Gossios TD, et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376:1916- 1922.

17. Athyros VG, Giouleme O, Ganotakis ES, et al. Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study. Arch Med Sci. 2011;7:796- 805.

18. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Managing the combination of non-alcoholic fatty liver disease and metabolic syndrome. Expert Opin Pharmacother. 2012;13:287-288.

19. Athyros VG, Tziomalos K, Daskalopoulos GN, Karagiannis A, Mikhailidis DP. Statin-based treatment for cardiovascular risk and nonalcoholic fatty liver disease: killing two birds with one stone? Ann Med. 2011;43:167-171.

20. Musso G, Anty R, Petta S. Antioxidant therapy and drugs interfering with lipid metabolism: could they be effective in NAFLD patients [published online February 4, 2013]? Curr Pharm Des.

21. Rizzo M, Obradovic M, Labudovic-Borovic M, et al. Uric acid metabolism in pre-hypertension and the metabolic syndrome [published online April 25, 2013]. Curr Vasc Pharmacol.

22. Katsiki N, Karagiannis A, Athyros VG, Mikhailidis DP. Hyperuricaemia: more than just a cause of gout? J Cardiovasc Med (Hagerstown). 2013;14:397-402.

23. Athyros VG, Karagiannis A, Ganotakis ES, et al; Assessing The Treatment Effect in Metabolic syndrome without Perceptible diabeTes (ATTEMPT) Collaborative Group. Association between the changes in renal function and serum uric acid levels during multifactorial intervention and clinical outcome in patients with metabolic syndrome. A post hoc analysis of the ATTEMPT study. Curr Med Res Opin. 2011;27:1659-1668.

24. Athyros VG, Mikhailidis DP, Liberopoulos EN, et al. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol Dial Transplant. 2007;22:118-127.

25. Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Curr Pharm Des. 2005;11:4161-4175.

26. 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;32:1769-1818.

27. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations. Can J Cardiol. 2009;25:567-579.

28. Díaz-López A, Bulló M, Martínez-González MÁ, et al; PREDIMED (Prevención con Dieta Mediterránea) Reus Study Investigators. Effects of Mediterranean diets on kidney function: a report from the PREDIMED trial. Am J Kidney Dis. 2012;60:380-389.

29. Tirosh A, Golan R, Harman-Boehm I, et al. Renal function following three distinct weight loss dietary strategies during 2 years of randomized controlled trial [published online May 20, 2013]. Diabetes Care.

30. Appel LJ, Van Horn L. Did the PREDIMED trial test a Mediterranean diet? N Engl J Med. 2013;368:1353-1354.

31. Athyros VG, Kakafika AI, Papageorgiou AA, et al. Effect of a plant stanol ester-containing spread, placebo spread, or Mediterranean diet on estimated cardiovascular risk and lipid, inflammatory and haemostatic factors. Nutr Metab Cardiovasc Dis. 2011;21:213-221.

32. Zamora-Ros R, Serafini M, Estruch R, et al; on behalf of the PREDIMED Study Investigators. Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: Evidence for a mechanism of antioxidant tuning [published online February 25, 2013]. Nutr Metab Cardiovasc Dis.

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.

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