The Mediterranean Diet: Sailing the Wine Dark Sea

Over the years, research has accumulated to support a role for the Mediterranean diet in protecting against cardiovascular disease and diabetes, enough for professional organizations like the US Department of Agriculture (USDA) and the American Diabetes Association to highlight the diet in their recommendations.^1,2

Briefly, the Mediterranean diet is high in monounsaturated fats like those from olive oil. It emphasizes fish, fruits, vegetables, whole grains, legumes/nuts, and moderate alcohol, white meat, and dairy consumption, while advising avoidance of red meat. A healthy lifestyle-physical activity, outdoor exposure for vitamin D synthesis, and conviviality with friends and family-also plays into the mix. Research has tried to pinpoint contributions of individual constituents of the diet, suggesting a possible role for extra virgin olive oil. On the whole, though, evidence suggests that the whole package is important.

The Mediterranean diet seems to be a popular topic for reviews and meta-analyses. Generally, these have reached similar conclusions about the role of the diet in the prevention and management of metabolic syndrome and T2DM.³ Meta-analyses of randomized controlled trials have found significantly greater reductions in HbA1c, fasting plasma glucose, fasting insulin, body mass index, and body weight,⁴ as well as increased remission of metabolic syndrome and decreased risk of T2DM and cardiovascular events.^5,6

These analyses lie on the shoulders of several landmark studies, some bearing names that evoke Homeric images of the wine dark sea. Briefly, these include:

PREDIMED

The Prevención con Dieta Mediterránea (PREDIMED) study was a five-year multicenter, randomized, controlled clinical trial conducted between October 2003 and December 2010 in primary care centers in Spain. Researchers randomized participants at high risk for CVD to an unrestricted calorie, high-vegetable-fat Mediterranean diet supplemented with extra virgin olive oil (EVOO) or mixed nuts, or to a low-fat control diet. The study did not seek to increase physical activity or promote weight loss. 

The trial ended early after interim results suggested 30% reduction in CVD in the Mediterranean diet groups.

Results also suggested a number of beneficial metabolic outcomes. These included reversal of metabolic syndrome (control v. MedDiet + EVOO HR 1.35, 95% CI 1.15-1.58, P<0.001; control v. MedDiet + nuts HR 1.28, 95% CI 1.08-1.51, P<0.001),⁷ as well as decreased fasting glucose, glycemic load, and glycemic index. There was also a 40% reduced risk of T2DM in the Mediterranean diet plus EVOO group, and 18% reduced risk of T2DM in the Mediterranean diet with nuts group (HR 0.60 [95% CI, 0.43 to 0.85] and 0.82 [CI, 0.61 to 1.10]), compared with the low-fat control diet.⁸

The study may also have been game-changing by suggesting that a diet high in vegetable fats is not necessarily a bad thing. Compared with the low-fat control group, both Mediterranean diet groups had less weight gain over five years (MedDiet + EVOO: -0·43 kg [95% CI -0·86 to -0·01]; P=0·044, and MedDiet + nuts: -0·08 kg [-0·50 to 0·35; P=0·730]). These groups also had significantly improved central adiposity (MedDiet + EVOO: P=0·048, Med Diet + nuts: P=0·006), compared with the control group.⁹

A posthoc analysis in participants with T2DM revealed that those who followed the Mediterranean diet had lower risk of diabetic retinopathy (MedDiet + EVOO: HR 0.56 [95% CI 0.32-0.97] and MedDiet+ nuts HR 0.63 [0.35-1.11]), although there were no significant differences in risk for nephropathy.¹⁰

Other prominent studies, mostly in the Mediterranean region, include the MOLI-SANI study, a prospective cohort of 24,325 adult women and men from the Molise region of Southern Italy. Results in diabetic participants followed for a median of 4.0 years suggested 19% reduced risk of overall death (hazard ratio = 0.81; 0.62-1.07) associated with the Mediterranean diet.¹¹

An analysis confined to the Greek population in the European-Prospective Investigation into Cancer and Nutrition (EPIC) study suggested that higher adherence to the Mediterranean diet was linked to 12% decreased risk of T2DM (OR 0.88, CI: 0.77-0.99, P trend=0.021). A combined Mediterranean diet and low glycemic load diet conferred 18% decreased risk of T2DM (OR 0.82, CI: 0.71-0.95).¹²

Finally, the ATTICA cohort study evaluated the effects of physical activity and the Mediterranean diet in 1128 men and 1154 women without cardiovascular disease or diabetes mellitus at baseline. Participants came from the greater Athens area and were enrolled between 2001 to 2002.

Ten-year results showed that medium and high adherence to the Mediterranean diet decreased diabetes risk by 49% (95% CI: 0.30, 0.88) and 62% (95% CI: 0.16, 0.88), respectively, compared with low adherence. Those with high waist circumference benefited most. These results correlated with levels of tumor necrosis factor-α, homocysteine, and total antioxidant capacity, suggesting that the Mediterranean diet may attenuate inflammation and improve total antioxidant capacity.¹³

Criticisms

These results are not without controversy. Critics argue that studies about the Mediterranean diet may have ignored other healthy eating patterns in the world. The Seven Countries study, which originally spurred interest in the Mediterranean diet in the 1950s, may have under-represented many parts of the world by including mainly westernized counties in four regions of the world (United States, Northern Europe, Southern Europe, Japan).

Others have questioned the methods, arguing that studies of Mediterranean diets do not necessarily evaluate the same diet, which is a pattern of eating and not a distinct diet per se. Still others have questioned whether the diet’s benefits apply to non-Mediterranean populations. In fact, a recent meta-analysis found that interventions of the Mediterranean-style diet are more beneficial when conducted in Europe.¹⁴ Expense and availability of key constituents like extra virgin olive oil may play a role.

Most nutritional studies are based on food frequency questionnaires, which are inherently subject to recall bias. Yet, despite these limitations, studies of the Mediterranean diet have underscored the vital importance of diet and lifestyle in prevention of cardiometabolic disease. The future may be about fine-tuning. Unanswered questions include: teasing out the role of fats and dairy, pinpointing critical individual nutrients (if any), and comparing the Mediterranean diet to other types of healthy eating patterns in the world.          

Take-home Points

• Professional organizations and meta-analyses have highlighted the role of the Mediterranean diet in cardiometabolic protection.

• Key studies like the PREDIMED, MOLI-SANI, EPIC-Greece, and Attica have linked the Mediterranean diet to decreased risk for metabolic syndrome, T2DM, and overall death.

• Critics have pointed to methodological issues, under-representation of large parts of the world, and generalizability of results to non-Mediterranean populations.

• Studies of the Mediterranean diet highlight the critical importance of diet and lifestyle in prevention of cardiometabolic disease.

References:

1. US Department of Agriculture. Dietary Guidelines for Americans 2015-2020, Eighth Edition: Appendix 4. USDA Food Patterns: Healthy Mediterranean-Style Eating. Accessed July 23 2016 at: https://health.gov/dietaryguidelines/2015/guidelines/appendix-4/

2. American Diabetes Association. Standards of Medical Care in Diabetes. 2016: 38 (Suppl 1): S1-S112. Accessed July 23, 2016 at: http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf

3. Salas-Salvadó J, et al. Protective effects of the Mediterranean diet on type 2 diabetes and metabolic syndrome. J Nutr. 2016 Mar 9.

4. Huo R, et al. Effects of Mediterranean-style diet on glycemic control, weight loss and cardiovascular risk factors among type 2 diabetes individuals: a meta-analysis. Eur J Clin Nutr. 2015 Nov;69(11):1200-1208.

5. Esposito K, et al. A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses. BMJ Open. 2015 Aug 10;5(8):e008222.

6. Bloomfield HE, et al. Effects on health outcomes of a Mediterranean diet with no restriction on fat intake: a systematic review and meta-analysis. Ann Intern Med. 2016 Jul 19.

7. Babio N, et al. PREDIMED Study Investigators. Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial. CMAJ. 2014 Nov 18;186(17):E649-657.

8. Salas-Salvadó J, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. J Nutr Metab. 2014;2014:985373.

9. Estruch R, et al. PREDIMED Study Investigators. Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: a prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial. PREDIMED study: Lancet Diabetes Endocrinol. 2016 Jun 6.

10. Díaz-López A, et al. PREDIMED Study Investigators. Mediterranean diet, retinopathy, nephropathy, and microvascular diabetes complications: a post hoc analysis of a randomized trial. Diabetes Care. 2015 Nov;38(11):2134-2141.

11. Bonaccio M, et al; MOLI-SANI study Investigators. Adherence to the traditional Mediterranean diet and mortality in subjects with diabetes. Prospective results from the MOLI-SANI study. Eur J Prev Cardiol. 2016 Mar;23(4):400-407.

12. Rossi M, et al. Mediterranean diet and glycaemic load in relation to incidence of type 2 diabetes: results from the Greek cohort of the population-based European Prospective Investigation into Cancer and Nutrition (EPIC). Diabetologia. 2013 Nov;56(11):2405-2413.

13. Koloverou E, et al. ATTICA Study Group. Adherence to Mediterranean diet and 10-year incidence (2002-2012) of diabetes: correlations with inflammatory and oxidative stress biomarkers in the ATTICA cohort study. Diabetes Metab Res Rev. 2016 Jan;32(1):73-81.

14. Garcia M, et al. The effect of the traditional Mediterranean-style diet on metabolic risk factors: a meta-analysis. Nutrients. 2016 Mar 15;8(3):168.