Adherence to the Mediterranean diet (MED) is associated with a 25% reduction in the risk for cardiovascular disease (CVD), compared with those who do not follow this diet, new research suggests.
Investigators used data from the Women’s Health Study, which followed close to 26,000 women between their late forties and early sixties over a 12-year period, assessing 40 biomarkers known to be associated with CVD risk.
Higher baseline MED intake was associated with a 28% relative risk reduction in CVD events, attributed mostly to a reduction in biomarkers of inflammation, glucose metabolism and insulin resistance, and adiposity, the researchers say.
“The cardiovascular benefit seen with a Mediterranean dietary pattern in this large US population of women was similar in magnitude to benefit from statins or other commonly used preventive medications,” senior author Samia Mora, MD, MHS, Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, told theheart.org | Medscape Cardiology.
“Even modest changes in CVD risk factors with a heart-healthy diet contribute to the benefit of the Mediterranean diet on CVD risk and may have important downstream consequences for primary prevention,” she said.
The study was published online December 7 in JAMA Network Open .
Precise Mechanisms Unknown
“The Mediterranean diet has been associated with lower risk of CVD events, but the precise mechanisms through which Mediterranean diet intake may reduce long-term risk of CVD are not well understood,” Mora said.
“We aimed to investigate the biological mechanisms that may mediate this cardiovascular benefit,” she noted.
Previous observational studies have reported that a 20-percentile higher MED intake was associated with a 9% lower CVD event risk reduction, but the follow-up period was short (only 4 years), leaving uncertainty about whether MED intake protects against CVD events in American populations over the long term.
To elucidate the question, the researchers analyzed blood samples of 25,994 participants in the Women’s Health Study (mean [SD] age, 54.7 [7.1] years).
At baseline, participants completed a 131-item questionnaire on their dietary patterns and provided demographic information about history of hypertension, use of postmenopausal hormone therapy, smoking, physical activity, alcohol consumption, and family history of myocardial infarction (MI).
Body mass index (BMI) and blood pressure were also reported at baseline.
A MED score was calculated on the basis of nine components of MED intake, including vegetables, fruits, nuts, whole grains, legumes, fish, and the ratio of monounsaturated fatty acids to saturated fatty acids.
The primary end point was incident CVD, defined as a first event of MI, stroke, coronary arterial revascularization, or cardiovascular death. Coronary and stroke events were also examined separately.
Because baseline measures of MED intake “attenuate with time,” the primary analyses were conducted with a maximum follow-up of 12 years from baseline, whereas secondary analyses were performed in the sample with a median (IQR) follow-up of 21.4 (19.2 – 22.1) years.
The researchers measured total cholesterol, high-density cholesterol (HDL), low-density cholesterol (LDL), high-sensitivity C-reactive protein (hsCRP), triglycerides, apolipoprotein (apo)B100, and apoA1, soluble intracellular adhesion molecule 1 (ICAM-1), fibrinogen, creatinine, and homocysteine.
Nuclear magnetic resonance (MR) spectroscopy was used to measure lipoprotein subfraction particles for LDL, HDL, and very low-density lipoproteins (VLDL), branched-chain amino acids, glycoprotein acetylation (a measure of inflammation).
Lipoprotein insulin resistance index and insulin resistance diabetes risk factor index are insulin resistance scores, including subfractions of triglyceride-rich lipoproteins also derived from nuclear MR spectroscopy.
Of the 25,994 female participants, 39.0%, 36.2%, and 24.8% had low (≤3), middle (4 or 5), and high (6 – 9) MED scores, respectively, and of the total sample, 3.96% experienced a first CVD event.
Participants with higher MED intake had a higher intake of vegetables, fruits, nuts, whole grains, legumes, and fish, and a greater ratio of monounsaturated to saturated fat. They also had a lower intake of processed and red meat.
Participants with low MED intake experienced the most incident CVD events (4.2%), followed by those with middle and high MED intake scores (both 3.8%).
The middle and upper groups experienced the greatest CVD risk reductions, with respective hazard ratios (HRs0 of 0.77 (95% CI, 0.67 – 0.90) and 0.72 (95% CI, 0.61 – 0.86, P for trend <.001), compared with the lowest group.
A total of 1030 individuals experienced a first CVD event during a maximum follow-up of 12 years (mean [SD], 11.6 [1.5] years), including 681 coronary events and 339 strokes.
The middle and upper groups both showed CVD risk reduction (HR, 0.77; 95% CI, 0.67 – 0.90 and 0.72, 0.61 – 0.86, respectively, P for trend < .001), compared with the reference group of participants with low MED intake.
The researchers also observed CVD relative risk reductions of 23% and 28% for middle and higher groups, respectively, compared with the lower MED intake group, after adjusting for age, randomized treatment, and energy intake.
“American women consuming a Mediterranean-type diet had a quarter reduction in CVD events over long-term (12 year) follow-up,” Mora summarized.
Inflammatory Mediators Most Important
Beyond actual CVD events, MED intake was generally associated with more favorable profiles of CVD risk factors and biomarkers.
However, there were several exceptions. For example, total cholesterol was actually significantly more elevated in the higher than in the lower MED intake group (median, 209.0 [184.0 – 236.0] and 207.0 [183.0 – 234.0], respectively; P = .03).
In contrast, systolic blood pressure, LDL-C, apoB100, LDL particle concentration, creatinine, and HbA1c were similar across the groups (P > .05).
However, when separate Cox models were additionally adjusted with each of the individual biomarkers one at a time, there was some attenuation of HRs (comparing higher vs lower MED intake) before and after adjustment for most variables, except for LDL-C, total cholesterol, Lp(a), citrate, and creatinine.
Biomarkers of inflammation turned out to be the largest mediators of the CVD risk, accounting for 29.2%of the MED-CVD association, followed closely by glucose metabolism and insulin resistance (27.9%), and body mass index (27.3%).
Blood pressure, traditional lipids, HDL measures or VLDL measures (26.6%, 26.0%, 24,0%, and 20.8%, respectively) were next, with lesser contributions from low-density lipoproteins (13.0%), branched-chain amino acids (13.6%), apolipoproteins (6.5%), or other small-molecule metabolites (5.8%).
The fully adjusted CVD HRs for the middle- and upper-intake groups, compared with the low-intake group, were 0.88 (0.76 – 1.02) and 0.89 (0.74 – 1.06), respectively (P for trend = .15).
The total mediation effect was 27.3%, with a “generally similar pattern of risk reduction” was observed for CHD and stroke risk.
When the researchers repeated these analyses using the total follow-up of 21.4 median years, they observed “materially similar results.”
“For the MED-CVD risk reduction, biomarkers of inflammation, glucose-metabolism/insulin resistance, and adiposity contributed most to explaining the association, with additional contributions from pathways related to blood pressure and lipids — in particular, HDL or triglyceride-rich lipoprotein metabolism and, to a lesser extent, LDL cholesterol, branched chain amino acids, and small molecule metabolites,” Mora said.
“Palatable and Achievable”
Commenting on the study for theheart.org | Medscape Cardiology, Erin D. Michos, MD, MHS, associate professor of medicine and epidemiology and associate director of preventive cardiology, Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, who was not involved with the study, said that, although it is observational, “it helps to fill in a few gaps.”
She noted that the study focused on “a broad pattern of eating more adherent to Mediterranean style and did not focus on any single component of the score,” suggesting that overall dietary patterns, “rather than any single component, matter.”
She said her patients frequently ask about “reducing inflammation,” and that “a Mediterranean-style diet pattern may be one means to do so.”
Diet is frequently tied to “sociocultural norms,” and behaviors can be “difficult to change,” so the Mediterranean diet might be a good choice to recommend because “it is very palatable and achievable, not too restrictive or extreme,” she suggested.
“Dietary recommendations likely need to be tailored to the individuals, based on personal preferences and cardiometabolic considerations,” and “there is no one diet that fits all,” Michos advised.
Also commenting on the study for theheart.org | Medscape Cardiology, Thomas Keyserling, MD, MPH, professor of medicine, Division of General Medicine and Clinical Epidemiology, University of North Carolina at Chapel Hill School of Medicine, who was not involved with the study, called it “consistent with prior studies; that is, a Mediterranean dietary pattern is associated with a substantial reduction in risk for CVD events.”
The study “adds to the literature on the mechanisms of risk reduction, including the Mediterranean diet’s impact on inflammation and glucose metabolism,” he said, adding that more research into this association is needed.
Mora suggested that there “may be additional pathways, such as improvements in vascular function or antiarrhythmic effects, which could be improved with the Mediterranean diet, that we did not measure in our study.
The Women’s Health Study is supported by the National Institutes of Health. Mora was supported by the research grants from the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; the American Heart Association; and the Molino Family Trust. The other authors’ sources of individual support are listed on the original paper. Mora received institutional research grant support from Atherotech Diagnostics for research outside the current work, served as a consultant and member of the scientific advisory board to Quest Diagnostics, and has a patent regarding the use of glycoprotein acetylation in relation to colorectal cancer risk. The other authors’ disclosures are listed on the original paper. Michos and Keyserling report no conflicting interests.
JAMA Network Open. Published online December 7, 2018. Abstract