.jpg)
.png)
Introduction
“Let food by thy medicine and medicine thy food,” are words that have been widely attributed to Hippocrates, the father of Western medicine. Yet it’s one of the most misquoted phrases of all time, since it has never been found in the more than 60 texts known as The Hippocratic Corpus.1 While food certainly was used in Hippocratic medicine, the purpose of food was to ensure the balance of the four humors – blood, phlegm, yellow bile and black bile. Medicines, on the other hand, were used to purge the body of excess humors and other impure fluids.
While food seems to play a role in our overall health and well-being, it’s important not to confuse food with medicine. Diet and nutrition long have been a focus of our efforts to prevent cardiovascular disease (CVD), which has remained the leading cause of death in the United States since the 1930s.2 While nearly every healthcare professional would agree that diet and nutrition are important, there is a wide range of evidence and opinions on the ideal dietary pattern to recommend for CVD prevention. Such diets often are seen as very restrictive (e.g., Ornish diet, Atkins diet) or are perceived as too expensive (e.g., Jenny Craig diet). Furthermore, the intent of following a specific dietary pattern for CVD prevention often is lost in myriad diets targeting surrogate markers, such as weight loss, and improving blood pressure and cholesterol levels.
One of the most widely recommended diets for CVD prevention is the Mediterranean diet, which recommends following a dietary pattern that includes mostly fresh fruits and vegetables, whole grains, nuts and poultry.3 The Mediterranean diet also emphasizes a moderate intake of red wine, only when appropriate or not contraindicated, and mono- and poly-unsaturated fats from olive oil and fish. Intake of red meat, desserts and processed meats is limited. The Lyon Heart Study4 demonstrated the effectiveness of a Mediterranean diet in a randomized, single-blind study of 423 patients after their first myocardial infarction. After a mean 46 months of follow-up per patient, nonfatal myocardial infarction and cardiovascular death were reduced by 65% (95% CI 0.15-0.83; p<0.01). Despite the impressive findings, doubts remained because of methodological concerns and the small number of patients. Until recently, the effects of a Mediterranean diet on primary prevention were unknown.
PREDIMED Study Design and Results
The Prevención con Dieta Mediterránea, or Prevention with Mediterranean Diet, (PREDIMED) study5 is an intervention study that randomized 7,447 patients to either a Mediterranean diet supplemented with extra-virgin olive oil (at least 4 tablespoons per day), a Mediterranean diet supplemented with mixed nuts (30 g per day), or a control diet (low-fat). Importantly, calories were unrestricted in this study. Men and women ages 55 to 80 and 60 to 80, respectively, with no CVD at baseline and either diabetes mellitus or three major CVD factors, were enrolled from primary care clinics. The average participant was 67 years old, white and female. A majority of participants either were obese or had diabetes, dyslipidemia and hypertension. Nearly 62% met the criteria for metabolic syndrome at baseline. After a median follow-up of 4.8 years, there were 288 primary outcome events (acute myocardial infarction, stroke or CVD death). Both groups randomized to the Mediterranean diets achieved a significant 30% relative risk reduction in the primary composite endpoint compared to the control diet. Despite favorable trends for acute myocardial infarction and CVD death, the only component of the primary composite endpoint that met statistical significance was stroke (HR 0.61; 95% CI 0.44-0.86). There was no significant difference found for total mortality, but there was a favorable trend for the Mediterranean diet supplemented with extra-virgin olive oil.
Further analyses of the PREDIMED data also have been reported, with several important findings. Despite no change in physical activity, there was up to a 40% reduction in the number of new-onset cases of diabetes mellitus and metabolic syndrome reversed in as many as 14% of the participants assigned to one of the Mediterranean diet groups.6 Intermediate markers of CVD risk also improved in those assigned to the Mediterranean diets, including blood pressure, insulin sensitivity, lipid profile and markers of inflammation (e.g. hs-CRP).7 Importantly, a Mediterranean diet supplemented with either extra-virgin olive oil or mixed nuts did not result in additional weight gain, despite the lack of calorie restriction.8
Limitations of the PREDIMED Study
Despite the favorable results, there are some notable limitations of the PREDIMED study. As with most nutrition studies, the investigators relied on subject self- reporting, which introduces the potential for recall bias. The investigators did, however, objectively measure compliance to the Mediterranean diets by measuring urinary hydroxytyrosol for extra-virgin olive oil and alpha linolenic acid for nuts. The control diet protocol was modified during the study to provide a similar support and visit schedule as the other two intervention groups, which could have introduced bias. There also were some irregularities between the groups at baseline regarding the use of diuretics and oral antihyperglycemic therapies. Importantly, the control diet was intended to be low-fat, but fat intake was higher than anticipated in the control diet group. The study dropout rate also was much higher in the control diet group compared to both Mediterranean diet groups combined (11.3% vs. 4.9%, respectively). The generalizability of the study also is limited, given the participants were from Mediterranean countries. While the primary composite endpoint was met, despite an overall low event rate, this was driven by a significant reduction in stroke and not myocardial infarction or mortality.
Discussion and Conclusions
Based on the PREDIMED findings, should we widely recommend a Mediterranean diet with extra-virgin olive oil or mixed nuts for primary prevention of CVD? Before addressing this question, let’s imagine the intervention in the PREDIMED study was a new pharmacological agent being compared to placebo and had the same positive findings. The next obvious question about this therapy would be about the adverse effect profile. What if this new therapy was associated with essentially no adverse effects? While it’s important to note nutritional studies often are not set up to evaluate safety or adverse effects, we have no reason to believe there are any with the Mediterranean diet. As such, PREDIMED offers us an intervention that provides a significant benefit that also is of low risk to our patients. However, it’s convenient to undermine the results from PREDIMED given the aforementioned study limitations and the fact that the observed significant stroke reduction may be hard for some to believe.
As Hippocrates did or didn’t say about letting “food by thy medicine and medicine thy food,” one interpretation of this quote might be that both medicine and food are necessary for the prevention and management of disease. The difference, however, is that medicine has the potential to cause serious harm that may outweigh any potential benefit, which is why an intensive evaluation of a novel drug therapy is warranted before it’s approved by the U.S. Food and Drug Administration (FDA) for widespread use in the general population. While those of us in academic circles can debate the nuances of one dietary approach over another, we should accept the evidence we do have as we would with any other type of intervention and implement it in those most likely to benefit.
Diet and nutrition play a critical role in improving CVD risk factors and should be prescribed to all patients. While the Mediterranean diet is only one of several healthy dietary patterns that clinicians may consider recommending to patients, the cumulative evidence seems to support its effectiveness in improving CVD risk factors and reducing cardiovascular events.
Disclosure statement: Dr. Dixon has received honoraria from Sanofi.
References are available here.
Article By:
Associate Professor
Virginia Commonwealth University School of Pharmacy
Richmond, VA
Diplomate, Accreditation Council of Clinical Lipidology