A recent literature search on the “Mediterranean diet” at the time of writing this chapter reveals over 4000 published articles in PubMed.²⁵ This diet has been purported to have benefit for several chronic lifestyle-induced conditions, including CVD, metabolic syndrome and type 2 diabetes, cancer, liver disease, depression, and anxiety.³ Based on the quantity of articles published, the Mediterranean diet could be considered the most “well-studied” diet, even though its scientific recognition roughly began only 2 decades ago when it was observed that people living on the Greek island of Crete had reduced risk of CVD.²⁶ In addition to being one of the most researched dietary patterns, it is shared by multiple countries in the Mediterranean basin within the context of varying populations of people living within different degrees of industrialization of food production. As a result of the intercountry differences, it has become necessary to more specifically define the contents of this dietary pattern for research purposes.

Although it varies to some degree, the broad definition of the traditional Mediterranean diet has been deemed to have these characteristics²⁷:

For maintaining consistency and for research study purposes, a quantitative and qualitative research tool has been developed to assess a percentage compliance to the Mediterranean diet.²⁸ Such a questionnaire may be valuable for patients who are following this way of eating so that the clinician can better assess their adherence to the dietary program. Several studies²⁹ indicate that various levels of adherence (from first quartile to fourth) are associated with
differing health benefits (eg, reduced risk for metabolic syndrome) with the highest compliance being associated with greatest benefit.³⁰ Factors that may determine compliance include the following: dietitian involvement, education, goal setting, mindfulness, recipe books and other materials such as meal plans, consistent contact with staff, clinic visits, and recipes.³

Numerous studies tout the efficacy of the Mediterranean diet for cardiovascular and metabolic benefit, specifically being protective against ischemic stroke, MI, and vascular death.³¹ A 10% lower incidence of nonfatal and fatal CVD was documented for each two-unit increment in the Mediterranean diet score in a meta-analysis and review of prospective cohort studies.³² With greater adherence to this dietary pattern, there was a 56% lower incidence of fatal CVD in a Dutch cohort compared with the group who had lower adherence over an almost 12-year period.³³

Furthermore, the Mediterranean diet has been shown to be superior in its ability to produce clinically relevant shifts in body weight, BMI, blood pressure, fasting glucose, total cholesterol, and hsCRP compared with the long-standing, widely recognized and advocated low-fat diet.³⁴ The well-known PREDIMED trial indicated that a Mediterranean diet in conjunction with nuts or olive oil led to a 30% reduction in major cardiovascular events compared with a low-fat diet.³⁵

An overall summary of the cardiovascular and metabolic benefits of the Mediterranean diet include the following as based on the review article by Houston et al.¹:

The DASH diet was unlike the Mediterranean diet in that it had no cultural underpinning, but it was unique for its time because it emphasized a pattern of eating instead of simply avoiding certain foods, which was the nutritional trend at that time.³⁶ The DASH diet was conceived in the 1990s to create an evidence-based dietary prescription to reduce the incidence of hypertension.³⁷

The DASH diet is similar to the Mediterranean diet. It touts high intake of fruits, vegetables, whole grains, low-fat dairy foods, legumes, and nuts; moderate intake of poultry and fish; and low intake of sodium, sweetened beverages, and red and processed meat.³⁸ In general, it was designed to reduce cholesterol, saturated fat, trans fat, salt, and added sugars, and, at the same time, increase minerals such as potassium, magnesium, and calcium, along with protein and fiber.³⁹ There were two versions of the DASH diet: DASH 1 had a sodium content of about 3100 mg per day,⁴⁰ whereas DASH 2 had about half as much sodium at 1500 mg daily.⁴¹ As one might anticipate, the second version was more effective in reducing blood pressure.⁴¹

Although the DASH diet was designed for hypertension specifically, its implementation has led to significant improvements in cardiovascular risk factors, such as vascular and autonomic function (pulse wave velocity, baroreflex sensitivity), reduced left ventricular mass, and a lowering of total cholesterol and LDL-cholesterol.⁴² A meta-analysis⁴³ of 12 prospective cohort studies (n = 548,632) with 5.7 to 24 years of follow-up found that greater adherence to the DASH diet was related to a reduced risk of stroke (relative risk, 0.88), with a greater benefit in Asian compared with Western populations. For each four points in the DASH diet score, there was a 4% risk reduction in total stroke events. Additionally, a meta-analysis of prospective studies found that the DASH diet, along with the Mediterranean diet and Alternative Healthy Eating Index, reduced the risk of type 2 diabetes.⁴⁴

In contrast, the DASH diet has led to no effect on triglycerides and a reduction in HDL-cholesterol.⁴² Additional effects include reductions in homocysteine, C-reactive protein (CRP), and IL-6⁴⁵,⁴⁶ and an even better blood pressure lowering response in those who are carriers of the A allele of the β2-adrenergic receptor.⁸,⁴⁷

Proposed mechanisms for reduction in cardiovascular risk include¹:

The sum of current evidence would suggest that vegetarian diets are beneficial for cardiometabolic health. Plant-based diets have been touted for both the prevention and treatment of heart failure, cerebrovascular disease, and CHD.⁴⁸ For decades, Dean Ornish has studied their efficacy, together with lifestyle strategies, for the reversal of CHD.⁴⁹,⁵⁰ Vegetarian dietary patterns can reduce the risk of metabolic syndrome, type 2 diabetes, and CHD (by 40%),⁴⁸ in addition to being able to lower blood pressure, blood lipids, and reduce platelet aggregation
over nonvegetarian diets. In a prospective investigation⁵¹ of 131,342 participants from both the Nurses’ Health Study and Health Professionals Follow-up Study, it was found that high plant protein intake was negatively associated with all-cause and cardiovascular mortality (hazard ratio [HR], 0.90 per 3% energy increment; 95% confidence interval [CI], 0.86-0.95; P for trend < .001, and HR, 0.88 per 3% energy increment; 95% CI, 0.80-0.97; P for trend = .007, respectively), whereas animal protein intake was positively correlated with cardiovascular mortality. Substituting plant protein for animal protein (processed or unprocessed red meat, and eggs) led to lower mortality.

Depending on the type of vegetarian diet, there may be certain nutrients that require additional supplementation⁵² such as vitamins B12 and D, omega-3 fatty acids, the minerals iron and zinc, L-carnitine, and possibly some high-quality amino acids, especially sulfur-containing amino acids, and protein.

Avoiding gluten-containing foods, including select whole grains and even processed foods and beverages, has been on the rise for a variety of reasons. Traditionally, it is held that following a gluten-free diet is a necessity for individuals with celiac disease, an autoimmune condition that leads to gastrointestinal and systemic dysfunction in response to the intake of the gluten protein commonly found in wheat, barley, and rye. However, there is awareness of the potential health effects of dietary gluten in nonceliac populations. Laboratory testing is available to detect nonceliac gluten sensitivity (NCGS), which is associated with the dysfunctional effects on gastrointestinal tight junctions through the protein zonulin.⁵³

With respect to cardiometabolic health, there is some emerging research in the literature. In a review of published studies on celiac disease and cardiovascular conditions,⁵⁴ the authors noted that there were studies on the relationship between celiac disease and cardiomyopathy (33 studies), thrombosis (27 studies), cardiovascular risk (17 studies), atherosclerosis (13 studies), stroke (12 studies), arterial function (11 studies), and ischemic heart disease (11 studies). They concluded that there can be cardiovascular issues in those with celiac disease, particularly if they are untreated.

Some concern has been raised about the quality of a gluten-free diet and whether it may result in decreased intake of vitamins and minerals and increased exposure to environmental toxins such as arsenic (which is high in rice, an alternate grain in the gluten-free diet).⁵⁵ In a systematic review⁵⁵ of the literature of the gluten-free diet and cardiometabolic parameters (blood pressure, glycemia, BMI, waist circumference, and serum lipids), it was noted that most studies were done in those with celiac disease and there were consistent increases in total cholesterol, HDL, fasting blood glucose, and BMI.

Moreover, one study⁵⁶ in 185 patients with celiac disease found an increased risk of developing both metabolic syndrome (3.24% before gluten-free diet and 14.59% after the gluten-free diet) and hepatic steatosis after following a gluten-free diet (1.7% at the time of diagnosis and 11.1% after the gluten-free diet). The authors report that several criteria of metabolic syndrome were increased after the gluten-free diet compared with baseline at celiac disease diagnosis, including elevated waist circumference and BMI >25, hypertension, hyperglycemia, hypercholesterolemia, and lowered HDL-cholesterol.

However, more studies are required to look more specifically at NCGS and the exact dietary composition, as there can be a wide spectrum of unhealthy and healthy gluten-free diets.⁵⁷

Presently, the timing of eating and the amount of food eaten, along with patterns of caloric cycling, have been gaining traction in the cardiovascular and diabetic arenas. Indeed, there are a plethora of animal studies to suggest that fasting to the point of maintaining normal body weight in the absence of malnutrition may be highly beneficial for extending lifespan and enhancing cardiovascular and metabolic health⁵⁸,⁵⁹ by reducing oxidative stress, inflammation, and atherosclerosis.⁶⁰ Although limited, some clinical studies suggest that these benefits may translate to humans as well.⁶¹ In general, preliminary and observational clinical studies indicate that several cardiovascular and diabetic risk factors may improve with some degree of caloric restriction, from body composition to inflammation, blood pressure, and insulin sensitivity.⁶²

Similar effects, such as weight loss and reductions in cardiometabolic parameters such as CRP, cholesterol fractions, triglycerides, and blood pressure,⁶³,⁶⁴,⁶⁵ are being reported with alternate-day (fasting 1 day and eating ad libitum the next) or intermittent fasting (typically described as a 12- to 16-hour nightly fast), which has become popular within certain nutrition-focused groups.

Whether it is caloric restriction, food restriction, or some pattern of food withdrawal and fasting, it is best to advise patients to plan for engaging in such a protocol to the extent that when they are eating, they are eating nutrient-dense foods such as fruits, vegetables, nuts, seeds, and other high-quality protein- and fat-containing foods so as to ensure they are not becoming nutritionally depleted, hungry, or not feeling satiated, all of which can affect compliance to the regimen.⁶⁶

Eating cooked food has advantages of improving digestibility and, at the same time, the downside of creating glycosylated protein compounds known as advanced glycation end products (AGEs). This acronym provides an effective way for patients to remember the effect of these deleterious compounds that cause premature aging,⁶⁷ like what is seen in cardiometabolic conditions, especially type 2 diabetes.⁶⁸

AGEs are formed endogenously, such as the case with hemoglobin A1C (a glycosylated protein), or taken in
exogenously through the diet, primarily though cooked foods as heat facilitates this inflammatory complex of carbohydrate and protein (known as the Maillard reaction). Often, patients will be able to recognize the presence of AGEs in food as it can appear as the “browning” of food through broiling, frying, grilling, roasting, and searing.⁶⁹ A list of AGE content in a wide array of foods can be found in the practical guide by Uribarri et al.⁶⁹ It is of note that animal-based foods high in fat and protein (eg, bacon, fried chicken) tend to be high in AGE content, whereas vegetables, fruits, whole grains, and even milk (with some cheeses as exceptions) contain relatively less AGEs, even with heat methods applied. Although cooking is one of the primary drivers of AGE formation, some foods are naturally high in AGEs and should be reduced in the diet. High-fat and aged cheeses are among the highest in AGE levels, so choosing a lower-fat cheese or one that has not been cured as long would be preferred.⁶⁹

Eating less AGEs in the diet directly translates to lower circulating AGE levels in serum, along with lower inflammatory cytokines.⁷⁰ A single meal consisting of a chicken breast, potatoes, carrots, tomatoes, and vegetable oil caused significant postprandial endothelial function and oxidative stress in type 2 diabetic patients when the meal underwent frying or broiling rather than when it was steamed or boiled.⁷¹ In a crossover design with healthy subjects fed for 1 month a meal containing either high AGEs formed by cooking with high temperatures or low AGEs through mild steaming, it was reported that the high-AGE meals caused lower insulin sensitivity, omega-3 fatty acids, and vitamins C and E and increased cholesterol and triglycerides.⁷² In contrast, diabetic patients following a low-AGE diet had lower inflammation and oxidative stress compared with those eating a standard diet.⁷³

Clinically, in some cases, it may be easier to effect change in a patient’s eating by first starting with altering cooking methods rather than asking them to shift the foods in their dietary pattern. From a therapeutic perspective, there is great benefit in doing so, and it can be easily done. One way to reduce AGEs in foods is by foregoing the high-heat methods of cooking such as frying and grilling and substituting with slow, moist, lower-heat methods including boiling, poaching, steaming, and stewing.⁷⁴ Or, if cooking with heat, preferentially use water to steam, and as a second tier to use an oil with a higher smoke point such as olive oil or avocado oil. Oil use over butter led to 50% to 75% less AGE formation.⁶⁹ The second way is to reduce or avoid foods high in AGEs, such as full-fat cheeses, whole milk, meats, and highly processed foods (eg, crackers, French fries, potato chips).

A cornerstone concept recognized in naturopathic medicine and discussion on Paleolithic dietary principles is that of an alkaline versus an acidic diet.⁷⁵ More specifically, diet-induced “low-grade” metabolic acidosis translates to the imbalance between foods in the diet due to their differing electrolyte content. Potassium alkali salts found primarily in vegetables and fruits would be desirable and essentially reduce the dietary net acid load, whereas eating foods that are low in essential minerals and rich in either amino “acids” and/or fatty “acids” such as animal products would lead to increased acid (low alkaline) load.⁷⁶,⁷⁷ The general basis for this concept in nutritional medicine seems to have come, in part, from exploration into the Paleolithic diet by Loren Cordain⁷⁸ and others,⁷⁶ as it would have featured high-fiber, wild-cultivated, highly alkalizing plant foods and less of the more “acidic” foods that came into being with the agricultural revolution such as cereal grains, dairy products, and meats.

Although it may be difficult to discern if the therapeutic benefit of eating more “alkaline” is simply because of eating more fruits and vegetables, a large, prospective, population study with 22,034 men and women aged 39 to 78 years did find that urinary pH shifted to more alkaline with a diet higher in fruits and vegetables.⁷⁹ With respect to cardiovascular markers, Murkami et al.⁸⁰ demonstrated that higher dietary acid load was associated with CVD risk factors such as blood pressure, total and LDL-cholesterol, and body composition metrics, including BMI and waist circumference. Furthermore, lowering risk of hypertension has been noted in some studies utilizing dietary acid load, although results are not consistent.⁸¹,⁸² There is also an indication that diet-induced acidosis may perturb insulin sensitivity and, ultimately, CVD risk.⁸³

Quite simply, although the science for such positioning is not as compelling, the outcome or therapeutic approach is in line with what has been discussed previously. It entails an approach that is like that of both the Mediterranean and DASH diets, both of which are high in plant-based, “alkalizing” foods and lower in animal-based, “acidifying” foods.

Because of its implication in blood glucose balance, dietary carbohydrate is often seen as a significant macronutrient for type 2 diabetes, whereas dietary fat is typically associated with
CVD. However, dietary carbohydrate quality and quantity are essential for both type 2 diabetes and CVD. In some nutrition-oriented protocols, there is discussion that a patient should have no carbohydrate whatsoever. Yet, there are many forms of carbohydrate that need to be acknowledged and assessed as there is sufficient evidence that whole-food sources of plant-based carbohydrates, including fruits, legumes, vegetables, and whole grains, may not only be suitable for those with type 2 diabetes and/or CVD but also actually be therapeutic and serve as part of a treatment protocol. Hence, there is no need to vilify the entire class of carbohydrates when instructing a patient.

The role of carbohydrate quantity has been evaluated in several studies, one of which was a meta-analysis by Hu et al.⁸⁵ who surveyed the impact of either a low-carbohydrate or low-fat diet on cardiometabolic parameters in 2788 participants from 23 trials. Low-carbohydrate diets were better at lowering total cholesterol, LDL-cholesterol, and triglycerides, and, at the same time, improving HDL-cholesterol, compared with the low-fat diets. These findings are not always consistent, however, as Nordmann et al.⁸⁶ did a meta-analysis with five trials consisting of 447 overweight individuals and found that the low-fat diet led to better reductions in total cholesterol and LDL-cholesterol (but not triglycerides or HDL-cholesterol). Another meta-analysis published by Santos et al.⁸⁷ found similar mixed results with the low-carbohydrate diet lowering systolic and diastolic blood pressure, plasma triglycerides, and raising HDL-cholesterol, but there was no significant change in the primary CVD marker of LDL-cholesterol. In a review by Jung and Choi,⁸⁸ high-carbohydrate diets were found to be comparable with low-carbohydrate diets on metabolic parameters in patients with type 2 diabetes. Indeed, as explained previously, the discrepancies within these studies may be due to the quality of carbohydrate that was consumed, the glycemic index, glycemic load, and even the phytochemicals the food contains.

Among the three classes of macronutrients, dietary fats and oils have been most scrutinized for their implication in CVD risk and, to some degree, cardiometabolic dysfunction. The same principle mentioned in the section on carbohydrates would apply here: that the universal guideline of quality and quantity needs to be considered. As Harvard epidemiologist Walter Willett¹²² suggested, the amount of total fat in the diet is likely not as important as the diet itself. Along similar lines, there is complexity within the different fatty acids, including a variety of carbon chain lengths, single or double bonds, and configuration (cis- and trans-).

For the most part, dietary fat provides a substantial source of energy (9 kcal/g), and fatty acids comprise the bilayer membrane of the cell, which implies that they can be responsible for the activity of receptor sites and cell signaling cascades that could ultimately lead to inflammation, insulin resistance, and stress response intracellularly.¹²³