*6.4.1 Comparison to other CV studies to intervene in traditional CV risk factors*

Although the primary end point was positive in the entire cohort of subjects including those in primary and secondary prevention studies, of the CANVAS program (canagliflozin) [201], the DECLARE-TIMI58 study (dapagliflozin) [202], or the LEADER study (liraglutide) [203], the subgroup analyses have shown a very small reduction in primary endpoint in subjects without established atherosclerotic diseases (**Figure 15**).

The absolute and relative risk reduction by aspirin was 0.06%/year and 12% in primary prevention group [204] and thus, because of increased bleeding complications, aspirin has not been indicated in subjects without CV diseases. What is remarkable in the PREDIMED study is that the huge reduction in CV events was

#### **Figure 15.**

*The hazard ratios and 95% CI in the PREDIMED, CANVAS, DECLARE, and LEADER studies according to presence or absence of established CV diseases [6, 201–203].*

#### **Figure 16.**

*(a) Kaplan-Meier event curves for the primary end point in the Lyon Diet Heart, PREDIMED, CARE, and ODYSSEY OUTCOMES studies [6, 201–203]. (b) Kaplan-Meier event curves for the primary end point in the ADVANCE, SPRINT, CANVAS, and LEADER studies [201, 203, 206, 207].*

observed in the primary prevention cohort (**Figure 15**), where rates of CV events are usually low and historically, effects of drugs are rarely observed in pharmacological trials. The absolute risk reduction was almost five times higher in the PREDIMED study (0.32%/year) than that of aspirin (0.06%/year) [204].

The rapid onset of reduction in CV events should also be addressed. **Figure 16a** and **b** shows the Kaplan-Myers curves of the Lyon Diet Heart, PREDIMED, dyslipidemia (CARE [205] and ODESSEY OUTCOME [181]), hypertension (ADVANCE [206] and SPRINT [207]), and diabetes (CANVAS program [201] and LEADER [203]) studies. Whereas it takes 6 months to 2 years before the decline in CV events in most of these studies, the Kaplan-Myer curves of the two Mediterranean diet studies were separated early in the course, less than half a year. Previous studies have shown that it takes years for imaging parameters to significantly change during antihypertensive agents with carotid ultrasound [208], statin therapy [209] or an antidiabetic drug [210] with coronary intravascular ultrasound (IVUS). Considering that process in regression of plaque size needs years from studies with these image modalities, the Mediterranean diet in the PREDIMED study may be associated with early changes in plaque component, causing more stable atherosclerotic plaque which results in reduction of CV events.

#### *6.4.2 Comparison of macronutrients between groups in PREDIMED study*

**Figure 17** shows comparison of total calories and percent energy from protein, fat, and carbohydrate (**Figure 17a**), and percent energy from each fatty acids (**Figure 17b**) in the PREDIMED study at the end of the study. For comparison with residents in non-Mediterranean diet cultures, data for Japanese in their 60s in 2015 [140] and US adults at age > 60 years old (total calories) and >20 years old (3 major nutrients) in 2011 [120] are also shown. In the two Mediterranean diet groups, high fat food was allowed, as long as the fat was derived from vegetable sources, particularly olive oils and nuts, and also from fatty fish. As a result, the total calories reached approximately 2200 kcal/day with fat calories exceeding more than 40% of total calories, and both of them were higher than in the low-fat control diet group (1960 kcal/day and 37%). Clearly, this was a calorie-unrestricted, high-fat diet, which is usually not recommend in obese subjects.

**Figure 17.**

**99**

*(a) Total calories and percent energy from protein, fat, and carbohydrate in the PREDIMED study at the end of study [6] compared with those of Japanese in their 60s in 2015 [140] and those of US adults at age > 60 years old (total calories) and >20 years old (protein, fat, and carbohydrate) in 2011 [120]. (b) Percent energy from SFA, MUFA, and PUFA in the PREDIMED study at the end of the study compared with those of Japanese in*

*their 60s in 2015 [140] and those of US adults at age > 20 years old in 2011 [120].*

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.93261*

*Effects and Issues of Diet Fat on Cardiovascular Metabolism DOI: http://dx.doi.org/10.5772/intechopen.93261*

#### **Figure 17.**

observed in the primary prevention cohort (**Figure 15**), where rates of CV events are usually low and historically, effects of drugs are rarely observed in pharmacological trials. The absolute risk reduction was almost five times higher in the PREDIMED study (0.32%/year) than that of aspirin (0.06%/year) [204].

*(a) Kaplan-Meier event curves for the primary end point in the Lyon Diet Heart, PREDIMED, CARE, and ODYSSEY OUTCOMES studies [6, 201–203]. (b) Kaplan-Meier event curves for the primary end point in the*

*ADVANCE, SPRINT, CANVAS, and LEADER studies [201, 203, 206, 207].*

and **b** shows the Kaplan-Myers curves of the Lyon Diet Heart, PREDIMED, dyslipidemia (CARE [205] and ODESSEY OUTCOME [181]), hypertension

**Figure 16.**

*New Insights into Metabolic Syndrome*

**98**

stable atherosclerotic plaque which results in reduction of CV events.

*6.4.2 Comparison of macronutrients between groups in PREDIMED study*

which is usually not recommend in obese subjects.

**Figure 17** shows comparison of total calories and percent energy from protein,

fat, and carbohydrate (**Figure 17a**), and percent energy from each fatty acids (**Figure 17b**) in the PREDIMED study at the end of the study. For comparison with residents in non-Mediterranean diet cultures, data for Japanese in their 60s in 2015 [140] and US adults at age > 60 years old (total calories) and >20 years old (3 major nutrients) in 2011 [120] are also shown. In the two Mediterranean diet groups, high fat food was allowed, as long as the fat was derived from vegetable sources, particularly olive oils and nuts, and also from fatty fish. As a result, the total calories reached approximately 2200 kcal/day with fat calories exceeding more than 40% of total calories, and both of them were higher than in the low-fat control diet group (1960 kcal/day and 37%). Clearly, this was a calorie-unrestricted, high-fat diet,

The rapid onset of reduction in CV events should also be addressed. **Figure 16a**

(ADVANCE [206] and SPRINT [207]), and diabetes (CANVAS program [201] and LEADER [203]) studies. Whereas it takes 6 months to 2 years before the decline in CV events in most of these studies, the Kaplan-Myer curves of the two Mediterranean diet studies were separated early in the course, less than half a year. Previous studies have shown that it takes years for imaging parameters to significantly change during antihypertensive agents with carotid ultrasound [208], statin therapy [209] or an antidiabetic drug [210] with coronary intravascular ultrasound (IVUS). Considering that process in regression of plaque size needs years from studies with these image modalities, the Mediterranean diet in the PREDIMED study may be associated with early changes in plaque component, causing more

*(a) Total calories and percent energy from protein, fat, and carbohydrate in the PREDIMED study at the end of study [6] compared with those of Japanese in their 60s in 2015 [140] and those of US adults at age > 60 years old (total calories) and >20 years old (protein, fat, and carbohydrate) in 2011 [120]. (b) Percent energy from SFA, MUFA, and PUFA in the PREDIMED study at the end of the study compared with those of Japanese in their 60s in 2015 [140] and those of US adults at age > 20 years old in 2011 [120].*

Average BMI of participants at baseline was approximately 30 and half of them fell within the class 1 obesity category (BMI > 30). A calorie-restricted diet with limited fat consumption (<30–35% of calories as fat) is usually recommended for these subjects. In the control diet group, although the focus was to reduce all types of fat and they were advised to avoid fatty foods, fat calories was elevated at 37%. This value is actually higher than in the standard low-fat diet (<30%), and higher than in Japanese and even the US adults. Therefore, all participants in the PREDIMED study represent people receiving a high fat diet. Regarding carbohydrates, in the control group, low-fat dairy products, refined carbohydrates, fruits, and vegetables were recommended as substitution for high-fat foods Therefore, a decrease in fat calories in the control group was compensated with an increase in carbohydrate calories, which was higher than the two Mediterranean diet groups. However, the level of carbohydrate calories in the control group was still lower than in Japanese and US adults.

Percent calories from fat type after 5 years of treatment in the PREDIMED study deserve attention (**Figure 17b**). The participants of all three groups were to restrict intake of red and processed meat, commercial bakery goods, sweets, and pastries, all of which are abundant sources of SFA, and were advised to select white meats (poultry without skin or rabbit). However, white meat contains a high content of SFA (30–40% of all fat). Olive oil (15%) and nuts (40% in walnuts, 7% in hazelnuts and peanuts) also contain significant amounts of SFA. As a result, the SFA was equally increased to 9% in each group, which is beyond the recommended level of SFA (<7%) in authoritative opinions. The percent SFA calories in the participants in the PREDIMED study was higher than in Japanese (in their 60s) and less than in US adults (>20 y/o).

Because of increased consumption of EVOO or nuts, MUFA was substantially higher in the EVOO and nuts group (22.1, 20.9 vs. 18.8% in control group) than in the control group. Compared with intake of MUFA in Japan (9.6%) and the US (13%), the very high percent of calories from MUFA is the most distinctive feature that characterizes the changes in nutrition in the two intervention groups. The daily recommend dose of MUFA is not defined in many guidelines except the AACE 2017 guideline which defines it as less than 10% of calories. Even in the control group, the percent of calories from MUFA (18.8%) was much higher than in subjects assigned to the Mediterranean diet in the Lyon Heart Diet study (12.9%) [82, 195]. This is because, in addition to daily intake of olive oil and nuts, many foods in Mediterranean diets are rich in MUFA, and are lower in SFA. The percent energy of PUFA was similar between the three groups and was not very different from in Japan and US. Furthermore, because the consumption of important food components for Mediterranean diet, such as fish, fruits, and vegetables (**Figure 18**), was maintained at high levels during the course of the study, the compliance in diet as described in the protocol was excellent in most participants in the PREDIMED study.

constituents [211, 212]. This is further supported by data that the reduction of CV disease is correlated with rating for overall adherence of the Mediterranean diet [193, 213, 214]. The control group in the PREDIMED study did not consume a typical low-fat diet but rather a Mediterranean diet with mild restriction of olive oil or nuts. The subjects in the control group consumed food constituents affecting CV disease risk such as fish, vegetables, and fruits to the similar extent as in the Mediterranean diet groups except for EVOO and nuts (**Figures 14** and **18**). These findings indicate that, contrary to the previous concept of beneficial effects by synergy of all nutrients in the Mediterranean diet, extra-loaded EVOO and nuts play a critical role in the reduction of CV events in the PREDIMED study.

*Daily consumption of fish, meat, fruit, and vegetable in the PREDIMED study at the end of the study compared with those of Japanese in their 60s in 2015 [140] and those of US adults at age > 20 years old in 2011 [120].*

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.93261*

**Figure 18.**

**101**

The key message in the PREDIMED study is that only adding EVOO or nuts to calorie-unrestricted Mediterranean diet has cut CV events by approximately 30%. High-sensitive CRP (hsCRP) in blood reflects systemic vascular inflammation. In the PROVE-IT study, 80 mg atorvastatin decreased hsCRP by 36% along with reduction of CV events by 16% [215]. In the PREDIMED study, hsCRP decreased by 50 and 40% in the EVOO and nuts groups compared with the control group [6, 198]. The magnitude of changes in hsCRP and CV events were numerically greater in the PREDIMED study than in the stain trials. These data indicate that the diet interventions have resulted in substantial improvement of vascular inflammation resulting in 30% CV event reduction. The mechanism(s) responsible for stabilization of vascular inflammation with the Mediterranean diet remains still unclear. How about the magnitude of the well-known antioxidant effects of EVOO and nuts in the two Mediterranean diet intervention groups? The difference in amounts of polyphenol, a representative antioxidant in EVOO and nuts in the intervention groups vs. the control group, is estimated to be around 10 mg/day. Polyphenol is very abundant in other foods, such as red wine (200–400 mg/100 ml), beans (500–

#### *6.4.3 Potential mechanisms of reduction of CV events by olive oil and nuts*

The Mediterranean diet protects against CV disease via numerous mechanisms, including reduction of blood pressure, LDL cholesterol, and blood glucose, improvement of vascular endothelium, vasodilation, anticoagulation, antiinflammation, and antioxidant activity [192, 211]. Although components of the Mediterranean diet, which consists of fish, olive oil, vegetables, fruits, whole grains, legumes/nuts, and moderate red wine consumption, have been found to reduce CV disease risk, the general consensus is that a Mediterranean diet offers benefit against CV disease in aggregate rather than considering the effects of individual

*Effects and Issues of Diet Fat on Cardiovascular Metabolism DOI: http://dx.doi.org/10.5772/intechopen.93261*

#### **Figure 18.**

Average BMI of participants at baseline was approximately 30 and half of them fell within the class 1 obesity category (BMI > 30). A calorie-restricted diet with limited fat consumption (<30–35% of calories as fat) is usually recommended for these subjects. In the control diet group, although the focus was to reduce all types of fat and they were advised to avoid fatty foods, fat calories was elevated at 37%. This value is actually higher than in the standard low-fat diet (<30%), and higher

Percent calories from fat type after 5 years of treatment in the PREDIMED study deserve attention (**Figure 17b**). The participants of all three groups were to restrict intake of red and processed meat, commercial bakery goods, sweets, and pastries, all of which are abundant sources of SFA, and were advised to select white meats (poultry without skin or rabbit). However, white meat contains a high content of SFA (30–40% of all fat). Olive oil (15%) and nuts (40% in walnuts, 7% in hazelnuts and peanuts) also contain significant amounts of SFA. As a result, the SFA was equally increased to 9% in each group, which is beyond the recommended level of SFA (<7%) in authoritative opinions. The percent SFA calories in the participants in the PREDIMED study was higher than in Japanese (in their 60s) and less than in

Because of increased consumption of EVOO or nuts, MUFA was substantially higher in the EVOO and nuts group (22.1, 20.9 vs. 18.8% in control group) than in the control group. Compared with intake of MUFA in Japan (9.6%) and the US (13%), the very high percent of calories from MUFA is the most distinctive feature that characterizes the changes in nutrition in the two intervention groups. The daily recommend dose of MUFA is not defined in many guidelines except the AACE 2017 guideline which defines it as less than 10% of calories. Even in the control group, the percent of calories from MUFA (18.8%) was much higher than in subjects assigned to the Mediterranean diet in the Lyon Heart Diet study (12.9%) [82, 195]. This is because, in addition to daily intake of olive oil and nuts, many foods in Mediterranean diets are rich in MUFA, and are lower in SFA. The percent energy of PUFA was similar between the three groups and was not very different from in Japan and US. Furthermore, because the consumption of important food components for Mediterranean diet, such as fish, fruits, and vegetables (**Figure 18**), was maintained at high levels during the course of the study, the compliance in diet as described in the protocol was excellent in most participants in the PREDIMED

*6.4.3 Potential mechanisms of reduction of CV events by olive oil and nuts*

including reduction of blood pressure, LDL cholesterol, and blood glucose, improvement of vascular endothelium, vasodilation, anticoagulation, antiinflammation, and antioxidant activity [192, 211]. Although components of the Mediterranean diet, which consists of fish, olive oil, vegetables, fruits, whole grains, legumes/nuts, and moderate red wine consumption, have been found to reduce CV disease risk, the general consensus is that a Mediterranean diet offers benefit against

CV disease in aggregate rather than considering the effects of individual

The Mediterranean diet protects against CV disease via numerous mechanisms,

than in Japanese and even the US adults. Therefore, all participants in the PREDIMED study represent people receiving a high fat diet. Regarding carbohydrates, in the control group, low-fat dairy products, refined carbohydrates, fruits, and vegetables were recommended as substitution for high-fat foods Therefore, a decrease in fat calories in the control group was compensated with an increase in carbohydrate calories, which was higher than the two Mediterranean diet groups. However, the level of carbohydrate calories in the control group was still lower than

in Japanese and US adults.

*New Insights into Metabolic Syndrome*

US adults (>20 y/o).

study.

**100**

*Daily consumption of fish, meat, fruit, and vegetable in the PREDIMED study at the end of the study compared with those of Japanese in their 60s in 2015 [140] and those of US adults at age > 20 years old in 2011 [120].*

constituents [211, 212]. This is further supported by data that the reduction of CV disease is correlated with rating for overall adherence of the Mediterranean diet [193, 213, 214]. The control group in the PREDIMED study did not consume a typical low-fat diet but rather a Mediterranean diet with mild restriction of olive oil or nuts. The subjects in the control group consumed food constituents affecting CV disease risk such as fish, vegetables, and fruits to the similar extent as in the Mediterranean diet groups except for EVOO and nuts (**Figures 14** and **18**). These findings indicate that, contrary to the previous concept of beneficial effects by synergy of all nutrients in the Mediterranean diet, extra-loaded EVOO and nuts play a critical role in the reduction of CV events in the PREDIMED study.

The key message in the PREDIMED study is that only adding EVOO or nuts to calorie-unrestricted Mediterranean diet has cut CV events by approximately 30%. High-sensitive CRP (hsCRP) in blood reflects systemic vascular inflammation. In the PROVE-IT study, 80 mg atorvastatin decreased hsCRP by 36% along with reduction of CV events by 16% [215]. In the PREDIMED study, hsCRP decreased by 50 and 40% in the EVOO and nuts groups compared with the control group [6, 198]. The magnitude of changes in hsCRP and CV events were numerically greater in the PREDIMED study than in the stain trials. These data indicate that the diet interventions have resulted in substantial improvement of vascular inflammation resulting in 30% CV event reduction. The mechanism(s) responsible for stabilization of vascular inflammation with the Mediterranean diet remains still unclear.

How about the magnitude of the well-known antioxidant effects of EVOO and nuts in the two Mediterranean diet intervention groups? The difference in amounts of polyphenol, a representative antioxidant in EVOO and nuts in the intervention groups vs. the control group, is estimated to be around 10 mg/day. Polyphenol is very abundant in other foods, such as red wine (200–400 mg/100 ml), beans (500– 1500 mg/100 g), vegetables, and fruits, and more than 1000 mg/day is usually consumed in a typical dinner on the Mediterranean diet. Furthermore, although laboratory experiments have shown beneficial effects of many antioxidants (vitamin A, C, E, NAC, polyphenol) on vascular atherosclerosis, results of human studies have generally been negative [216]. All of these data strongly suggest that the anti-oxidant effects of EVOO or nuts alone is unlikely to explain reduction in CV events observed in the two Mediterranean diet groups in the PREDIMED study.

important question [79]. Replacing about 1 teaspoon per day (5 g/day) of margarine, butter, or mayonnaise, or daily fat with an equivalent amount of olive oil was associated with a 5–7% lower risk for total CV disease. When olive oil was compared with other plant-derived oils, there were no significant associations. Mean intake in the group using the highest amount of olive oil was 12 g/day in this study, not as high as in the Spanish participants of the PREDIMED study at 50 g/day. This study has provided further support for the recommendation to replace saturated fat from animal fat with plant oils, such as olive oil, that contain more MUFA for the

The protocol of the PREDIMED study did not restrict total calorie intake and did not recommend any exercise therapy. Therefore, it was criticized as showing very small beneficial effects on body weight. Although the two Mediterranean diet groups consumed 200–270 kcal more, the incidence of new diabetes was reduced about 50% compared with the control group (10.1, 11 vs. 17.9%, EVOO, nuts vs. control) [221]. If the participants in the PREDIMED study could have received calorie-restricted diet with optimal exercise therapy, then this could have resulted

Currently another study, the PREDIMED-PLUS study, a 6-year, multicenter, randomized clinical trial for the primary prevention of CVD is ongoing [222]. The objectives of this study is to compare an energy-restricted Mediterranean diet plus advice to increase physical activities with a control, energy-unrestricted Mediterranean diet without counseling on physical activities in 6874 older individuals (www. isrctn.com/ISRCTN 89898870). The energy-reduced Mediterranean diet features more restrictive limits for red and processed meats, butter, and carbonated sweetened drinks than an unrestricted Mediterranean diet. Although this is definitely the optimal treatment for overweight or obese individuals, the major challenge is participant adherence. However, initial results from a pilot study in 626 participants showed better adherence of the energy-reduced Mediterranean group [223]. This study is expected to result in more reduction in CV events with further fine-tuning

The two Mediterranean diet intervention studies, the Lyon Heart Diet and PREDIMED studies, have reduced CV events by 72 and 30%, respectively. The magnitude of efficacy of these results are more powerful compared with those in statin trials. CV specialists usually lack the nutrition education to effectively implement diet therapy. In the current era of a shift from disease treatment toward prevention, how can we maintain our knowledge for updated nutritional science to provide best diet therapy to patients? Characteristics of diet therapy should be simple, understandable, and long lasting for many subjects. For this purpose, physicians must keep studying nutritional science, and should be practicing healthy diet life by themselves. A recent study using an online survey has shown that only 20% of cardiologists eat 5 servings of vegetables and fruits per day [3]. Consuming healthy food by themselves will help to more confidently and comfortably recommend appropriate diet therapy to their patients. In contrast to evidence levels in pharmacological therapy, there have been few trustworthy RCTs in nutrition, which thus has created substantial inconsistent understanding of diet therapy at present. In the future, it is by far the most important task for related parties to be

united to build up a foundation of high quality data of nutritional science.

prevention of CV disease in the general population in the US.

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.93261*

in fewer incidence of new patients with diabetes.

of the Mediterranean diet in the future.

**7. Final remarks**

**103**

In human, two cohort studies have shown that there was an inverse association between the dose of olive oil and CV risk [199, 217]. In the EPIC-Spain cohort study, the highest quartile of olive oil consumption (>30 g/day) was associated with a 26% reduction in risk of overall mortality and a 44% reduction in CVD mortality in comparison with non-consumers. For each increase of 10 g/day in olive oil, there was a 7% decreased risk of overall mortality and a 13% decreased risk of CVD mortality. In the PREDIMED study, the highest tertile group of mean intake of total EVOO (56.9 g/day) showed 48% reduced risk of CV mortality compared with those of the lowest tertile (21.4 g) [78]. As in previous study [21], for each 10 g/day increase in EVOO consumption, CV disease and mortality risk decreased by 10 and 7%, respectively, in the PREDIMED study. Results of all these data suggest that more CV benefit is expected for higher intake of EVOO up to 30–60 g/day.

In contrast to olive oil, the beneficial effects of nut consumption on CV disease were not consistently shown in three recent meta-analyses [218–220], whereas significant reduction in LDL cholesterol, and inflammatory and oxidants mediators were consistently reported with nuts consumption. It is important to note that the amount of walnuts consumed in previous trials was relatively large (30–108 g/day), representing 5–25% of total calories. This level of consumption appears to be difficult to maintain in a non-research setting. Recommended daily dose of nuts according to FDA is one ounce (28 g). The average nut consumption was 30 g/day in the nuts group in the PREDIMED study [6, 198]. For the first time, the PREDIMED study clearly showed that relatively small amount of nuts (30 g/day, about 180 kcal) is enough to reduce CV events.

### *6.4.4 Effects of olive oil in the US population and the PREDIMED-PLUS study*

Although the results of the PREDIMED study have highlighted effects of olive oil and nuts, it is of note that CV benefits of olive oil and nuts were seen in conjunction with the other components of the Mediterranean diet. It still remains unclear what are the biological effects of EVOO and nuts that underlie the reduction of CV events. What is more important practically is whether similar effects on reduction in CV events is reproduced with supplements of EVOO and nuts on other types of diets, or whether lower amounts of EVOO and nuts have similar CV benefit as seen in the PREDIMED study.

All the previous studies in this area have been conducted in Mediterranean countries. The effects of olive oil on CV risk have not yet been evaluated in the U.S. population. As shown in **Figure 18**, the consumption of fish, fruit, and vegetables for the US population, important components in Mediterranean-style diet, is in the rage of 25–50% compared with that the participants in the PREDIMED study. Conversely, the consumption of meat for the US population is more than double. The critical question is whether olive oil or nuts can exhibit beneficial effects on CV risk on the background of the western style diet similarly as they have in previous observational, cohort, and RCTs of the Mediterranean diet. The recent pooled analysis from 61,181 women from the Nurses' Health Study and 31,797 men from the Health Professionals Follow-up Study has shown some answer for this

## *Effects and Issues of Diet Fat on Cardiovascular Metabolism DOI: http://dx.doi.org/10.5772/intechopen.93261*

1500 mg/100 g), vegetables, and fruits, and more than 1000 mg/day is usually consumed in a typical dinner on the Mediterranean diet. Furthermore, although laboratory experiments have shown beneficial effects of many antioxidants (vitamin A, C, E, NAC, polyphenol) on vascular atherosclerosis, results of human studies have generally been negative [216]. All of these data strongly suggest that the anti-oxidant effects of EVOO or nuts alone is unlikely to explain reduction in CV events observed in the two Mediterranean diet groups in the PREDIMED study. In human, two cohort studies have shown that there was an inverse association between the dose of olive oil and CV risk [199, 217]. In the EPIC-Spain cohort study, the highest quartile of olive oil consumption (>30 g/day) was associated with a 26% reduction in risk of overall mortality and a 44% reduction in CVD mortality in comparison with non-consumers. For each increase of 10 g/day in olive oil, there was a 7% decreased risk of overall mortality and a 13% decreased risk of CVD mortality. In the PREDIMED study, the highest tertile group of mean intake of total EVOO (56.9 g/day) showed 48% reduced risk of CV mortality compared with those of the lowest tertile (21.4 g) [78]. As in previous study [21], for each 10 g/day increase in EVOO consumption, CV disease and mortality risk decreased by 10 and 7%, respectively, in the PREDIMED study. Results of all these data suggest that more CV benefit is expected for higher intake of EVOO up to 30–60 g/day.

In contrast to olive oil, the beneficial effects of nut consumption on CV disease were not consistently shown in three recent meta-analyses [218–220], whereas significant reduction in LDL cholesterol, and inflammatory and oxidants mediators were consistently reported with nuts consumption. It is important to note that the amount of walnuts consumed in previous trials was relatively large (30–108 g/day), representing 5–25% of total calories. This level of consumption appears to be difficult to maintain in a non-research setting. Recommended daily dose of nuts according to FDA is one ounce (28 g). The average nut consumption was 30 g/day

in the nuts group in the PREDIMED study [6, 198]. For the first time, the PREDIMED study clearly showed that relatively small amount of nuts (30 g/day,

*6.4.4 Effects of olive oil in the US population and the PREDIMED-PLUS study*

oil and nuts, it is of note that CV benefits of olive oil and nuts were seen in conjunction with the other components of the Mediterranean diet. It still remains unclear what are the biological effects of EVOO and nuts that underlie the reduction of CV events. What is more important practically is whether similar effects on reduction in CV events is reproduced with supplements of EVOO and nuts on other types of diets, or whether lower amounts of EVOO and nuts have similar CV benefit

Although the results of the PREDIMED study have highlighted effects of olive

All the previous studies in this area have been conducted in Mediterranean countries. The effects of olive oil on CV risk have not yet been evaluated in the U.S. population. As shown in **Figure 18**, the consumption of fish, fruit, and vegetables for the US population, important components in Mediterranean-style diet, is in the rage of 25–50% compared with that the participants in the PREDIMED study. Conversely, the consumption of meat for the US population is more than double. The critical question is whether olive oil or nuts can exhibit beneficial effects on CV risk on the background of the western style diet similarly as they have in previous observational, cohort, and RCTs of the Mediterranean diet. The recent pooled analysis from 61,181 women from the Nurses' Health Study and 31,797 men from

the Health Professionals Follow-up Study has shown some answer for this

about 180 kcal) is enough to reduce CV events.

as seen in the PREDIMED study.

*New Insights into Metabolic Syndrome*

**102**

important question [79]. Replacing about 1 teaspoon per day (5 g/day) of margarine, butter, or mayonnaise, or daily fat with an equivalent amount of olive oil was associated with a 5–7% lower risk for total CV disease. When olive oil was compared with other plant-derived oils, there were no significant associations. Mean intake in the group using the highest amount of olive oil was 12 g/day in this study, not as high as in the Spanish participants of the PREDIMED study at 50 g/day. This study has provided further support for the recommendation to replace saturated fat from animal fat with plant oils, such as olive oil, that contain more MUFA for the prevention of CV disease in the general population in the US.

The protocol of the PREDIMED study did not restrict total calorie intake and did not recommend any exercise therapy. Therefore, it was criticized as showing very small beneficial effects on body weight. Although the two Mediterranean diet groups consumed 200–270 kcal more, the incidence of new diabetes was reduced about 50% compared with the control group (10.1, 11 vs. 17.9%, EVOO, nuts vs. control) [221]. If the participants in the PREDIMED study could have received calorie-restricted diet with optimal exercise therapy, then this could have resulted in fewer incidence of new patients with diabetes.

Currently another study, the PREDIMED-PLUS study, a 6-year, multicenter, randomized clinical trial for the primary prevention of CVD is ongoing [222]. The objectives of this study is to compare an energy-restricted Mediterranean diet plus advice to increase physical activities with a control, energy-unrestricted Mediterranean diet without counseling on physical activities in 6874 older individuals (www. isrctn.com/ISRCTN 89898870). The energy-reduced Mediterranean diet features more restrictive limits for red and processed meats, butter, and carbonated sweetened drinks than an unrestricted Mediterranean diet. Although this is definitely the optimal treatment for overweight or obese individuals, the major challenge is participant adherence. However, initial results from a pilot study in 626 participants showed better adherence of the energy-reduced Mediterranean group [223]. This study is expected to result in more reduction in CV events with further fine-tuning of the Mediterranean diet in the future.
