**6.4 Protocol and results**

The second RCT of the Mediterranean diet was the PREDIMED study [6]. There are several distinctions between the Lyon Diet Heart and PREDIMED studies. First, the PREDIMED study had much more participants (605 vs. 7447 subjects). Second, the Lyon Diet Heart study enrolled subjects with a history of acute myocardial infarction, and by contrast, the target is primary prevention with a high CVD risk in the PREDIMED study. Third, the Mediterranean diets were substantially different in the two studies. In the Lyon Diet Heart study, the Mediterranean diet was enriched with alpha-linolenic acid (n-3 PUFA), because margarine was provided freely in substitution for butter and cream, but not olive oil, and, by contrast, in the PREDIMED study, the diet for participants assigned to be the Mediterranean groups was loaded with extra-virgin olive oil or nuts. Finally, regarding the fat content in the control group diet, a high-fat diet was used in the Lyon Diet Heart and a low-fat diet in the PREDIMED study.

After the original version of the PREDIMED study was protocol was published in 1993 [198], statistical issues and randomization errors had been corrected, and then a revised version was published in 2018 [6]. Participants were randomized into one of three interventions: Mediterranean diet supplemented with extra-virgin olive oil (EVOO, a minimum of 50 ml/day for participants), or Mediterranean diet supplemented with nuts (30 g/day: 15 g walnuts, 7.5 g almonds and 7.5 g hazelnuts) or control diet (advice to follow a low-fat diet). The reasons for recommending EVOO was that the content of polyphenol is quite variable among olive oils, and that EVOO has reduced CV events to a greater extent compared with non-EVOO (HR 0.84 vs. 0.97) [199]. All participants were Spanish people living in the Mediterranean area. Olive oil is a rich source of MUFA (usually more than 70% of all fat) as well as phenolic antioxidants. Walnuts contain much more PUFA (n-3: 14%, n-6: 58%) than MUFA (14%) compared with EVOO (PUFA: 13%, MUFA: 70% or more). The other half of the nut allowance was almonds and hazelnuts, both rich in MUFA (80%) and polyphenols. Thus, although having the same general food pattern as the Mediterranean diet, the EVOO group was enriched in MUFA and polyphenols and the nuts group was enriched in MUFA and (n-3, n-6) PUFA as well as polyphenols. late to change dietary habits to improve CV health. It should be stressed that the two Mediterranean diets decreased systolic blood pressure by 5–6 mmHg, LDL- cholesterol by 5% or less, and fasting blood glucose by 2–4 md/dl, and that these small changes of risk factors alone can hardly explain the very early and significant 30%

*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

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

*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].*

risk reduction of the primary end point.

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

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

diseases (**Figure 15**).

**Figure 15.**

**97**

**Figure 14** shows the daily intake of EVOO and nuts in the three groups in the PREDIMED study compared with that of Japanese aged of >60 y/o in 2015. Consumption of EVOO and nuts was very high in subjects who followed the Mediterranean diet with EVOO or nuts, respectively. It is noteworthy that even the control group had much higher consumption of EVOO than in Japanese (data on average consumption is not available; however, based on amounts of import and domestic production of olive oil in Japan, this value is very likely to be in the low single digits) and in the US population (4.2 g/day/person) [79]. Consumption of nuts was also high in the two Mediterranean groups and substantially higher in the control lowfat group than in Japanese, and probably in Americans, because according to statistical data in a US national survey in 2009–2010, 63.3% of men and 60.5% of women in the US did not consume any nuts on a given day [200]. These data indicate that all participants including those in the control cohort in this study had, to some extent, Mediterranean-style diet.

The primary endpoint (MI, stroke, and CV death) was significantly reduced, with an adjusted hazard ratio of 0.69 (CI, 0.53–0.91) for the EVOO group and 0.72 (9CI, 0.54–0.95) for the nuts group, as compared with the control diet (**Figure 2**). The Kaplan-Meier curves for the primary end point diverged soon after the trial started. The average age of participants in this study was 67 years old and a subgroup analysis showed that CV events were reduced by 30% in people more than 70 years old, similar to the value in younger people, indicating that it is never too

#### **Figure 14.**

*Daily consumption of olive oil and nuts in the PREDIMED study at the end of the study compared with those in Japanese in their 60s [6, 140].*

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

After the original version of the PREDIMED study was protocol was published in 1993 [198], statistical issues and randomization errors had been corrected, and then a revised version was published in 2018 [6]. Participants were randomized into one of three interventions: Mediterranean diet supplemented with extra-virgin olive oil (EVOO, a minimum of 50 ml/day for participants), or Mediterranean diet supplemented with nuts (30 g/day: 15 g walnuts, 7.5 g almonds and 7.5 g hazelnuts) or control diet (advice to follow a low-fat diet). The reasons for recommending EVOO was that the content of polyphenol is quite variable among olive oils, and that EVOO has reduced CV events to a greater extent compared with non-EVOO (HR 0.84 vs. 0.97) [199]. All participants were Spanish people living in the Mediterranean area. Olive oil is a rich source of MUFA (usually more than 70% of all fat) as well as phenolic antioxidants. Walnuts contain much more PUFA (n-3: 14%, n-6: 58%) than MUFA (14%) compared with EVOO (PUFA: 13%, MUFA: 70% or more). The other half of the nut allowance was almonds and hazelnuts, both rich in MUFA (80%) and polyphenols. Thus, although having the same general food pattern as the Mediterranean diet, the EVOO group was enriched in MUFA and polyphenols and the nuts group was enriched in MUFA and (n-3, n-6) PUFA as well as polyphenols. **Figure 14** shows the daily intake of EVOO and nuts in the three groups in the PREDIMED study compared with that of Japanese aged of >60 y/o in 2015. Consumption of EVOO and nuts was very high in subjects who followed the Mediterranean diet with EVOO or nuts, respectively. It is noteworthy that even the control group had much higher consumption of EVOO than in Japanese (data on average consumption is not available; however, based on amounts of import and domestic production of olive oil in Japan, this value is very likely to be in the low single digits) and in the US population (4.2 g/day/person) [79]. Consumption of nuts was also high in the two Mediterranean groups and substantially higher in the control lowfat group than in Japanese, and probably in Americans, because according to statistical data in a US national survey in 2009–2010, 63.3% of men and 60.5% of women in the US did not consume any nuts on a given day [200]. These data indicate that all participants including those in the control cohort in this study had, to some

The primary endpoint (MI, stroke, and CV death) was significantly reduced, with an adjusted hazard ratio of 0.69 (CI, 0.53–0.91) for the EVOO group and 0.72 (9CI, 0.54–0.95) for the nuts group, as compared with the control diet (**Figure 2**). The Kaplan-Meier curves for the primary end point diverged soon after the trial started. The average age of participants in this study was 67 years old and a subgroup analysis showed that CV events were reduced by 30% in people more than 70 years old, similar to the value in younger people, indicating that it is never too

*Daily consumption of olive oil and nuts in the PREDIMED study at the end of the study compared with those in*

extent, Mediterranean-style diet.

*New Insights into Metabolic Syndrome*

**Figure 14.**

**96**

*Japanese in their 60s [6, 140].*

late to change dietary habits to improve CV health. It should be stressed that the two Mediterranean diets decreased systolic blood pressure by 5–6 mmHg, LDL- cholesterol by 5% or less, and fasting blood glucose by 2–4 md/dl, and that these small changes of risk factors alone can hardly explain the very early and significant 30% risk reduction of the primary end point.
