**3. Effects of dietary components on blood lipid**

Major diet factors that affect blood LDL cholesterol include calories, three major nutrients (protein, fat, and carbohydrate), fat type, fiber, food sterol, etc. By modifying these factors, a Mediterranean diet and DASH diet are intended to improve cardiometabolic risk factors. These two diets ranked as top diets according to a US News and World report in 2018. They share many aspects beneficial for maintaining health. Especially, intake of healthy fats such as olive oil rather than saturated fatty acids (SFA) is a mainstay in the Mediterranean diet. The basic principle in diet is not to eat too much or too little of one component of foods, but rather to eat good balance of foods. Trials that change a single dietary factor have an advantage that makes them suitable to clarify the contribution of some specific component on diet parameters. Studies to evaluate effects of SFA or salt on LDL cholesterol or blood pressure are good examples. By contrast, the degree of efficacy and durability are, generally, greater in trials changing the entire diet style. Thus, this type of intervention trial, such as Mediterranean vs. typical western-style diet, is more suitable as a hard endpoint study.

#### **3.1 Calories and plasma lipids**

Optimization of intake of total calories is a foundation of maintenance of healthy life. Reducing food intake to induce undernutrition extends the life spans of multiple species, ranging from single-celled organisms to mammals [7]. By contrast, whether calorie restriction decreases CV events in human remains unclear except in bariatric surgery. The LookAHEAD study examined whether an intensive lifestyle intervention for weight loss for 10 years would decrease CV morbidity and

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

like to focus on the role of fatty acids with special relation on their effects on blood

In Japan, formal professional dietary intervention is not so common. Generally, registered dietitians provide recommendations for meals according to the patients' disease conditions from medical, nutritional, and hygienic aspects. Statistical data from the two university hospitals in Tokyo indicate that the number of dietary referrals from physicians for patients with dyslipidemia is less than 5% of total cases, which is in sharp contrast to those with diabetes at more than 50% [4, 5]. There are several reasons to explain the fewer consultations, including scanty data in diet intervention trials in Japanese population, weak recognition of effectiveness of diet therapy for dyslipidemia among physicians, and most importantly, patients find it easier to take statins than follow diet therapy. Compared with LDL cholesterol reduction by diet therapy, statins are more powerful, with up to 50% reduction in LDL cholesterol. Results in the PREDIMED study have clearly shown that a Mediterranean diet enriched with extra-virgin olive oil or nuts reduced CV events by 30% [6]. This magnitude of CV event reduction was compatible with those of statin trials, and importantly, it was achieved with small changes in LDL cholesterol, blood pressure, and blood glucose. The data in the PREDIMED study have clearly shed light on distinctive features of the power of diet therapy, which affects many aspects of not only classical risk factors but also other unknown biological

Major diet factors that affect blood LDL cholesterol include calories, three major

Optimization of intake of total calories is a foundation of maintenance of healthy life. Reducing food intake to induce undernutrition extends the life spans of multiple species, ranging from single-celled organisms to mammals [7]. By contrast, whether calorie restriction decreases CV events in human remains unclear except in bariatric surgery. The LookAHEAD study examined whether an intensive lifestyle intervention for weight loss for 10 years would decrease CV morbidity and

nutrients (protein, fat, and carbohydrate), fat type, fiber, food sterol, etc. By modifying these factors, a Mediterranean diet and DASH diet are intended to improve cardiometabolic risk factors. These two diets ranked as top diets according to a US News and World report in 2018. They share many aspects beneficial for maintaining health. Especially, intake of healthy fats such as olive oil rather than saturated fatty acids (SFA) is a mainstay in the Mediterranean diet. The basic principle in diet is not to eat too much or too little of one component of foods, but rather to eat good balance of foods. Trials that change a single dietary factor have an advantage that makes them suitable to clarify the contribution of some specific component on diet parameters. Studies to evaluate effects of SFA or salt on LDL cholesterol or blood pressure are good examples. By contrast, the degree of efficacy and durability are, generally, greater in trials changing the entire diet style. Thus, this type of intervention trial, such as Mediterranean vs. typical western-style diet,

lipids and cardiovascular events.

*New Insights into Metabolic Syndrome*

**2. Incidence of formal diet consultation in Japan**

processes modulating the pathophysiology of diseases.

**3. Effects of dietary components on blood lipid**

is more suitable as a hard endpoint study.

**3.1 Calories and plasma lipids**

**70**

mortality among 5145 obese patients with type 2 diabetes [8]. The intensive lifestyle intervention was aimed at achieving and maintaining weight loss of at least 7% by focusing on reduced caloric intake (calorie goal of 1200–1800 kcal per day, restricting fat calories to <30%) and increased physical activity. Although greater reductions in all CV risk factors was observed in the intervention group than in the control group, the rate of CV mortality and myocardial infarction was not different (**Figure 1a**). Rebound of weight in the intervention group (**Figure 1b**) increased the statin use in the control group, and the lack of instruction about saturated and unsaturated fats is suggested for reasons of the negative results in this study. Five years later, in the PREDIMED study [6], a Mediterranean diet loaded with high content of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUSA) without calorie restriction and exercise recommendation reduced CV events significantly approximately by 30% compared to the control low-fat diet group (**Figure 2**). It is noteworthy that the reduction of CV events occurred in the Mediterranean diet groups that consumed about 200–250 kcal higher calories as fat than in the control group. The data of these two studies [6, 8] have strongly suggested that intake of unsaturated fat is more effective than a low-fat, low-calorie diet for reduction of CV events. However, weight reduction by the low-fat diet in the LookAHEAD study has brought in important health benefits other than CV event reduction. Patients in the low-fat group were more likely to have a partial remission of diabetes during the first 4 years of the trial [9], more improvement in terms of reductions in urinary incontinence [10], sleep apnea [11], and depression [12] and improvements in quality of life [12], physical functioning [13], and mobility [14] than were those in the control group. Calorie restriction by diet is effective in reducing body weight in obese subjects. Therefore, diet therapy should be individualized dependent on the treatment goal, patient's characteristics such as underlying disease, BMI, and daily diet habits.

The difference in LDL cholesterol in the two groups in the LookAHEAD study was 1 mg/dl at the end of study [8]. By contrast, the effects of bariatric surgery on plasma LDL cholesterol and CV events have been clearer, because bariatric surgery reduces body weight to a greater extent, 20–40% from baseline. In a study of registry data in Sweden, LDL cholesterol was reduced approximately 40% associated with a 30% decrease in all-cause mortality 15 years after the surgery [15].

#### **Figure 1.**

*(a) Kaplan-Meier curves of the primary end point in look AHEAD study [8]. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. (b) Changes in body weight in the look AHEAD study [8].*

dyslipidemia, and insulin resistance. Thus, the restriction of carbohydrates results in not only weight reduction but also improvement of dyslipidemia and insulin

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

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

Evidence has shown that under the controlled condition, both of the total calorie and the type of carbohydrate can affect body weight positively or negatively and plasma lipid profile as well. Even when receiving a high-calorie diet with increased fat content, obese subjects (BMI > 30) could reduce more weight with a low refined carbohydrate diet, compared with high-refined carbohydrate, low-fat, and energyrestricted diets in 1 year, based on a meta-analysis [22] and a 2-year intervention study [23]. One general consensus is that because refined carbohydrates are associated with high glycemic index, limiting intake of refined carbohydrates improves postprandial hyperglycemia, resulting in lower insulin release as well as decrease in body weight. In the period 1980–1990, calorie restriction by eating low-fat food was strongly recommended in many places in the US. The big issue of this nation-wide trend of low-fat diet was that most people were eating food containing refined carbohydrates with high glycemic index instead of fatty food (**Figure 3a**). An obesity epidemic in this period in the US coincided with the low-fat campaign. During the epidemic, the rate of obesity was almost triple, and the rate of diabetes doubled compared with three decades earlier [24, 25] (**Figure 3b**). It is ironic that people lost more money (low-fat food was generally more expensive) and gained

In the OmniHeart study [26], the recommendation of fructose-sweetened beverages defined in the protocol could be one reason why the high-carbohydrate diets group showed the worst cardiometablic effects. Because of recent data showing fructose has worse effects on cardiometabolic risk markers than any other carbohydrates, the conclusion from the OmniHeart study cannot be extrapolated to all carbohydrates. Beverage makers in the US used to actively campaign by insisting that "over calories" was the reason for obesity rather than the type of sweetened carbohydrates included in beverages. However, each mono- and disaccharide has different effects on body metabolism. In a feeding study in overweight subjects, comparison of drinking glucose- or fructose-sweetened beverages for 10 weeks showed that after fructose intake, fasting plasma glucose, insulin levels, and visceral adipose volume increased with a decrease in insulin sensitivity compared with the intake of glucose-sweetened beverages [27]. Glucose metabolism in blood and liver

is tightly regulated by insulin and glucagon. On the other hand, because

*(a) Changes in average fat and carbohydrate caloric consumption in adults from 1965 to 2011 [25].*

*(b) Changes in average BMI in adults from 1965 to 2011 [25].*

fructokinase does not play any role in the regulation of accumulation of fructose in the liver, the concentration of fructose in blood and liver increases with oral intake of fructose, which is called unregulated fructose uptake [28, 29]. Consequently,

resistance.

**Figure 3.**

**73**

weight while eating a low-fat diet.

#### **Figure 2.**

*Kaplan-Meier curves of the primary end point in the PREDIMED study [6]. The primary end point is a composite of acute myocardial infarction, stroke, and death from cardiovascular causes.*

Bariatric surgery has also resulted in the remission of concomitant risk factors. A US cohort study in 2458 obese subjects showed that after gastric bypass surgery, the remission rate of was 62% for dyslipidemia, 38% for hypertension, and 68% for diabetes [16]. More than 150,000 bariatric surgeries had been performed in the US in 2013, which were almost one third of operations performed globally in 2013 [17]. Data from the bariatric surgery clearly indicate that it is important to provide substantial and sustainable body weight reduction for obese subjects in order to decrease CV events. If patients have difficulty maintaining calorie restriction, emerging evidence has been accumulating that a calorie-unlimited but well-balanced diet with MUFA/PUFA is a good choice.

#### **3.2 Data and issues of low-carbohydrate vs. low-fat diet**

In order to prevent muscle and bone wasting in aged people with sarcopenia, many scientific guidelines recommend that protein intake should be at least 1 g/kg/ day of standard body weight unless renal function is abnormal. Thus, in limiting dietary calories, the requirement for protein usually cannot be changed. Much controversial data have been reported regarding whether the restriction of carbohydrate or fat is better in subjects with obesity or diabetes. Reduced carbohydrate diets are defined as having carbohydrate intake below the Dietary Guidelines for Americans (DGA) recommendation (45–65% of total energy intake). Regarding effects on body weight, several previous systematic reviews and meta-analyses [18–20] have shown that low-carbohydrate high-fat diets are just as effective, if not more so, than low-fat high-carbohydrate diets. Excess energy from carbohydrates stimulates the induction of lipogenesis in the liver via SREBP-1, resulting in accumulation of triglycerides (TG) in many organs [21], which induces obesity,

dyslipidemia, and insulin resistance. Thus, the restriction of carbohydrates results in not only weight reduction but also improvement of dyslipidemia and insulin resistance.

Evidence has shown that under the controlled condition, both of the total calorie and the type of carbohydrate can affect body weight positively or negatively and plasma lipid profile as well. Even when receiving a high-calorie diet with increased fat content, obese subjects (BMI > 30) could reduce more weight with a low refined carbohydrate diet, compared with high-refined carbohydrate, low-fat, and energyrestricted diets in 1 year, based on a meta-analysis [22] and a 2-year intervention study [23]. One general consensus is that because refined carbohydrates are associated with high glycemic index, limiting intake of refined carbohydrates improves postprandial hyperglycemia, resulting in lower insulin release as well as decrease in body weight. In the period 1980–1990, calorie restriction by eating low-fat food was strongly recommended in many places in the US. The big issue of this nation-wide trend of low-fat diet was that most people were eating food containing refined carbohydrates with high glycemic index instead of fatty food (**Figure 3a**). An obesity epidemic in this period in the US coincided with the low-fat campaign. During the epidemic, the rate of obesity was almost triple, and the rate of diabetes doubled compared with three decades earlier [24, 25] (**Figure 3b**). It is ironic that people lost more money (low-fat food was generally more expensive) and gained weight while eating a low-fat diet.

In the OmniHeart study [26], the recommendation of fructose-sweetened beverages defined in the protocol could be one reason why the high-carbohydrate diets group showed the worst cardiometablic effects. Because of recent data showing fructose has worse effects on cardiometabolic risk markers than any other carbohydrates, the conclusion from the OmniHeart study cannot be extrapolated to all carbohydrates. Beverage makers in the US used to actively campaign by insisting that "over calories" was the reason for obesity rather than the type of sweetened carbohydrates included in beverages. However, each mono- and disaccharide has different effects on body metabolism. In a feeding study in overweight subjects, comparison of drinking glucose- or fructose-sweetened beverages for 10 weeks showed that after fructose intake, fasting plasma glucose, insulin levels, and visceral adipose volume increased with a decrease in insulin sensitivity compared with the intake of glucose-sweetened beverages [27]. Glucose metabolism in blood and liver is tightly regulated by insulin and glucagon. On the other hand, because fructokinase does not play any role in the regulation of accumulation of fructose in the liver, the concentration of fructose in blood and liver increases with oral intake of fructose, which is called unregulated fructose uptake [28, 29]. Consequently,

#### **Figure 3.**

*(a) Changes in average fat and carbohydrate caloric consumption in adults from 1965 to 2011 [25]. (b) Changes in average BMI in adults from 1965 to 2011 [25].*

Bariatric surgery has also resulted in the remission of concomitant risk factors. A US cohort study in 2458 obese subjects showed that after gastric bypass surgery, the remission rate of was 62% for dyslipidemia, 38% for hypertension, and 68% for diabetes [16]. More than 150,000 bariatric surgeries had been performed in the US in 2013, which were almost one third of operations performed globally in 2013 [17]. Data from the bariatric surgery clearly indicate that it is important to provide substantial and sustainable body weight reduction for obese subjects in order to decrease CV events. If patients have difficulty maintaining calorie restriction, emerging evidence has been accumulating that a calorie-unlimited but

*Kaplan-Meier curves of the primary end point in the PREDIMED study [6]. The primary end point is a*

*composite of acute myocardial infarction, stroke, and death from cardiovascular causes.*

In order to prevent muscle and bone wasting in aged people with sarcopenia, many scientific guidelines recommend that protein intake should be at least 1 g/kg/ day of standard body weight unless renal function is abnormal. Thus, in limiting dietary calories, the requirement for protein usually cannot be changed. Much controversial data have been reported regarding whether the restriction of carbohydrate or fat is better in subjects with obesity or diabetes. Reduced carbohydrate diets are defined as having carbohydrate intake below the Dietary Guidelines for Americans (DGA) recommendation (45–65% of total energy intake). Regarding effects on body weight, several previous systematic reviews and meta-analyses [18–20] have shown that low-carbohydrate high-fat diets are just as effective, if not more so, than low-fat high-carbohydrate diets. Excess energy from carbohydrates stimulates the induction of lipogenesis in the liver via SREBP-1, resulting in accumulation of triglycerides (TG) in many organs [21], which induces obesity,

well-balanced diet with MUFA/PUFA is a good choice.

**Figure 2.**

*New Insights into Metabolic Syndrome*

**72**

**3.2 Data and issues of low-carbohydrate vs. low-fat diet**

accumulated fructose in the liver stimulates de novo lipogenesis and results in detrimental effects on glucose and lipoprotein metabolism [27].

Because of few reliable RCT, there have been many controversial results when comparing beneficial effects between low-fat and low-carbohydrate diet. It appears that the type of macronutrients replaced for fat or carbohydrate has significant effects on those results. A recent meta-analysis of studies with 432,179 subjects has shown that participants in low (<40%) and high (>70%) carbohydrate consumption groups had greater mortality than in moderate consumption groups, which is consistent with a U-shaped association [30]. The results varied according to the source of macronutrients. Namely, the mortality increased when carbohydrate was replaced with animal-derived fat or protein, and the mortality decreased when the substitutions were plant-based. This indicates that food source can be an important consideration for CV outcomes when one macronutrient is replaced with another macronutrient. It has been hypothesized that diets of lower plant carbohydrate with increased animal protein and fat stimulate inflammation, aging, and oxidative stress. On the contrary, nutrition based on low-carbohydrate and high-fat diet may have anti-inflammatory, anti-oxidative, and anticancer effects. A diet that contains reduced carbohydrate with higher fat or even a ketogenic diet, very low carbohydrate diet (<10% of carbohydrate calorie), slows down cancer growth and proliferation [31, 32]. Before instructing a patient to follow a low-fat or low-carbohydrate diet, clinical factors should be considered, including age, body weight, diet habits, underlying diseases, and kidney function. For example, a 75 y/o obese subject with diabetes who consumes a high-calorie diet with high content of fat from animal origin should decrease animal fat intake to reduce total calories for control of body weight. It makes sense to replace animal-fat with complex carbohydrates rather than plant-based unsaturated fat. This way would protect against the increase in total calories and let the glucose level decrease. If a subject has a history of myocardial infarction, partial substitution of animal fats with MUFA, such as found in olive oil, is another option, because of protection of CV disease by intake of olive oil. By considering many aspects of benefit and harm of carbohydrates and fat in this way, appropriate dietary composition should be individually fine-tuned based on patients' clinical characteristics and treatment goals.

## **3.3 Comparison of guidelines in Japan, the US, and Europe regarding fat content**

By contrast, in of the 2014 ADA guideline [36], lifestyle management by American Heart Association (AHA)/the American College of Cardiology (ACC, 2013) [38], European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS, 2016) [39], and the Dietary Guidelines for Americans 2015–2020 [40], the upper limit in fat calories has been actually dropped, and they describe that it is advisable to determine it on an individual basis along with maintaining whole calories. Each of these guidelines stresses quality of fat rather than the total quantity of fat intake. There are a few important considerations for this major change. First, many people tend to often eat more refined carbohydrates as replacement for fat, and previous data have not shown clearly that this would reduce CV mortality and motility. A high-fat diet reduces body weight more than a high-refined carbohydrate diet [22, 23], which favors abandoning the upper limit of total fat intake from many guidelines. Second, limiting overall fat intake habitually carries the potential risk of reducing consumption of "good fat" such as MUFA/PUFA [36, 38–40]. All

**Atherosclerosis/dyslipidemia Diabetes**

Total fat 20–25% N/A<sup>a</sup> N/R<sup>b</sup> 20–30% N/R<sup>c</sup> 25–35% N/R MUFA N/A<sup>d</sup> N/A<sup>d</sup> N/A N/A N/A<sup>e</sup> <10% N/A<sup>d</sup> PUFA N/A<sup>d</sup> N/A<sup>d</sup> <10%<sup>e</sup> N/A N/A <20% N/A<sup>d</sup>

SFA 4.5–7% <5–6% <7% <7% <10% <7% <10% Trans fat <1% ↓<sup>i</sup> <1% ↓<sup>i</sup> ↓<sup>i</sup> <1% ↓<sup>i</sup> Cholesterol <200 mg N/A<sup>j</sup> <300 mg <300 mg <300 mg <200 mg N/A<sup>j</sup> *N/A: not available; N/R: no restriction; MUFA: monounsaturated fatty acids; and PUFA: polyunsaturated fatty*

*No restriction of fat intake, which is dependent upon individual preferences. However, fat intakes at >35% of calories*

*No restriction of fat intake, inconclusive for an ideal amount of total fat intake for people with diabetes; therefore,*

*Intake of n-6 PUFAs should be limited to 10% of the energy intake in order to minimize the risk of lipid peroxidation*

*Recommend intake of fish. Increase in n-3 fat decreases plasma TG level with potential beneficial effects on CV events.*

*Not stated on intake of mono- and polyunsaturated fat. However, there are comments of improvement of LDL*

*Recommend intake of fish. Increase in n-3 fat decreases plasma TG level. Unknown for reduction of CV events.*

*Recommend intake of fish. However, increase n-3 fat has no effects on prevention of diabetes and on CV events in*

**JDS (2016)**

↑<sup>g</sup> ↑<sup>h</sup> >Two

**ADA (2014)**

times/week

**AACE (2013)**

>Two times/week

**USDA (2015)**

>8 oz/ week

**ESC/EAS (2016)**

**JAS (2017)**

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

Fish (n-3) ↑<sup>f</sup> >Two

*acids. a*

*c*

*d*

*e*

*f*

*g*

*h*

*j*

*diabetes. i*

**Table 1.**

*No upper limit.*

**AHA/ACC (2013)**

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

times/week

*Recommendation for Mediterranean diet which usually has 32–35% as fat calorie. <sup>b</sup>*

*goals should be individualized. Fat quality appears to be far more important than quantity.*

*Recommendations for intake of fat and cholesterol-related nutrients in major guidelines.*

*are generally associated with increased intakes of both saturated fat and calories.*

*of plasma lipoproteins and to avoid any clinically relevant HDL-C decrease.*

*No upper limit defined. However, should decrease as much as possible.*

*cholesterol by substitution of SFA with MUSA or PUFA.*

the guidelines have quoted data in the PREDIMED study, where a calorie-

high-quality fat in the diet.

**75**

unlimited, fat-unrestricted Mediterranean diet reduced CV events about 30% compared with a low-fat diet [6]. It is noteworthy that fat calories in the Mediterranean intervention group was exceeded 40% in the PREDIMED study. The important message in removing the upper limit for fat calories from these guidelines is that to maintain consumption of an appropriate level of calories, one must include healthy

**Table 1** summarizes comparison of recommendations about dietary fat in several key scientific societies in the US, Europe, and Japan. Calorie intake from fat is restricted to 20–30% in guidelines of Ministry of Health, Labour and Welfare (MHLW) of Japan [33], Japanese Diabetes Societies (JDS) [34], and Atherosclerosis Societies (JAS) [35]. This value of 30% is classified as low-fat diet as defined by the 2014 the American Diabetes Association (ADA) guideline [36]. There are several reasons why restriction of calories from fat still remains in these recommendations in Japan. First, the LDL cholesterol level in Japanese is steadily increasing recently and at present it is higher among Japanese females than in American females [37]. A high-fat diet generally increases intake of SFA, resulting in increases in LDL cholesterol. Second, BMI in Japanese people is lower than in Caucasians. It is well known that thin Asian people are prone to develop diabetes with a mild increase in body weight. Therefore, because increases in fat calories are usually associated with increases in total calories and subsequently in body weight, restricting fat calories is often helpful to prevent worsening in blood glucose in diabetic subjects.


*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

Cholesterol <200 mg N/A<sup>j</sup> <300 mg <300 mg <300 mg <200 mg N/A<sup>j</sup> *N/A: not available; N/R: no restriction; MUFA: monounsaturated fatty acids; and PUFA: polyunsaturated fatty acids.*

SFA 4.5–7% <5–6% <7% <7% <10% <7% <10% Trans fat <1% ↓<sup>i</sup> <1% ↓<sup>i</sup> ↓<sup>i</sup> <1% ↓<sup>i</sup>

*a Recommendation for Mediterranean diet which usually has 32–35% as fat calorie. <sup>b</sup>*

times/week

*No restriction of fat intake, which is dependent upon individual preferences. However, fat intakes at >35% of calories are generally associated with increased intakes of both saturated fat and calories.*

times/week

times/week

week

*c No restriction of fat intake, inconclusive for an ideal amount of total fat intake for people with diabetes; therefore, goals should be individualized. Fat quality appears to be far more important than quantity.*

*d Not stated on intake of mono- and polyunsaturated fat. However, there are comments of improvement of LDL cholesterol by substitution of SFA with MUSA or PUFA.*

*e Intake of n-6 PUFAs should be limited to 10% of the energy intake in order to minimize the risk of lipid peroxidation of plasma lipoproteins and to avoid any clinically relevant HDL-C decrease.*

*f Recommend intake of fish. Increase in n-3 fat decreases plasma TG level with potential beneficial effects on CV events. g Recommend intake of fish. Increase in n-3 fat decreases plasma TG level. Unknown for reduction of CV events. h*

*Recommend intake of fish. However, increase n-3 fat has no effects on prevention of diabetes and on CV events in diabetes.*

*i No upper limit defined. However, should decrease as much as possible. j No upper limit.*

#### **Table 1.**

accumulated fructose in the liver stimulates de novo lipogenesis and results in

appropriate dietary composition should be individually fine-tuned based on

**3.3 Comparison of guidelines in Japan, the US, and Europe regarding fat**

**Table 1** summarizes comparison of recommendations about dietary fat in several key scientific societies in the US, Europe, and Japan. Calorie intake from fat is restricted to 20–30% in guidelines of Ministry of Health, Labour and Welfare (MHLW) of Japan [33], Japanese Diabetes Societies (JDS) [34], and Atherosclerosis Societies (JAS) [35]. This value of 30% is classified as low-fat diet as defined by the 2014 the American Diabetes Association (ADA) guideline [36]. There are several reasons why restriction of calories from fat still remains in these recommendations in Japan. First, the LDL cholesterol level in Japanese is steadily increasing recently and at present it is higher among Japanese females than in American females [37]. A high-fat diet generally increases intake of SFA, resulting in increases in LDL cholesterol. Second, BMI in Japanese people is lower than in Caucasians. It is well known that thin Asian people are prone to develop diabetes with a mild increase in body weight. Therefore, because increases in fat calories are usually associated with increases in total calories and subsequently in body weight, restricting fat calories is often helpful to prevent worsening in blood glucose in

patients' clinical characteristics and treatment goals.

**content**

diabetic subjects.

**74**

Because of few reliable RCT, there have been many controversial results when comparing beneficial effects between low-fat and low-carbohydrate diet. It appears that the type of macronutrients replaced for fat or carbohydrate has significant effects on those results. A recent meta-analysis of studies with 432,179 subjects has shown that participants in low (<40%) and high (>70%) carbohydrate consumption groups had greater mortality than in moderate consumption groups, which is consistent with a U-shaped association [30]. The results varied according to the source of macronutrients. Namely, the mortality increased when carbohydrate was replaced with animal-derived fat or protein, and the mortality decreased when the substitutions were plant-based. This indicates that food source can be an important consideration for CV outcomes when one macronutrient is replaced with another macronutrient. It has been hypothesized that diets of lower plant carbohydrate with increased animal protein and fat stimulate inflammation, aging, and oxidative stress. On the contrary, nutrition based on low-carbohydrate and high-fat diet may have anti-inflammatory, anti-oxidative, and anticancer effects. A diet that contains reduced carbohydrate with higher fat or even a ketogenic diet, very low carbohydrate diet (<10% of carbohydrate calorie), slows down cancer growth and proliferation [31, 32]. Before instructing a patient to follow a low-fat or low-carbohydrate diet, clinical factors should be considered, including age, body weight, diet habits, underlying diseases, and kidney function. For example, a 75 y/o obese subject with diabetes who consumes a high-calorie diet with high content of fat from animal origin should decrease animal fat intake to reduce total calories for control of body weight. It makes sense to replace animal-fat with complex carbohydrates rather than plant-based unsaturated fat. This way would protect against the increase in total calories and let the glucose level decrease. If a subject has a history of myocardial infarction, partial substitution of animal fats with MUFA, such as found in olive oil, is another option, because of protection of CV disease by intake of olive oil. By considering many aspects of benefit and harm of carbohydrates and fat in this way,

detrimental effects on glucose and lipoprotein metabolism [27].

*New Insights into Metabolic Syndrome*

*Recommendations for intake of fat and cholesterol-related nutrients in major guidelines.*

By contrast, in of the 2014 ADA guideline [36], lifestyle management by American Heart Association (AHA)/the American College of Cardiology (ACC, 2013) [38], European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS, 2016) [39], and the Dietary Guidelines for Americans 2015–2020 [40], the upper limit in fat calories has been actually dropped, and they describe that it is advisable to determine it on an individual basis along with maintaining whole calories. Each of these guidelines stresses quality of fat rather than the total quantity of fat intake. There are a few important considerations for this major change. First, many people tend to often eat more refined carbohydrates as replacement for fat, and previous data have not shown clearly that this would reduce CV mortality and motility. A high-fat diet reduces body weight more than a high-refined carbohydrate diet [22, 23], which favors abandoning the upper limit of total fat intake from many guidelines. Second, limiting overall fat intake habitually carries the potential risk of reducing consumption of "good fat" such as MUFA/PUFA [36, 38–40]. All the guidelines have quoted data in the PREDIMED study, where a calorieunlimited, fat-unrestricted Mediterranean diet reduced CV events about 30% compared with a low-fat diet [6]. It is noteworthy that fat calories in the Mediterranean intervention group was exceeded 40% in the PREDIMED study. The important message in removing the upper limit for fat calories from these guidelines is that to maintain consumption of an appropriate level of calories, one must include healthy high-quality fat in the diet.

## **3.4 Issues and limitations around nutritional trials**

There have been several limitations of studies in nutritional science. Usually, a nutritional study lacks a double-blind design and a placebo for food. Without a placebo-controlled design, the study can provide no true evidence of either benefit or harm of the intervention. For example, if SFA were replaced by carbohydrate or protein, the isolated effect of SFA would be influenced by the changes in the composition of the other macronutrients to keep the diet calorie constant, which would make the isolated effect of SFA difficult to evaluate. Even in the subcategories of SFA, MUFA, and n-3, n-6 PUFA, there exists clear heterogeneity within each group that contributes to different biological effects. Furthermore, the food content within its SFA can have a significant impact on CV risk. The fermentation of dairy products provides a good example. The content of SFA in cheese is very high (20 g in 100 g of natural cheese compared with 3 g in 100 g of beef sirloin). A 10-year cohort study showed that the consumption of SFA from dairy products was associated with decreased risk of CV disease, and, by contrast, a higher intake of SFA from meat (including red and processed meat and poultry) was associated with greater CV disease risk [41].

of data showing that reducing SFA in food resulted in health benefit by lowering blood LDL cholesterol and CV events in RCT [49, 50], prospective cohort studies [51–53], and epidemiological studies [54]. Based on this evidence, AHA has

recommended to decrease over-consumption of SFA since 1961. On the other hand, one RCT [55], a prospective cohort study [43], and meta-analysis [56] have reported that increases in SFA are not associated with increases in CV events. In the US where both myocardial infarction and consumption of beef are more than triple than that in Japan, whether the consumption of SFA in food results in health problems should be a serious issue [57, 58]. One recent article in the Annals of Internal Medicine in 2019 has concluded that red meat may have little or no effect on CV outcomes and cancer mortality based on low- to very-low-certainty evidence [59]. Just after this publication, roughly 2000 emails, mostly caustic in tone, were sent to the inbox of an editor in the journal as a wave of backlash, including a push from one group attempting to

The message from guidelines in major scientific societies reaches the same conclusion that limiting intake of SFA by replacing with MUFA and PUFA reduces LDL cholesterol and potentially reduces CV diseases. This conclusion was summarized in a position paper by the 2017 AHA presidential advisory board [60], which relied on four core randomized trials [61–64]. Results of a meta-analysis of these four core trials [60] are shown in **Figure 4**. The results showed that lowering calorie from SFA down to 7% and replacing them with vegetable oil rich in PUFA, primarily soybean oil, lowered blood cholesterol by 15% and the incidence of coronary heart disease (CHD) by 29%. The degree of efficacy by cutting this amount of SFA is

Although it has become now widely accepted that the dominant dietary factor involving coronary heart disease is an excessive intake of SFA, recent new evidence has suggested that SFA may play a much less important role in coronary heart disease than was previously believed. As discussed previously, potential biases have been often included in diet studies, and earlier meta-analyses did not sufficiently account for major confounding variables. One study has shown different results in two meta-analyses of collecting only adequately controlled trials from collecting only inadequately controlled trials (**Figure 5**) [66]. These data clearly represent one typical example of difficulty in conducting well-controlled diet trials. The manuscript of the 2017 AHA presidential advisory board [60] that selected the 4 core RCTs may have had potential bias by excluding or including some studies from the

have the guideline retracted even prior to publication.

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

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

*Meta-analysis of core trials on replacing saturated with polyunsaturated fat [60].*

compatible with that of statins [65].

**Figure 4.**

**77**

Under- and over-reporting of dietary intake is common in nutritional studies. In contrast to easily countable items like coffee and sweetened beverages, the percentages of energy from fat and added sugar based on a food frequency questionnaire (FFQ) were underestimated [42]. Regarding longevity of habits of food intake, the protocol design in one cohort study had a diet assessment at baseline and approximately 36,000 participants were followed for 12 years [43]. This is a common type of study, in which a one time-point assessment can predict the occurrence of disease many years later.

The logic behind limiting the intake of SFA is derived from the risk factor model for coronary heart disease (CHD) causality, in which LDL cholesterol is a causal factor for CHD and a diet including SFA increases LDL cholesterol compared with other macronutrients. However, other biomarkers that predict CHD risk more have been proposed such as total cholesterol to HDL cholesterol ratio, small dense LDL cholesterol, apolipoprotein B, and others. Therefore, total CHD risk may be increased with elevations of these biomarkers even if LDL cholesterol does not change after the diet intervention.

Evidence coming from RCT is generally positioned above evidence from cohort studies in the research hierarchy. Findings in diet- and health-related RCTs are not necessarily more reliable than those from well-conducted cohort studies [44]. RCTs sometimes include subjects with underlying diseases and follow them up with a relatively short period. This means substantial limitation to extrapolate findings from RCTs to healthy persons, when CV events occur rarely over many years. Cohort studies also have their own sources of error, especially issues of confounding factors. For example, SFA intake is associated with behaviors indicating lower health consciousness, [45] whereas PUFA intake is either associated with behaviors indicating greater health consciousness [46], or is not related to health consciousness [47]. Therefore, confounding variables also often explain the inconsistent results regarding the replacement of SFA with PUFA for prevention of coronary heart disease. When reading manuscripts in nutritional studies, one must keep in mind these limitations and issues included in the studies.

#### **3.5 Effects of replacement of SFA with PUFA**

A high-SFA diet is quite palatable with weak effect on satiation, which results in potentially overconsumption and obesity [48]. There has been a tremendous amount

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

**3.4 Issues and limitations around nutritional trials**

*New Insights into Metabolic Syndrome*

greater CV disease risk [41].

of disease many years later.

change after the diet intervention.

mind these limitations and issues included in the studies.

**3.5 Effects of replacement of SFA with PUFA**

**76**

There have been several limitations of studies in nutritional science. Usually, a nutritional study lacks a double-blind design and a placebo for food. Without a placebo-controlled design, the study can provide no true evidence of either benefit or harm of the intervention. For example, if SFA were replaced by carbohydrate or protein, the isolated effect of SFA would be influenced by the changes in the composition of the other macronutrients to keep the diet calorie constant, which would make the isolated effect of SFA difficult to evaluate. Even in the subcategories of SFA, MUFA, and n-3, n-6 PUFA, there exists clear heterogeneity within each group that contributes to different biological effects. Furthermore, the food content within its SFA can have a significant impact on CV risk. The fermentation of dairy products provides a good example. The content of SFA in cheese is very high (20 g in 100 g of natural cheese compared with 3 g in 100 g of beef sirloin). A 10-year cohort study showed that the consumption of SFA from dairy products was associated with decreased risk of CV disease, and, by contrast, a higher intake of SFA from meat (including red and processed meat and poultry) was associated with

Under- and over-reporting of dietary intake is common in nutritional studies. In contrast to easily countable items like coffee and sweetened beverages, the percentages of energy from fat and added sugar based on a food frequency questionnaire (FFQ) were underestimated [42]. Regarding longevity of habits of food intake, the protocol design in one cohort study had a diet assessment at baseline and approximately 36,000 participants were followed for 12 years [43]. This is a common type of study, in which a one time-point assessment can predict the occurrence

The logic behind limiting the intake of SFA is derived from the risk factor model for coronary heart disease (CHD) causality, in which LDL cholesterol is a causal factor for CHD and a diet including SFA increases LDL cholesterol compared with other macronutrients. However, other biomarkers that predict CHD risk more have been proposed such as total cholesterol to HDL cholesterol ratio, small dense LDL cholesterol, apolipoprotein B, and others. Therefore, total CHD risk may be increased with elevations of these biomarkers even if LDL cholesterol does not

Evidence coming from RCT is generally positioned above evidence from cohort studies in the research hierarchy. Findings in diet- and health-related RCTs are not necessarily more reliable than those from well-conducted cohort studies [44]. RCTs sometimes include subjects with underlying diseases and follow them up with a relatively short period. This means substantial limitation to extrapolate findings from RCTs to healthy persons, when CV events occur rarely over many years. Cohort studies also have their own sources of error, especially issues of confounding factors. For example, SFA intake is associated with behaviors indicating lower health consciousness, [45] whereas PUFA intake is either associated with behaviors indicating greater health consciousness [46], or is not related to health consciousness [47]. Therefore, confounding variables also often explain the inconsistent results regarding the replacement of SFA with PUFA for prevention of coronary heart disease. When reading manuscripts in nutritional studies, one must keep in

A high-SFA diet is quite palatable with weak effect on satiation, which results in potentially overconsumption and obesity [48]. There has been a tremendous amount of data showing that reducing SFA in food resulted in health benefit by lowering blood LDL cholesterol and CV events in RCT [49, 50], prospective cohort studies [51–53], and epidemiological studies [54]. Based on this evidence, AHA has recommended to decrease over-consumption of SFA since 1961. On the other hand, one RCT [55], a prospective cohort study [43], and meta-analysis [56] have reported that increases in SFA are not associated with increases in CV events. In the US where both myocardial infarction and consumption of beef are more than triple than that in Japan, whether the consumption of SFA in food results in health problems should be a serious issue [57, 58]. One recent article in the Annals of Internal Medicine in 2019 has concluded that red meat may have little or no effect on CV outcomes and cancer mortality based on low- to very-low-certainty evidence [59]. Just after this publication, roughly 2000 emails, mostly caustic in tone, were sent to the inbox of an editor in the journal as a wave of backlash, including a push from one group attempting to have the guideline retracted even prior to publication.

The message from guidelines in major scientific societies reaches the same conclusion that limiting intake of SFA by replacing with MUFA and PUFA reduces LDL cholesterol and potentially reduces CV diseases. This conclusion was summarized in a position paper by the 2017 AHA presidential advisory board [60], which relied on four core randomized trials [61–64]. Results of a meta-analysis of these four core trials [60] are shown in **Figure 4**. The results showed that lowering calorie from SFA down to 7% and replacing them with vegetable oil rich in PUFA, primarily soybean oil, lowered blood cholesterol by 15% and the incidence of coronary heart disease (CHD) by 29%. The degree of efficacy by cutting this amount of SFA is compatible with that of statins [65].

Although it has become now widely accepted that the dominant dietary factor involving coronary heart disease is an excessive intake of SFA, recent new evidence has suggested that SFA may play a much less important role in coronary heart disease than was previously believed. As discussed previously, potential biases have been often included in diet studies, and earlier meta-analyses did not sufficiently account for major confounding variables. One study has shown different results in two meta-analyses of collecting only adequately controlled trials from collecting only inadequately controlled trials (**Figure 5**) [66]. These data clearly represent one typical example of difficulty in conducting well-controlled diet trials. The manuscript of the 2017 AHA presidential advisory board [60] that selected the 4 core RCTs may have had potential bias by excluding or including some studies from the

#### **Figure 5.**

*Forest plot showing pooled RR with 95% CI for the number of total CHD events [66].*

analysis. Notwithstanding apparently consistency of the description in many authoritative guidelines of harmful effects of SFA, some experts are insisting that there have been no solid evidence indicating that the consumption of SFA is related with higher incidence of CV disease [67].

The source and origin of MUFA within a specific diet may explain the inconsistent previous results with MUFA [74]. One huge meta-analysis including 32 cohort studies in 840,000 subjects has shown data that effects of MUFA on CV disease and its mortality varied depending on the different dietary sources of MUFA. Whereas MUFA of mixed animal and vegetable sources per se did not yield any significant effects on major CV outcomes, importantly, significant associations could only be found between higher intake of olive oil and reduced risk of CV events. It is of note that all studies which showed benefit for CV risk were conducted in the Mediterranean nations where extra-virgin olive oil is the most dominant source of this type of fatty acid [75]. The amounts of olive oil in the highest consumption group used in those studies were > 30 g/day in the EPIC cohort (in Spain), 48 g/day in the EPIC cohort in Greece [76], 52 g/day in a case-controlled study in Spain [77], and 56 g/day in the PREDIMED study [78]. Although mean olive oil consumption in the US is increasing, it is still very low at 4.2 g/day in 2010 compared with those in the Mediterranean areas (**Figure 7**) [79]. Another study in Spain has shown clearly different effects on cardiometabolic parameters between olive oil and sunflower oil (11% for MUFA and 60% for PUFA) [80]. With a slight increase in LDL cholesterol in the olive oil group, olive oil improved other risk factors such as glucose, TG, and body weight to a greater extent than in the sunflower oil group. The amount of olive oil in this study was expected to be more than 40 g/day, based on data showing that Spanish diet usually includes olive oil accounting for 18% of calorie intake [81]. All of these findings indicate that a large amount of olive oil (probably > 30 g/day) has distinctive effects compared with other oils from plant or animal origin.

*Estimated percent change in the risk of CHD after isocaloric substitute of SFA (upper half) or refined*

**Figure 6.**

**79**

*carbohydrate (lower half) by other nutrients [73].*

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

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

Along with firm evidence of CV event reduction in two RCTs (Lyon Diet Heart study [82, 83] and PREDIMED [6]), olive oil should be viewed not only as "better" MUFA but also as a nutrient including many biologically active ingredients such as polyphenol. In 2018, the FDA approved a qualified health claim for consuming oils with high levels of oleic acid (major MUFA in olive oils) to reduce risk for coronary heart disease [84]. This new claim allows manufactures of olive oils to state that "supportive but not conclusive scientific evidence" suggest that daily consumption

of one and half tablespoon (20 g) of olive oil may reduce CHD risk.

It seems that one common key message in studies that the overestimated harmful effects of SFA is that other factors (e.g., increased refined carbohydrate/added sugar included in soft drinks, or trans fat; or decreased fish, fruit, and vegetables) play a more role in development of coronary heart disease than SFA [68]. However, previous data of substitution of SFA with PUFA have consistently shown improved blood lipid profile and blood pressure. Furthermore, increased intake of SFA from animal meat and butter generally is accompanied by more consumption of trans fat or other substances with potentially harmful effects on humans. The Mediterranean and DASH diets, which include high amount of MUFA and PUFA with low contents of SFA, have constantly shown health benefits. Based on all these data, as in the authorized opinions, restriction of SFA is a reasonable strategy.

#### **3.6 Effects of replacement of SFA with MUFA**

Compared with PUFA, less data have been available evaluating benefits of MUFA [69]. In human cohort studies, the replacement of SFA with MUFA yielded smaller reduction of LDL cholesterol [70] and incidence of CHD [71–73], compared with PUFA. One huge cohort study in 127,536 subjects combining the Nurses' Health Study and the Health Professionals Follow-up Study has shown that replacing 5% of energy intake from SFAs with equivalent energy intake from PUFA or MUFA was associated with a 25 and 15% lower risk of CHD, respectively (**Figure 6**) [73]. A review of the Cochran database in 2015 has concluded that replacing the energy from SFA with PUFA appears to be a useful strategy and that, by contrast, effects of replacement with MUFA were unclear due to inclusion of only one small trial [69].

#### **Figure 6.**

analysis. Notwithstanding apparently consistency of the description in many authoritative guidelines of harmful effects of SFA, some experts are insisting that there have been no solid evidence indicating that the consumption of SFA is related

*Forest plot showing pooled RR with 95% CI for the number of total CHD events [66].*

authorized opinions, restriction of SFA is a reasonable strategy.

**3.6 Effects of replacement of SFA with MUFA**

only one small trial [69].

**78**

It seems that one common key message in studies that the overestimated harmful effects of SFA is that other factors (e.g., increased refined carbohydrate/added sugar included in soft drinks, or trans fat; or decreased fish, fruit, and vegetables) play a more role in development of coronary heart disease than SFA [68]. However, previous data of substitution of SFA with PUFA have consistently shown improved blood lipid profile and blood pressure. Furthermore, increased intake of SFA from animal meat and butter generally is accompanied by more consumption of trans fat or other substances with potentially harmful effects on humans. The Mediterranean and DASH diets, which include high amount of MUFA and PUFA with low contents of SFA, have constantly shown health benefits. Based on all these data, as in the

Compared with PUFA, less data have been available evaluating benefits of MUFA [69]. In human cohort studies, the replacement of SFA with MUFA yielded smaller reduction of LDL cholesterol [70] and incidence of CHD [71–73], compared with PUFA. One huge cohort study in 127,536 subjects combining the Nurses' Health Study and the Health Professionals Follow-up Study has shown that

replacing 5% of energy intake from SFAs with equivalent energy intake from PUFA

or MUFA was associated with a 25 and 15% lower risk of CHD, respectively (**Figure 6**) [73]. A review of the Cochran database in 2015 has concluded that replacing the energy from SFA with PUFA appears to be a useful strategy and that, by contrast, effects of replacement with MUFA were unclear due to inclusion of

with higher incidence of CV disease [67].

*New Insights into Metabolic Syndrome*

**Figure 5.**

*Estimated percent change in the risk of CHD after isocaloric substitute of SFA (upper half) or refined carbohydrate (lower half) by other nutrients [73].*

The source and origin of MUFA within a specific diet may explain the inconsistent previous results with MUFA [74]. One huge meta-analysis including 32 cohort studies in 840,000 subjects has shown data that effects of MUFA on CV disease and its mortality varied depending on the different dietary sources of MUFA. Whereas MUFA of mixed animal and vegetable sources per se did not yield any significant effects on major CV outcomes, importantly, significant associations could only be found between higher intake of olive oil and reduced risk of CV events. It is of note that all studies which showed benefit for CV risk were conducted in the Mediterranean nations where extra-virgin olive oil is the most dominant source of this type of fatty acid [75]. The amounts of olive oil in the highest consumption group used in those studies were > 30 g/day in the EPIC cohort (in Spain), 48 g/day in the EPIC cohort in Greece [76], 52 g/day in a case-controlled study in Spain [77], and 56 g/day in the PREDIMED study [78]. Although mean olive oil consumption in the US is increasing, it is still very low at 4.2 g/day in 2010 compared with those in the Mediterranean areas (**Figure 7**) [79]. Another study in Spain has shown clearly different effects on cardiometabolic parameters between olive oil and sunflower oil (11% for MUFA and 60% for PUFA) [80]. With a slight increase in LDL cholesterol in the olive oil group, olive oil improved other risk factors such as glucose, TG, and body weight to a greater extent than in the sunflower oil group. The amount of olive oil in this study was expected to be more than 40 g/day, based on data showing that Spanish diet usually includes olive oil accounting for 18% of calorie intake [81]. All of these findings indicate that a large amount of olive oil (probably > 30 g/day) has distinctive effects compared with other oils from plant or animal origin.

Along with firm evidence of CV event reduction in two RCTs (Lyon Diet Heart study [82, 83] and PREDIMED [6]), olive oil should be viewed not only as "better" MUFA but also as a nutrient including many biologically active ingredients such as polyphenol. In 2018, the FDA approved a qualified health claim for consuming oils with high levels of oleic acid (major MUFA in olive oils) to reduce risk for coronary heart disease [84]. This new claim allows manufactures of olive oils to state that "supportive but not conclusive scientific evidence" suggest that daily consumption of one and half tablespoon (20 g) of olive oil may reduce CHD risk.

At present, intact or minimally processed carbohydrates where fiber, bran, and germ content is high are generally called complex carbohydrates. Bran of whole grain is fiber-filled outer layer with many vitamins and minerals, and germ, which is a nutrient-packed core, includes phytochemicals, unsaturated fat as well as vitamins. Differences in complex and refined (simple) carbohydrates are shown in **Table 2**. The mechanisms for harmful cardiometabolic effects of refined carbohydrates are mostly explained by their ability to increase insulin release and shorten satiety [87]. Refined carbohydrate also do not have as much vitamins and fibers as complex carbohydrates. A diet with refined carbohydrates with high glycemic index such as rice is associated with higher incidence of coronary heart disease and diabetes [88–91]. Reduction of refined carbohydrates in food has decreased blood pressure, TG, and high-sensitivity CRP, and improved insulin

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

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

Emerging evidence regarding the harmful effects of SFA and refined carbohydrates on cardiometabolic markers has exerted significant effects on the food label authorized by FDA. Some experts have opinion to recommend on leaving percent daily value of SFA with dropping % total fat, and adding on % refined carbohydrate instead of % carbohydrate against the daily value of these nutrients [94]. Because of data showing that refined carbohydrates with high glycemic indices worsen diabetic status, the FDA changed the nutrition facts section of the food label in 2019 to require listing the amount of and percent daily value for added sugars (**Figure 8**, arrow 1). Furthermore, "Calories from Fat" was removed, because abundant data show that the type of fat is more important than the amount (**Figure 8**, arrow 2). Foods and drinks that contain no significant nutrients but are high in calories are said to have "empty calories." Drinks with added sugar are a typical example of empty calories. Sugar-sweetened beverages are the largest source of added sugar in the diet. In the US, the consumption of sugar-sweetened beverages has decreased modestly since around 2009; however, the intake level is still high (**Figure 9**) [95]. The Dietary Guidelines for Americans [40] and WHO [96] recommend no more than 10% of daily calories from all added sugars. As shown in **Figure 9**, adults in the US consumed an average of 160 kcal/day from sugar-sweetened beverages in 2014. This means that sugar-sweetened beverages alone correspond to 8% of total calories. To date, a large body of evidence supports a strong link between intake of sugar-sweetened beverages and weight gain [97], risk of type 2 diabetes [98], and CV diseases [99–101]. Sugar-sweetened beverages, as well as saturated fat, present a

Structure Polysaccharides Mono, disaccharides Taste No taste Sweet Digestion Slow Easy Blood sugar Slowly increases Rapidly increases Insulin response Low High Glycemic index Low High Satiety Longer Shorter Fiber High Low Body weight Loss Gain

*Differences in two types of carbohydrate: complex vs. simple (refined).*

**Complex Simple (or refined)**

resistance [92, 93].

clear target for health policy.

**Table 2.**

**81**

**Figure 7.**

*Trends of types of fat intake from 1990 to 2010 in Nurses' Health Study (NHS) [79].*

#### **3.7 Effects of replacement of saturated fat with carbohydrate**

In many studies which replaced SFA with carbohydrate, total calories from fat was roughly reduced from 40% to 20–30%, and this has affected diet adherence in subjects who are accustomed to eating oily food. In the Women's Health Initiative Study [85], the protocol intended originally to reduce fat calories from 37 to 20% in the low-fat/high carbohydrate group. In 8 years, the fat calories increased to 37% in this group, which was higher than the fat calories in the control group (35%) because of poor compliance. In the low-fat/high carbohydrate group, although LDL cholesterol decreased by 3 md/dl, CV events were not reduced significantly. One meta-analysis including 15 randomized controlled trials with 59,000 participants [69] concluded that the replacement of SFA with carbohydrates reduced LDL cholesterol mildly (5%) without affecting CV events. In most of the studies used in this meta-analysis, it is noteworthy that refined carbohydrates were incorporated as replacement for SFA. A growing weight of authoritative opinion is to recommend intake of complex carbohydrates including much fiber and minerals. Two recent studies [56, 86] have also shown the same results that the CV benefit by reduced SFA tends to be neutralized by increasing intake of refined carbohydrates.

Combined analysis of two prospective, cohort studies [73] in the Nurses' Health Study (84,628 women) and the Health Professionals Follow-up Study (42,908 men) has the advantage of investigating effects of different sources of carbohydrates, refined or complex, on CHD risk for long periods up to 30 years. **Figure 6** shows that when 5% of energy from SFA was replaced with 5% of energy from carbohydrates, the risk of CHD decreased by 9%. By contrast, when replaced with refined carbohydrates/added sugars, the risk of CHD did not decrease. This study has also shown change of CHD risk when refined carbohydrates/added sugars were replaced with other nutrients. Replacing refined carbohydrates/added sugars with MUFA, PUFA, or complex carbohydrates was significantly associated with a lower risk of CHD (5, 21, and 12%, respectively). However, there was no change in the risk of CHD when refined carbohydrates/added sugars were replaced with SFA. Results of this cohort study provide additional evidence that effects of refined carbohydrates on CV risk are at least equipotent to those of SFA.

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

At present, intact or minimally processed carbohydrates where fiber, bran, and germ content is high are generally called complex carbohydrates. Bran of whole grain is fiber-filled outer layer with many vitamins and minerals, and germ, which is a nutrient-packed core, includes phytochemicals, unsaturated fat as well as vitamins. Differences in complex and refined (simple) carbohydrates are shown in **Table 2**. The mechanisms for harmful cardiometabolic effects of refined carbohydrates are mostly explained by their ability to increase insulin release and shorten satiety [87]. Refined carbohydrate also do not have as much vitamins and fibers as complex carbohydrates. A diet with refined carbohydrates with high glycemic index such as rice is associated with higher incidence of coronary heart disease and diabetes [88–91]. Reduction of refined carbohydrates in food has decreased blood pressure, TG, and high-sensitivity CRP, and improved insulin resistance [92, 93].

Emerging evidence regarding the harmful effects of SFA and refined carbohydrates on cardiometabolic markers has exerted significant effects on the food label authorized by FDA. Some experts have opinion to recommend on leaving percent daily value of SFA with dropping % total fat, and adding on % refined carbohydrate instead of % carbohydrate against the daily value of these nutrients [94]. Because of data showing that refined carbohydrates with high glycemic indices worsen diabetic status, the FDA changed the nutrition facts section of the food label in 2019 to require listing the amount of and percent daily value for added sugars (**Figure 8**, arrow 1). Furthermore, "Calories from Fat" was removed, because abundant data show that the type of fat is more important than the amount (**Figure 8**, arrow 2).

Foods and drinks that contain no significant nutrients but are high in calories are said to have "empty calories." Drinks with added sugar are a typical example of empty calories. Sugar-sweetened beverages are the largest source of added sugar in the diet. In the US, the consumption of sugar-sweetened beverages has decreased modestly since around 2009; however, the intake level is still high (**Figure 9**) [95]. The Dietary Guidelines for Americans [40] and WHO [96] recommend no more than 10% of daily calories from all added sugars. As shown in **Figure 9**, adults in the US consumed an average of 160 kcal/day from sugar-sweetened beverages in 2014. This means that sugar-sweetened beverages alone correspond to 8% of total calories. To date, a large body of evidence supports a strong link between intake of sugar-sweetened beverages and weight gain [97], risk of type 2 diabetes [98], and CV diseases [99–101]. Sugar-sweetened beverages, as well as saturated fat, present a clear target for health policy.


#### **Table 2.**

*Differences in two types of carbohydrate: complex vs. simple (refined).*

**3.7 Effects of replacement of saturated fat with carbohydrate**

*Trends of types of fat intake from 1990 to 2010 in Nurses' Health Study (NHS) [79].*

**Figure 7.**

*New Insights into Metabolic Syndrome*

**80**

on CV risk are at least equipotent to those of SFA.

In many studies which replaced SFA with carbohydrate, total calories from fat was roughly reduced from 40% to 20–30%, and this has affected diet adherence in subjects who are accustomed to eating oily food. In the Women's Health Initiative Study [85], the protocol intended originally to reduce fat calories from 37 to 20% in the low-fat/high carbohydrate group. In 8 years, the fat calories increased to 37% in this group, which was higher than the fat calories in the control group (35%) because of poor compliance. In the low-fat/high carbohydrate group, although LDL cholesterol decreased by 3 md/dl, CV events were not reduced significantly. One meta-analysis including 15 randomized controlled trials with 59,000 participants [69] concluded that the replacement of SFA with carbohydrates reduced LDL cholesterol mildly (5%) without affecting CV events. In most of the studies used in this meta-analysis, it is noteworthy that refined carbohydrates were incorporated as replacement for SFA. A growing weight of authoritative opinion is to recommend intake of complex carbohydrates including much fiber and minerals. Two recent studies [56, 86] have also shown the same results that the CV benefit by reduced SFA tends to be neutralized by increasing intake of refined carbohydrates.

Combined analysis of two prospective, cohort studies [73] in the Nurses' Health Study (84,628 women) and the Health Professionals Follow-up Study (42,908 men) has the advantage of investigating effects of different sources of carbohydrates, refined or complex, on CHD risk for long periods up to 30 years. **Figure 6** shows that when 5% of energy from SFA was replaced with 5% of energy from carbohydrates, the risk of CHD decreased by 9%. By contrast, when replaced with refined carbohydrates/added sugars, the risk of CHD did not decrease. This study has also shown change of CHD risk when refined carbohydrates/added sugars were replaced with other nutrients. Replacing refined carbohydrates/added sugars with MUFA, PUFA, or complex carbohydrates was significantly associated with a lower risk of CHD (5, 21, and 12%, respectively). However, there was no change in the risk of CHD when refined carbohydrates/added sugars were replaced with SFA. Results of this cohort study provide additional evidence that effects of refined carbohydrates

was 0.9, 0.4, and +1 mg/dl by substituting with PUFA, MUFA, or complex carbohydrates. These data indicate that in order to decrease LDL cholesterol or TG, the best strategy is to reduce the intake of SFA. SFA exert different LDL increasing ability depending on chain length. However, this difference is not clinically so important, because every oil contains several SFAs with various chain lengths. In general, there are progressive increases in LDL-C with diminishing chain length.

SFA may affect the risk of CV disease independently of LDL cholesterol, through

the effects on inflammation, endothelial function, thrombosis, and ventricular arrhythmias [104]. One ex vivo randomized cross-over study showed that a breakfast with butter (35% SFA) induced a higher increase in TNF-alfa mRNA than breakfasts with olive oil (36% MUFA) or walnuts (16% PUFA), and also a higher response in IL-6 mRNA than the walnut breakfast in peripheral blood mononuclear cells (PBMCs) in healthy subjects (**Figure 10**) [105]. In another study, LDL-induced adhesion of monocyte to endothelial cells was also lower after MUFA consumption than after SFA in healthy individuals [106]. Some other ex vivo studies in humans have shown that consumption of butter was associated with more activated genes involved in the regulation of cell proliferation and inflammation compared with consumption of olive oil or vegetable oil [107, 108]. In these studies, activation of inflammatory markers has occurred without significant changes in the blood lipid profile [106, 108]. In summary, the previous findings strongly suggest that saturated and unsaturated fats have unique biological effects on vascular walls which are independent on the reduction in LDL cholesterol, which is like the effects of

The potency of the LDL-raising effects of individual SFAs is lauric acid

(C12:0) > myristic acid (C14:0) > palmitic acid (C16:0) [103].

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

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

**3.9 Guideline recommendations for dietary intake of SFA**

Guidelines of authoritative opinions in Japan, the US, and Europe including cardiology, diabetes, and atherosclerosis societies except ADA [36] recommend less than 7% of calorie from SFA in subjects with background diseases (**Table 1**). In healthy subjects, the recommended upper limit of SFA is 7% in Japan [33] and 10% in the US [109]. Restriction of SFA to <10% rather than 7% in diabetic subjects as recommended by the ADA [36] may sound a little strange, because diabetes is associated with high CV risk, and on-target LDL cholesterol criteria is generally more stringent. This recommendation is based on the data from one small 3-week study that compared a low SFA diet (8% of total calories) vs. a high SFA diet (17% of total calories), and showed no significant difference in glycemic control and most CVD risk measures [110]. Therefore, there is limited research regarding effects of

*Response of mRNA TNFα (left) and IL-6 (right) in breakfast with butter, olive oil, and walnuts measured in*

statins.

**Figure 10.**

**83**

*peripheral blood mononuclear cells (PBMCs) [105].*

#### **Figure 8.**

*Changes in the format of the nutrition label of the original and the new version on Jan 2020.*

#### **Figure 9.**

*Sales of sugar-sweetened beverages (SSBs) in kcal/person/day by beverage type in 2009–2014 in some selected countries [95].*
