Postprandial Lipemia as Cardiovascular Disease Risk Factor

*Neil Francis Amba and Leilani B. Mercado-Asis*

## **Abstract**

Postprandial lipemia (PPL) is characterized by prolonged and increased levels of lipids especially triglycerides (TG) and triglyceride-rich lipoprotein levels after a meal. There are an increasing number of evidence that postprandial lipemia is a significant risk factor for cardiovascular disease because of its causative role in atherosclerosis and endothelial dysfunction. This has serious implications because common dietary patterns are characterized by high fat content and meal consumption; hence, most will be in a postprandial state resulting to frequent and prolonged exposure to high lipid levels. The review will present the current evidences for the role of postprandial lipemia as a risk factor for cardiovascular disease and its association with other cardiovascular risk factors, namely, diabetes and obesity. We will also present recommendations on the diagnosis and management of postprandial lipemia.

**Keywords:** postprandial lipemia, postprandial dyslipidemia, endothelial dysfunction, hypertriglyceridemia

## **1. Lipoprotein metabolism**

Lipoproteins are responsible for the distribution of cholesterol and triglyceride from the intestine and liver to peripheral cells. The process of lipoprotein distribution and metabolism is highly related to energy metabolism and the feed-fast cycle. Triglycerides (TG) are synthesized from dietary free fatty acids and glycerol in enterocytes. They are assembled together with phospholipids and cholesterol with apolipoproteins, mainly apoB-48 into chylomicron particles (apo A, C, E also present). These TG-rich particles enter the plasma via the intestinal lymph. Chylomicrons are then transported to peripheral cells where the enzyme lipoprotein lipase (LPL) hydrolyses their triglyceride content, releasing free fatty acids to be used by peripheral cells. The resulting chylomicron remnants are smaller and denser and are removed in the circulation by binding of the surface apo E to the LDL receptor or LDL receptor-related protein (LRP) [1]. Please also refer to the introductory chapter of this book for detailed and illustrated review of lipoprotein metabolism.

In the liver, synthesized TGs are released to the circulation by the very lowdensity lipoprotein (VLDL) particles. VLDL particles are TG-rich and, mainly, apo B-100-containing particles (apo A, C, E also present). VLDL synthesis takes place

#### **Figure 1.**

*Lipoprotein metabolism overview. Dietary TG transported via chylomicrons and hepatic TG transported via VLDL are delivered to peripheral tissue and acted upon by lipoprotein lipase to liberate fatty acids for energy fuel, cellular synthesis, or fat storage. Chylomicron and VLDL remnants are taken up by the liver. VLDL remnants can be further hydrolyzed by HTGL to form LDL particles.*

during fasting and prandial state. Once delivered to peripheral tissues, the TG contents are hydrolyzed to free fatty acids by LPL, similar to that of chylomicrons. VLDL remnants, also called intermediate-density lipoproteins (IDL), are taken up by the liver via apo E binding to LDL receptor or converted to LDL by removal of TG content by the hepatic triglyceride lipase (HTGL) enzyme. The removal of TG renders the particles smaller allowing better vascular penetration, hence increasing atherogenicity [2].

The cholesterol ester transfer protein (CETP) facilitates the transfer of cholesteryl esters from high-density lipoproteins (HDL) particles to VLDL in exchange for TGs. Cholesteryl ester-enriched particles are better substrates for HTGL allowing greater decrease in size of the particle, creating small dense (sd) LDL. Small, dense LDL are more atherogenic due to their smaller size as they readily enter the subendothelial space [1].

Chylomicrons, VLDL, and their respective remnants (remnant lipoproteins (RLP)) are termed triacylglycerol-rich lipoproteins (TRL) (**Figure 1**).

#### **2. Lipid profile in the postprandial state**

The plasma lipid levels normally fluctuate during the day, in response to food intake. TG levels vary more considerably compared to LDL and HDL cholesterol levels. Nowadays, the common dietary habit is characterized by high fat contents and high frequency of meals; hence, most individuals will be in a nonfasting state. Because of the evidence of association of nonfasting lipid levels as a risk factor for CVD, it is important to analyze postprandial lipoprotein physiology and metabolism [2].

In a study by Stanhope et al., it has been found that TG levels are significantly elevated during the day in association to food intake. When fructose was administered, there was significant increase in TG compared with the regular meal. Plasma cholesterol levels did not significantly change during the day [3]. In our previous studies, we were able to demonstrate the pattern of postprandial lipid rise. We have found that there was significant increase in the levels for total cholesterol,

**87**

*Postprandial Lipemia as Cardiovascular Disease Risk Factor*

the amount and type of dietary fat in a meal [7].

inversely correlated with fasting HDL levels [8].

tein production that prolongs postprandial lipemia [11].

DM [14]. However, evidence is still lacking.

**3. Postprandial lipemia in diabetes**

to fasting levels [10].

triglycerides, and HDL with peaking at the 4th–5th hour after a fatty meal [4]. The postprandial increase in TG is again demonstrated in another study by our group and has shown to be similar with VLDL postprandial increase beginning 4 hours after breakfast and sustained until 9–10 hours after [5]. In one of our trials, similar patterns of postprandial increase in TC, TG, and HDL were demonstrated with peaking at the 4th–5th hour and with noted decline at the 5th–6th hour [6]. None of

The postprandial period is characterized by an increase in atherogenic lipoprotein particles. These are the TRLs including chylomicrons, VLDL, and their remnant particles. Their levels are affected by multiple individual and environmental factors, including sex, age, body mass index, physical activity, and smoking, and by

In the study by Cohn et al., they have shown that there may be more than one peak in postprandial TG concentration, that the magnitude of postprandial rise is dependent on age and gender, that postprandial plasma cholesterol concentration can increase or remain at baseline, and that postprandial cholesterolemia is

The postprandial lipid response has been shown to be modified by polymorphisms within the genes for apo A-I, E, B, C-I, C-III, A-IV, and A-V, LPL, hepatic lipase, fatty acid-binding protein-2, the fatty acid transport proteins, microsomal

Diabetes is associated with premature atherosclerosis and cardiovascular disease, and this may be contributed to diabetic dyslipidemia. Diabetes is characterized by multiple lipoprotein metabolism abnormalities that promote atherogenesis. The common lipid abnormality in diabetes includes hypertriglyceridemia, low HDL, and increase in small, dense LDL (sdLDL) levels. In a study by Shukla that investigated the postprandial response of type 2 DM patients after a standard fat challenge, it has been found that compared to normal controls, DM patients have significantly higher postprandial triglyceride levels despite having similar fasting levels. No significant difference in postprandial HDL levels was seen when adjusted

The abnormalities in lipids among diabetics are secondary to multiple metabolic derangement that characterizes diabetes. For example, it has also been found that intestinal lipoprotein metabolism among diabetics is altered with increased lipopro-

In our clinic-based retrospective study, we have found that HbA1c has strong positive correlation with postprandial TG, while the 2-hour plasma glucose has moderate positive correlation. These significant correlations of postprandial lipemia with glycemic control and postprandial glycemia suggest that despite optimal fasting lipid levels, poor glycemic control is still associated with elevation of postprandial lipids, specifically postprandial triglycerides [12]. Similarly, Nakamura et al. have demonstrated that insulin resistance is closely related to postprandial hyperlipidemia among type 2 DM patients with CAD. Specifically, they have found that the 6th hour postprandial TG and remnant-like particle cholesterol were significantly higher among type 2 DM subjects and that plasma insulin levels and insulin resistance index were correlated with serum TG and RLP-C levels [13]. In addition, it has been shown in an animal study that postprandial hypertriglyceridemia predicts the development of insulin resistance, glucose intolerance, and type 2

triglyceride transfer protein, and scavenger receptor class B Type I [9].

our studies have demonstrated any pattern of postprandial rise for LDL.

*DOI: http://dx.doi.org/10.5772/intechopen.89933*

#### *Postprandial Lipemia as Cardiovascular Disease Risk Factor DOI: http://dx.doi.org/10.5772/intechopen.89933*

*Dyslipidemia*

**Figure 1.**

ing atherogenicity [2].

dothelial space [1].

and metabolism [2].

during fasting and prandial state. Once delivered to peripheral tissues, the TG contents are hydrolyzed to free fatty acids by LPL, similar to that of chylomicrons. VLDL remnants, also called intermediate-density lipoproteins (IDL), are taken up by the liver via apo E binding to LDL receptor or converted to LDL by removal of TG content by the hepatic triglyceride lipase (HTGL) enzyme. The removal of TG renders the particles smaller allowing better vascular penetration, hence increas-

*Lipoprotein metabolism overview. Dietary TG transported via chylomicrons and hepatic TG transported via VLDL are delivered to peripheral tissue and acted upon by lipoprotein lipase to liberate fatty acids for energy fuel, cellular synthesis, or fat storage. Chylomicron and VLDL remnants are taken up by the liver. VLDL* 

The cholesterol ester transfer protein (CETP) facilitates the transfer of cholesteryl esters from high-density lipoproteins (HDL) particles to VLDL in exchange for TGs. Cholesteryl ester-enriched particles are better substrates for HTGL allowing greater decrease in size of the particle, creating small dense (sd) LDL. Small, dense LDL are more atherogenic due to their smaller size as they readily enter the suben-

Chylomicrons, VLDL, and their respective remnants (remnant lipoproteins

The plasma lipid levels normally fluctuate during the day, in response to food intake. TG levels vary more considerably compared to LDL and HDL cholesterol levels. Nowadays, the common dietary habit is characterized by high fat contents and high frequency of meals; hence, most individuals will be in a nonfasting state. Because of the evidence of association of nonfasting lipid levels as a risk factor for CVD, it is important to analyze postprandial lipoprotein physiology

In a study by Stanhope et al., it has been found that TG levels are significantly elevated during the day in association to food intake. When fructose was administered, there was significant increase in TG compared with the regular meal. Plasma cholesterol levels did not significantly change during the day [3]. In our previous studies, we were able to demonstrate the pattern of postprandial lipid rise. We have found that there was significant increase in the levels for total cholesterol,

(RLP)) are termed triacylglycerol-rich lipoproteins (TRL) (**Figure 1**).

**2. Lipid profile in the postprandial state**

*remnants can be further hydrolyzed by HTGL to form LDL particles.*

**86**

triglycerides, and HDL with peaking at the 4th–5th hour after a fatty meal [4]. The postprandial increase in TG is again demonstrated in another study by our group and has shown to be similar with VLDL postprandial increase beginning 4 hours after breakfast and sustained until 9–10 hours after [5]. In one of our trials, similar patterns of postprandial increase in TC, TG, and HDL were demonstrated with peaking at the 4th–5th hour and with noted decline at the 5th–6th hour [6]. None of our studies have demonstrated any pattern of postprandial rise for LDL.

The postprandial period is characterized by an increase in atherogenic lipoprotein particles. These are the TRLs including chylomicrons, VLDL, and their remnant particles. Their levels are affected by multiple individual and environmental factors, including sex, age, body mass index, physical activity, and smoking, and by the amount and type of dietary fat in a meal [7].

In the study by Cohn et al., they have shown that there may be more than one peak in postprandial TG concentration, that the magnitude of postprandial rise is dependent on age and gender, that postprandial plasma cholesterol concentration can increase or remain at baseline, and that postprandial cholesterolemia is inversely correlated with fasting HDL levels [8].

The postprandial lipid response has been shown to be modified by polymorphisms within the genes for apo A-I, E, B, C-I, C-III, A-IV, and A-V, LPL, hepatic lipase, fatty acid-binding protein-2, the fatty acid transport proteins, microsomal triglyceride transfer protein, and scavenger receptor class B Type I [9].

## **3. Postprandial lipemia in diabetes**

Diabetes is associated with premature atherosclerosis and cardiovascular disease, and this may be contributed to diabetic dyslipidemia. Diabetes is characterized by multiple lipoprotein metabolism abnormalities that promote atherogenesis. The common lipid abnormality in diabetes includes hypertriglyceridemia, low HDL, and increase in small, dense LDL (sdLDL) levels. In a study by Shukla that investigated the postprandial response of type 2 DM patients after a standard fat challenge, it has been found that compared to normal controls, DM patients have significantly higher postprandial triglyceride levels despite having similar fasting levels. No significant difference in postprandial HDL levels was seen when adjusted to fasting levels [10].

The abnormalities in lipids among diabetics are secondary to multiple metabolic derangement that characterizes diabetes. For example, it has also been found that intestinal lipoprotein metabolism among diabetics is altered with increased lipoprotein production that prolongs postprandial lipemia [11].

In our clinic-based retrospective study, we have found that HbA1c has strong positive correlation with postprandial TG, while the 2-hour plasma glucose has moderate positive correlation. These significant correlations of postprandial lipemia with glycemic control and postprandial glycemia suggest that despite optimal fasting lipid levels, poor glycemic control is still associated with elevation of postprandial lipids, specifically postprandial triglycerides [12]. Similarly, Nakamura et al. have demonstrated that insulin resistance is closely related to postprandial hyperlipidemia among type 2 DM patients with CAD. Specifically, they have found that the 6th hour postprandial TG and remnant-like particle cholesterol were significantly higher among type 2 DM subjects and that plasma insulin levels and insulin resistance index were correlated with serum TG and RLP-C levels [13]. In addition, it has been shown in an animal study that postprandial hypertriglyceridemia predicts the development of insulin resistance, glucose intolerance, and type 2 DM [14]. However, evidence is still lacking.

#### *Dyslipidemia*

Although it has been shown that glycemia is correlated with postprandial dyslipidemia, there are evidences that even with good glycemic control, diabetes is still associated with postprandial dyslipidemia. Rivellese et al. have demonstrated that subjects with type 2 DM with good glucose control and optimal fasting triglyceride levels still presented with abnormal plasma lipid response after a standard mixed meal. In particular, large VLDL and chylomicron remnants were shown to be elevated postprandially [15].

## **4. Postprandial lipemia and obesity**

Obesity is a global epidemic affecting both children and adults. It is commonly defined as a body mass index (BMI) of ≥30 kg/m2 , but other indexes such as waist circumference and waist to hip ratio have been used. It is an established risk factor for cardiovascular disease, and it has been associated with dyslipidemia and abnormalities in lipoprotein metabolism. However, it is not yet established how obesity affects postprandial lipid levels.

Obesity is associated with insulin resistance, favoring catabolism and lipolysis [16]. Hence, it may be expected that obesity is associated with postprandial lipemia. In our previous unpublished study, we have found that there was no significant difference in postprandial lipid response in obese subjects compared to normal-weight subjects. Interestingly, postprandial lipid levels were actually slightly lower in the obese group compared to the normal group. This study used BMI to classify obese subjects, and different results were seen in studies that focused on abdominal obesity. Abdominal obesity has been known to be a risk factor for cardiovascular disease [17], and it has been demonstrated that abdominal obesity is associated with prolonged and amplified postprandial lipid levels [18]. Interestingly, postprandial lipemia can be seen in abdominal obesity despite normal fasting levels of TG [18, 19].

## **5. Role of postprandial lipemia in endothelial inflammation and dysfunction**

Postprandial lipemia is hypothesized to be a risk factor for cardiovascular disease by inducing endothelial dysfunction [20]. The vascular endothelial lining functions to maintain adequate blood flow and regulate coagulation and inflammation. Endothelial dysfunction signifies any disturbance to the vasodilatory response of the endothelium and impairment of its antithrombotic and antiproliferative function [21]. This eventually translates to atherosclerosis and CVD. Several studies have shown that intake of high-fat meals can induce an increase in postprandial TG levels and impair endothelial function [22, 23].

Postprandial lipemia promotes atherogenesis and endothelial dysfunction by contributing to the inflammatory state in the endothelial environment [24]. Postprandial lipemia has also been shown in in vitro and in vivo studies to activate leukocytes promoting adherence to endothelial walls and migration to the subendothelial space, therefore promoting atherosclerosis. VLDL, IDL, and chylomicron remnants have been shown to cause endothelial inflammation and promote increase in pro-inflammatory cells within the vascular walls. TG and TGRLs also induce pro-inflammatory cytokines that induce vascular cell adhesion molecule (VCAM)-1 expression in endothelial cells and monocyte adhesion. Lipolysis of TGRLs by the enzyme lipoprotein lipase (LPL) along with the endothelium produces by-products that are pro-inflammatory and pro-atherogenic. Lipolysis produces oxidized free

**89**

**Figure 2.**

*dilatation (FMD) after a standard diet.*

*Postprandial Lipemia as Cardiovascular Disease Risk Factor*

fatty acids that promote endothelial inflammation, vascular apoptosis, and reactive oxygen species (ROS). Inflammation in the endothelium increases permeability and

Maggi et al. have shown that postprandial levels of remnant lipoproteins (RLP) and TG contribute to endothelial dysfunction as measured by flowmediated dilatation (FMD) of the brachial artery. They have demonstrated that the increase in postprandial RLP and TG levels was associated to the decrease in FMD. In addition, the peak level of RLP at 6 hours after meal coincided with the maximal endothelial dysfunction [26]. Their findings are supported by similar

*The result from a study by Caringal et al. showing trends of lipid levels and brachial artery flow-mediated* 

*DOI: http://dx.doi.org/10.5772/intechopen.89933*

uptake of VDL in the vascular wall [25].

*Postprandial Lipemia as Cardiovascular Disease Risk Factor DOI: http://dx.doi.org/10.5772/intechopen.89933*

*Dyslipidemia*

elevated postprandially [15].

affects postprandial lipid levels.

normal fasting levels of TG [18, 19].

levels and impair endothelial function [22, 23].

**dysfunction**

**4. Postprandial lipemia and obesity**

defined as a body mass index (BMI) of ≥30 kg/m2

Although it has been shown that glycemia is correlated with postprandial dyslipidemia, there are evidences that even with good glycemic control, diabetes is still associated with postprandial dyslipidemia. Rivellese et al. have demonstrated that subjects with type 2 DM with good glucose control and optimal fasting triglyceride levels still presented with abnormal plasma lipid response after a standard mixed meal. In particular, large VLDL and chylomicron remnants were shown to be

Obesity is a global epidemic affecting both children and adults. It is commonly

circumference and waist to hip ratio have been used. It is an established risk factor for cardiovascular disease, and it has been associated with dyslipidemia and abnormalities in lipoprotein metabolism. However, it is not yet established how obesity

Obesity is associated with insulin resistance, favoring catabolism and lipolysis [16]. Hence, it may be expected that obesity is associated with postprandial lipemia. In our previous unpublished study, we have found that there was no significant difference in postprandial lipid response in obese subjects compared to normal-weight subjects. Interestingly, postprandial lipid levels were actually slightly lower in the obese group compared to the normal group. This study used BMI to classify obese subjects, and different results were seen in studies that focused on abdominal obesity. Abdominal obesity has been known to be a risk factor for cardiovascular disease [17], and it has been demonstrated that abdominal obesity is associated with prolonged and amplified postprandial lipid levels [18]. Interestingly, postprandial lipemia can be seen in abdominal obesity despite

**5. Role of postprandial lipemia in endothelial inflammation and** 

Postprandial lipemia is hypothesized to be a risk factor for cardiovascular disease by inducing endothelial dysfunction [20]. The vascular endothelial lining functions to maintain adequate blood flow and regulate coagulation and inflammation. Endothelial dysfunction signifies any disturbance to the vasodilatory response of the endothelium and impairment of its antithrombotic and antiproliferative function [21]. This eventually translates to atherosclerosis and CVD. Several studies have shown that intake of high-fat meals can induce an increase in postprandial TG

Postprandial lipemia promotes atherogenesis and endothelial dysfunction by contributing to the inflammatory state in the endothelial environment [24]. Postprandial lipemia has also been shown in in vitro and in vivo studies to activate leukocytes promoting adherence to endothelial walls and migration to the subendothelial space, therefore promoting atherosclerosis. VLDL, IDL, and chylomicron remnants have been shown to cause endothelial inflammation and promote increase in pro-inflammatory cells within the vascular walls. TG and TGRLs also induce pro-inflammatory cytokines that induce vascular cell adhesion molecule (VCAM)-1 expression in endothelial cells and monocyte adhesion. Lipolysis of TGRLs by the enzyme lipoprotein lipase (LPL) along with the endothelium produces by-products that are pro-inflammatory and pro-atherogenic. Lipolysis produces oxidized free

, but other indexes such as waist

**88**

fatty acids that promote endothelial inflammation, vascular apoptosis, and reactive oxygen species (ROS). Inflammation in the endothelium increases permeability and uptake of VDL in the vascular wall [25].

Maggi et al. have shown that postprandial levels of remnant lipoproteins (RLP) and TG contribute to endothelial dysfunction as measured by flowmediated dilatation (FMD) of the brachial artery. They have demonstrated that the increase in postprandial RLP and TG levels was associated to the decrease in FMD. In addition, the peak level of RLP at 6 hours after meal coincided with the maximal endothelial dysfunction [26]. Their findings are supported by similar

#### **Figure 2.**

*The result from a study by Caringal et al. showing trends of lipid levels and brachial artery flow-mediated dilatation (FMD) after a standard diet.*

#### *Dyslipidemia*

results in a study by Caringal et al. that investigated the relationship between postprandial lipid levels and endothelial dysfunction using FMD as surrogate marker. Five high-risk subjects with normal fasting lipid levels were given a standard low-fat diet. Interestingly, it was observed that even though the fasting lipid levels were normal, the peaking of TG and VLDL 6 hours postprandially and the decrease in HDL postprandially appear to coincide with the decrease in brachial artery FMD [27] (**Figure 2**).

A study by Giannattasio et al. involving 16 asymptomatic hypertriglyceridemic and 7 normotriglyceridemic controls showed attenuation of arterial vasodilatory response following a high-fat meal among subjects with dyslipidemia. This reflects postprandial impairment of endothelial function after a high-fat meal [23].

## **6. Postprandial lipemia and CV events**

Lipid-lowering therapy focusing on LDL-C reduction has been proven to reduce coronary events and stroke [28]. However, with the evidences of association of postprandial lipemia, specifically TG and RLP with endothelial dysfunction, it is important to assess their role in morbidity and mortality.

In a prospective cohort by Nordertgaard et al., involving a large number of white women and men of Danish descent, they have found that elevated levels of nonfasting triglyceride were associated with increased risk for CV events. They have specifically demonstrated that increasing levels of nonfasting TG were associated with progressively increasing hazard ratio for myocardial infarction (MI), ischemic heart disease (IHD), and death. In addition, they have also demonstrated that remnant lipoprotein cholesterol increases as nonfasting TG increase [29]. A study by Bansal et al. further supports the role of TG in predicting CV events. They have demonstrated that both fasting and nonfasting TG are risks for CV events. However, because HDL-C level is a confounding variable, after adjusting to HDL-C, they have seen that compared to fasting TG, nonfasting TG has a stronger independent relationship with cardiovascular events. Interestingly, they also demonstrated in secondary analyses that TG levels 2–4 hours postprandially had the strongest association with CV events [30]. This can be explained by the possibility that peaking of endothelial dysfunction coincides with peaking of postprandial lipemia [26]. Also, most studies mentioned have noted that peaking of postprandial TG and RLPs occurred 4 hours after a meal [5, 6, 26, 27]. On the contrary, in a study by Kats et al. involving 559 participants who underwent oral fat challenge, they have found that none of the measures of postprandial change were associated with incident CVD events. However, the study is inadequately powered [31]. Hence, there is a need for more robust prospective studies to clearly demonstrate the role and extent of postprandial lipemia effect on CV events. At present, the evidences should be enough to effect change in the way me manage dyslipidemia.

#### **7. Treatment**

Optimal treatment goals for postprandial lipid levels that will result to risk reduction have not been determined. At present, most guidelines are focused on LDL-C reduction and use fasting lipid profile. LDL-C target goals also depend on risk stratification, with extremely high-risk patients recommended to decrease LDL-C to as low as 55 mg/dl and low-risk patients to <130 mg/dl [32].

Normal TG levels have been set to be <150 mg/dl during the fasting state [32]. In a study by White et al. that aimed to determine optimal nonfasting TG levels

**91**

*Postprandial Lipemia as Cardiovascular Disease Risk Factor*

large HDL and in lowering LDL particle numbers [35].

lipoprotein levels postprandially [37].

involving middle-aged and older apparently healthy women, the diagnostic thresh-

The importance of lifestyle modification cannot be overemphasized. Patients with dyslipidemia are advised to have reduced-calorie diet. Saturated and trans fats should also be minimized [32]. In addition, it has been found that a minimum of 10 hours is needed for postprandial lipids to return to fasting or baseline levels [5]. Hence, to avoid prolonged exposure to elevated levels of postprandial lipids, fatty

Statins are considered one of the first-line treatments for dyslipidemia. It has been established that statins are efficacious in lowering fasting lipids and that statin treatment has resulted to significant reductions in cardiovascular morbidity and mortality. Some studies also have proven that statins can be used to lower postprandial lipid levels. However, in our study, we found that even on low fat diet, statin treatment, and normal fasting lipids, triglyceride and VLDL peaking and plateauing were still observed in patients with cardiovascular disease [34]. Furthermore, Schaefer et al. did a comparative study among statins and their efficacy in lowering postprandial levels. They have found that atorvastatin was significantly more effective in lowering LDL cholesterol and non-high-density lipoprotein cholesterol than all other statins and significantly more effective than all statins, except for simvastatin, in lowering triglyceride and remnant lipoprotein cholesterol. At 40 mg/day, atorvastatin was significantly more effective than all statins, except for lovastatin and simvastatin, in lowering cholesterol levels in small LDL, and was significantly more effective than all statins, except for simvastatin, in increasing cholesterol in

In a study by Cavallero et al., it has been found that fenofibrate normalized the abnormal postprandial response and improved the fasting lipoprotein abnormalities in patients with type 2 diabetes [36]. This is supported by the study of Ooi et al., which showed that fibrate treatment resulted to a significant decrease in remnant

A study by Turker et al. involving normolipidemic, obese women with normal glucose tolerance suggests that 12 weeks of treatment with orlistat 120 mg/d plus low-calorie diet was associated with a 4.1-fold change from baseline in PPL [38]. Abejuela et al. have shown that orlistat abolishes the peaking of TC, TG, and HDL after a 50% OFCT [6]. In a study by Gabriel et al. which compared the effects of orlistat on the postprandial lipid levels after sequential high-fat meals in healthy individuals with normal fasting lipid levels, they have seen that administration of orlistat abolished the significantly sustained postprandial rise of TG and VLDL levels

old for nonfasting hypertriglyceridemia is seen to be at 175 mg/dL [33].

meals should be avoided or should at least be spaced 12 hours accordingly.

*DOI: http://dx.doi.org/10.5772/intechopen.89933*

**8. Diet**

**9. Statins**

**10. Fibrates**

**11. Orlistat**

involving middle-aged and older apparently healthy women, the diagnostic threshold for nonfasting hypertriglyceridemia is seen to be at 175 mg/dL [33].

## **8. Diet**

*Dyslipidemia*

artery FMD [27] (**Figure 2**).

**6. Postprandial lipemia and CV events**

important to assess their role in morbidity and mortality.

effect change in the way me manage dyslipidemia.

results in a study by Caringal et al. that investigated the relationship between postprandial lipid levels and endothelial dysfunction using FMD as surrogate marker. Five high-risk subjects with normal fasting lipid levels were given a standard low-fat diet. Interestingly, it was observed that even though the fasting lipid levels were normal, the peaking of TG and VLDL 6 hours postprandially and the decrease in HDL postprandially appear to coincide with the decrease in brachial

A study by Giannattasio et al. involving 16 asymptomatic hypertriglyceridemic and 7 normotriglyceridemic controls showed attenuation of arterial vasodilatory response following a high-fat meal among subjects with dyslipidemia. This reflects

Lipid-lowering therapy focusing on LDL-C reduction has been proven to reduce

coronary events and stroke [28]. However, with the evidences of association of postprandial lipemia, specifically TG and RLP with endothelial dysfunction, it is

In a prospective cohort by Nordertgaard et al., involving a large number of white women and men of Danish descent, they have found that elevated levels of nonfasting triglyceride were associated with increased risk for CV events. They have specifically demonstrated that increasing levels of nonfasting TG were associated with progressively increasing hazard ratio for myocardial infarction (MI), ischemic heart disease (IHD), and death. In addition, they have also demonstrated that remnant lipoprotein cholesterol increases as nonfasting TG increase [29]. A study by Bansal et al. further supports the role of TG in predicting CV events. They have demonstrated that both fasting and nonfasting TG are risks for CV events. However, because HDL-C level is a confounding variable, after adjusting to HDL-C, they have seen that compared to fasting TG, nonfasting TG has a stronger independent relationship with cardiovascular events. Interestingly, they also demonstrated in secondary analyses that TG levels 2–4 hours postprandially had the strongest association with CV events [30]. This can be explained by the possibility that peaking of endothelial dysfunction coincides with peaking of postprandial lipemia [26]. Also, most studies mentioned have noted that peaking of postprandial TG and RLPs occurred 4 hours after a meal [5, 6, 26, 27]. On the contrary, in a study by Kats et al. involving 559 participants who underwent oral fat challenge, they have found that none of the measures of postprandial change were associated with incident CVD events. However, the study is inadequately powered [31]. Hence, there is a need for more robust prospective studies to clearly demonstrate the role and extent of postprandial lipemia effect on CV events. At present, the evidences should be enough to

Optimal treatment goals for postprandial lipid levels that will result to risk reduction have not been determined. At present, most guidelines are focused on LDL-C reduction and use fasting lipid profile. LDL-C target goals also depend on risk stratification, with extremely high-risk patients recommended to decrease

Normal TG levels have been set to be <150 mg/dl during the fasting state [32]. In a study by White et al. that aimed to determine optimal nonfasting TG levels

LDL-C to as low as 55 mg/dl and low-risk patients to <130 mg/dl [32].

postprandial impairment of endothelial function after a high-fat meal [23].

**90**

**7. Treatment**

The importance of lifestyle modification cannot be overemphasized. Patients with dyslipidemia are advised to have reduced-calorie diet. Saturated and trans fats should also be minimized [32]. In addition, it has been found that a minimum of 10 hours is needed for postprandial lipids to return to fasting or baseline levels [5]. Hence, to avoid prolonged exposure to elevated levels of postprandial lipids, fatty meals should be avoided or should at least be spaced 12 hours accordingly.

## **9. Statins**

Statins are considered one of the first-line treatments for dyslipidemia. It has been established that statins are efficacious in lowering fasting lipids and that statin treatment has resulted to significant reductions in cardiovascular morbidity and mortality. Some studies also have proven that statins can be used to lower postprandial lipid levels. However, in our study, we found that even on low fat diet, statin treatment, and normal fasting lipids, triglyceride and VLDL peaking and plateauing were still observed in patients with cardiovascular disease [34]. Furthermore, Schaefer et al. did a comparative study among statins and their efficacy in lowering postprandial levels. They have found that atorvastatin was significantly more effective in lowering LDL cholesterol and non-high-density lipoprotein cholesterol than all other statins and significantly more effective than all statins, except for simvastatin, in lowering triglyceride and remnant lipoprotein cholesterol. At 40 mg/day, atorvastatin was significantly more effective than all statins, except for lovastatin and simvastatin, in lowering cholesterol levels in small LDL, and was significantly more effective than all statins, except for simvastatin, in increasing cholesterol in large HDL and in lowering LDL particle numbers [35].

## **10. Fibrates**

In a study by Cavallero et al., it has been found that fenofibrate normalized the abnormal postprandial response and improved the fasting lipoprotein abnormalities in patients with type 2 diabetes [36]. This is supported by the study of Ooi et al., which showed that fibrate treatment resulted to a significant decrease in remnant lipoprotein levels postprandially [37].

## **11. Orlistat**

A study by Turker et al. involving normolipidemic, obese women with normal glucose tolerance suggests that 12 weeks of treatment with orlistat 120 mg/d plus low-calorie diet was associated with a 4.1-fold change from baseline in PPL [38]. Abejuela et al. have shown that orlistat abolishes the peaking of TC, TG, and HDL after a 50% OFCT [6]. In a study by Gabriel et al. which compared the effects of orlistat on the postprandial lipid levels after sequential high-fat meals in healthy individuals with normal fasting lipid levels, they have seen that administration of orlistat abolished the significantly sustained postprandial rise of TG and VLDL levels in healthy individuals who were fed sequential 50% fat meals. Specifically, they have seen that in the control group, there is a significant postprandial rise in the levels of TG and VLDL beginning at 4 hours after breakfast that was sustained until 9 hours for TG and up to 10 hours for VLDL postprandially. In contrast, only one significant rise in both TG and VLDL levels was noted in the group given orlistat [5].

## **12. Ezetimibe**

Ezetimibe is usually given to statin-intolerant patients or used in combination with statin to lower cholesterol, primarily LDL. There are evidences that it can also improve postprandial lipemia. In a study by Bozetto et al., they have shown that ezetimibe when given with simvastatin produces greater decrease in LDL cholesterol compared to simvastatin alone and produces a significant decrease in chylomicron lipid content both at fasting and postprandially, a significant decrease in chylomicron postprandial apoB-48, and significant fasting and postprandial decreases in the cholesterol content of VLDL, IDL, and LDL [39]. Yunoki et al. have demonstrated that a 4-week treatment with ezetimibe suppressed the postprandial peaking of TG, remnant lipoprotein, and apoB-48. Furthermore, they have shown that FMD reduction, which signifies endothelial dysfunction, also decreased with treatment [40].

## **13. Conclusion**

We recognize that postprandial dyslipidemia is an undertreated disorder. Although robust prospective clinical trials are lacking, there is still increasing evidence of the clinical significance of postprandial dyslipidemia as a risk factor for CV disease. Clearly, postprandial elevations of lipids, specifically TG and TRLs, result to endothelial dysfunction and atherosclerosis. These result to increase in morbidity and possible mortality due to cardiovascular diseases. This should translate to a paradigm shift in the diagnosis and treatment of dyslipidemia. Presently, statins, fibrates, ezetimibe, and orlistat in sequential or combination regimen or as needed (orlistat) are possible treatment options for postprandial dyslipidemia in addition to proper diet and exercise. However, studies that focus on treatment of postprandial lipemia with measurement of solid clinical outcomes such as cardiovascular events and mortality should be undertaken. **Table 1** summarizes our recommendation.


**93**

**Author details**

Neil Francis Amba and Leilani B. Mercado-Asis\*

\*Address all correspondence to: lmasis@ust.edu.ph

provided the original work is properly cited.

Section of Endocrinology and Metabolism, Department of Medicine, Faculty of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Medicine and Surgery, University of Santo Tomas, Manila, Philippines

*Postprandial Lipemia as Cardiovascular Disease Risk Factor*

The authors have no conflicts of interests.

*DOI: http://dx.doi.org/10.5772/intechopen.89933*

**Conflict of interests**

**Table 1.**

*Summary of recommendations on the diagnosis and management of postprandial lipemia.*

*Postprandial Lipemia as Cardiovascular Disease Risk Factor DOI: http://dx.doi.org/10.5772/intechopen.89933*

## **Conflict of interests**

*Dyslipidemia*

**12. Ezetimibe**

**13. Conclusion**

**Recommendations**

in healthy individuals who were fed sequential 50% fat meals. Specifically, they have seen that in the control group, there is a significant postprandial rise in the levels of TG and VLDL beginning at 4 hours after breakfast that was sustained until 9 hours for TG and up to 10 hours for VLDL postprandially. In contrast, only one significant

Ezetimibe is usually given to statin-intolerant patients or used in combination with statin to lower cholesterol, primarily LDL. There are evidences that it can also improve postprandial lipemia. In a study by Bozetto et al., they have shown that ezetimibe when given with simvastatin produces greater decrease in LDL cholesterol compared to simvastatin alone and produces a significant decrease in chylomicron lipid content both at fasting and postprandially, a significant decrease in chylomicron postprandial apoB-48, and significant fasting and postprandial decreases in the cholesterol content of VLDL, IDL, and LDL [39]. Yunoki et al. have demonstrated that a 4-week treatment with ezetimibe suppressed the postprandial peaking of TG, remnant lipoprotein, and apoB-48. Furthermore, they have shown that FMD reduction, which signifies endothelial dysfunction, also decreased with treatment [40].

We recognize that postprandial dyslipidemia is an undertreated disorder. Although robust prospective clinical trials are lacking, there is still increasing evidence of the clinical significance of postprandial dyslipidemia as a risk factor for CV disease. Clearly, postprandial elevations of lipids, specifically TG and TRLs, result to endothelial dysfunction and atherosclerosis. These result to increase in morbidity and possible mortality due to cardiovascular diseases. This should translate to a paradigm shift in the diagnosis and treatment of dyslipidemia. Presently, statins, fibrates, ezetimibe, and orlistat in sequential or combination regimen or as needed (orlistat) are possible treatment options for postprandial dyslipidemia in addition to proper diet and exercise. However, studies that focus on treatment of postprandial lipemia with measurement of solid clinical outcomes such as cardiovascular events and mortality should be undertaken. **Table 1** summarizes our recommendation.

Diagnosis • In addition to fasting lipid profile, postprandial lipid profile should also be determined,

• Postprandial lipid profile should include total cholesterol, TG, and HDL

• In high-risk individuals such as those with diabetes mellitus and those with diagnosed cardiovascular disease, postprandial lipid profile should routinely be evaluated

• Elevated postprandial total cholesterol should be treated with high-intensity statin • Ezetimibe can be considered if inadequately controlled by fibrates and statins

especially for patients at risk for cardiovascular disease

Treatment • Fibrates are the first-line drug of choice for postprandial lipemia with

• Orlistat as needed may be taken prior to a fatty meal

*Summary of recommendations on the diagnosis and management of postprandial lipemia.*

Target • Postprandial values must approximate normal fasting levels

hypertriglyceridemia

rise in both TG and VLDL levels was noted in the group given orlistat [5].

**92**

**Table 1.**

The authors have no conflicts of interests.

## **Author details**

Neil Francis Amba and Leilani B. Mercado-Asis\* Section of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines

\*Address all correspondence to: lmasis@ust.edu.ph

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Dominiczak MH. Lipoprotein Metabolism and Atherogenesis. Medical Biochemistry Fouth ed. Saunders; 2014. pp. 214-234

[2] Katsuyuki N, Takamitsu N, Yoshiharu T, Takeaki N, et al. Postprandial lipoprotein metabolism: VLDL vs chylomicrons. Clinica Chimica Acta. 2011;**412**:1306-1318

[3] Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose sweetened, beverages increase visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. The Journal of Clinical Investigation. 2009;**119**:1322-1334

[4] So T, Mercado-Asis LB, Zacarias MB, et al. A comparison of dose response postprandial lipid profile of healthy filipino subjects after an oral fat challenge test of varying fat contents. Philippine Journal of Internal Medicine. 2004;**42**:1-7

[5] Gabriel FS, Samson C, Abejuela Z, Sicat-Gabriel PR, Sumpio JP, Zacarias MB, et al. Post prandial effect of orlistat on the peaking of lipid level after sequential high fat meals. International Journal of Endocrinology and Metabolism. 2012;**10**(2):458-463

[6] Abejuela ZR, Macaballug AG, Sumpio JP, Zacarias MB, Mercado-Asis LB. Orlistat abolishes postprandial lipid peaking. International Journal of Endocrinology and Metabolism. 2009;**3**:179-186

[7] Rosenson RS, Helenowski IB, Tangney CC. Heterogeneous post prandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy. Cardiovascular Drugs and Therapy. 2010;**24**:439-447

[8] Cohn J, McNamara J, Cohn S, Ordovas J, Schaefer E. Postprandial plasma lipoprotein changes in human subjects of different ages. Journal of Lipid Research. 1988;**29**:469-479

[9] Lopez-Mirandal J, Williams C, Lairon D. Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism. British Journal of Nutrition. 2007;**98**:458-473

[10] Shukla A. Postprandial lipid abnormalities in type 2 diabetes mellitus, a study at NGMC, Kohalpur. Journal of Nepalgunj Medical College. 2015;**13**:21-24

[11] Arca M. Alterations of intestinal lipoprotein metabolism in diabetes mellitus and metabolic syndrome. Atherosclerosis Supplements. 2015;**17**:12-16

[12] Castro-Caringal J, Mendoza E, Mercado-Asis LB. Correlation of postprandial lipemia with postprandial hyperglycemia and poor glycemic control among patients with type 2 diabetes mellitus. Philippine Journal of Internal Medicine. 2015;**53**(4):1-4

[13] Nakamura A, Monma Y, Kajitani S, Noda K, Nakajima S, Endo H, et al. Effect of glycemic state on postprandial hyperlipidemia and hyperinsulinemia with coronary artery disease. Heart and Vessels. 2016;**31**(9):1446-1455

[14] Asiam M, Aggarwal S, Sharnma KK, Galay V, Madhu SV. Postprandial hypertriglyceridemia predicts development of insulin resistance, glucose in tolerance and type 2 DM. PLoS One. 2016;**11**(1):e0145730

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*Postprandial Lipemia as Cardiovascular Disease Risk Factor*

[23] Giannattasio C, Zoppo A, Gentile G, Failla M, Capra A, Maggi M, et al. Acute effect of high-fat meal on endothelial dysfunction in moderately dislipidemic subjects. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;**25**:406-410

[24] Burdge G, Clader P. Plasma cytokine response during the postprandial period: A potential causal process in vascular disease? British Journal of

Nutrition. 2005;**93**:3-9

[26] Maggi FM, Raselli S,

2004;**89**(6):2946-2950

[27] Castro-Caringal JA,

1278. Epub 2005 Sept 27

[29] Nordertgaard B, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.

JAMA. 2007;**298**(3):299-308

[30] Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting

Unpubished

[25] Lacroix S, Des RC, Tardif J, Nigam A. The role of oxidative stress in postprandial dysfunction. Nutrition Research Reviews. 2012;**25**:288-301

Grigore L, Redaelli L, Fantappiè S, Catapano AL. Lipoprotein remnants and endothelial dysfunction in the postprandial phase. The Journal of Clinical Endocrinology and Metabolism.

Valera L, Llave K, Samson C, Ramirez M, Zacarias M, Mercado-Asis LB. Flowmediated dilatation of brachial artery is inversely correlated with the postprandial peaking of triglyceride and very low-density lipoprotein.

[28] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterollowering treatment: Prospective meta-analysis of date from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;**366**(9493):1267-

*DOI: http://dx.doi.org/10.5772/intechopen.89933*

abnormalities in type 2 diabetic patients with optimal blood glucose control and optimal fasting triglyceride levels. The Journal of Clinical Endocrinology & Metabolism. 2004;**89**(5):2153-2159

[16] Singla P, Bardoloi A, Parkash A. Metabolic effects of obesity: A review. World Journal of Diabetes.

[17] Frayn K. Insulin resistance,

[18] Mekki N, Christofilis MA, Charbonnier M, Atlan-Gepner C, Defoort C, Juhel C, et al. Influence of obesity and body fat distribution on postprandial lipemia and triglyceriderich lipoprotein in adult women. The Journal of Clinical Endocrinology and

Metabolism. 1999;**84**:184-191

[20] Matsumoto S, Gotoh N, Hishinuma S, Abe Y, Shimizu Y, Katano Y, et al. The role of hypertriglyceridemia in the

2014;**6**:1236-1250

development of atherosclerosis and endotheliasl dysfunction. Nutrients.

[21] Murray T, Yang E, Brunner G, Kumar A, Lakkis N, Misra A, et al. Post prandial effects on arterial stiffness parameters in healthy young adults. Vascular Medicine. 2015;**20**(6):501-508

[22] Blendea M, Bard M, Sowers J, Winer N. High-fat meal impairs vascular compliance in a subgroup of young healthy subjects. Metabolism Clinical and Experimental. 2005;**54**:1337-1344

[19] Watts GF, Chan DCF, Barrett PHR, Martins IJ, Redgrave TG. Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: A study in central obesity. Clinical Science. 2001;**101**:683-690

2002;**11**(suppl 2):31-40

impaired postprandial lipid metabolism and abdominal obesity a deadely triad. Medical Principles and Practice.

2010;**1**(3):76-88

[15] Rivellese A, De Natale C, Di Lucrezia M, Lidia P, Ciro L, Sylvana C, et al. Exogenous and endogenous postprandial lipid

*Postprandial Lipemia as Cardiovascular Disease Risk Factor DOI: http://dx.doi.org/10.5772/intechopen.89933*

abnormalities in type 2 diabetic patients with optimal blood glucose control and optimal fasting triglyceride levels. The Journal of Clinical Endocrinology & Metabolism. 2004;**89**(5):2153-2159

[16] Singla P, Bardoloi A, Parkash A. Metabolic effects of obesity: A review. World Journal of Diabetes. 2010;**1**(3):76-88

[17] Frayn K. Insulin resistance, impaired postprandial lipid metabolism and abdominal obesity a deadely triad. Medical Principles and Practice. 2002;**11**(suppl 2):31-40

[18] Mekki N, Christofilis MA, Charbonnier M, Atlan-Gepner C, Defoort C, Juhel C, et al. Influence of obesity and body fat distribution on postprandial lipemia and triglyceriderich lipoprotein in adult women. The Journal of Clinical Endocrinology and Metabolism. 1999;**84**:184-191

[19] Watts GF, Chan DCF, Barrett PHR, Martins IJ, Redgrave TG. Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: A study in central obesity. Clinical Science. 2001;**101**:683-690

[20] Matsumoto S, Gotoh N, Hishinuma S, Abe Y, Shimizu Y, Katano Y, et al. The role of hypertriglyceridemia in the development of atherosclerosis and endotheliasl dysfunction. Nutrients. 2014;**6**:1236-1250

[21] Murray T, Yang E, Brunner G, Kumar A, Lakkis N, Misra A, et al. Post prandial effects on arterial stiffness parameters in healthy young adults. Vascular Medicine. 2015;**20**(6):501-508

[22] Blendea M, Bard M, Sowers J, Winer N. High-fat meal impairs vascular compliance in a subgroup of young healthy subjects. Metabolism Clinical and Experimental. 2005;**54**:1337-1344

[23] Giannattasio C, Zoppo A, Gentile G, Failla M, Capra A, Maggi M, et al. Acute effect of high-fat meal on endothelial dysfunction in moderately dislipidemic subjects. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;**25**:406-410

[24] Burdge G, Clader P. Plasma cytokine response during the postprandial period: A potential causal process in vascular disease? British Journal of Nutrition. 2005;**93**:3-9

[25] Lacroix S, Des RC, Tardif J, Nigam A. The role of oxidative stress in postprandial dysfunction. Nutrition Research Reviews. 2012;**25**:288-301

[26] Maggi FM, Raselli S, Grigore L, Redaelli L, Fantappiè S, Catapano AL. Lipoprotein remnants and endothelial dysfunction in the postprandial phase. The Journal of Clinical Endocrinology and Metabolism. 2004;**89**(6):2946-2950

[27] Castro-Caringal JA, Valera L, Llave K, Samson C, Ramirez M, Zacarias M, Mercado-Asis LB. Flowmediated dilatation of brachial artery is inversely correlated with the postprandial peaking of triglyceride and very low-density lipoprotein. Unpubished

[28] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterollowering treatment: Prospective meta-analysis of date from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;**366**(9493):1267- 1278. Epub 2005 Sept 27

[29] Nordertgaard B, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;**298**(3):299-308

[30] Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting

**94**

*Dyslipidemia*

**References**

pp. 214-234

2011;**412**:1306-1318

2009;**119**:1322-1334

2004;**42**:1-7

[1] Dominiczak MH. Lipoprotein Metabolism and Atherogenesis. Medical Biochemistry Fouth ed. Saunders; 2014.

[8] Cohn J, McNamara J, Cohn S, Ordovas J, Schaefer E. Postprandial plasma lipoprotein changes in human subjects of different ages. Journal of Lipid Research. 1988;**29**:469-479

[9] Lopez-Mirandal J, Williams C, Lairon D. Dietary, physiological, genetic

postprandial lipid metabolism. British Journal of Nutrition. 2007;**98**:458-473

and pathological influences on

[10] Shukla A. Postprandial lipid abnormalities in type 2 diabetes mellitus, a study at NGMC, Kohalpur. Journal of Nepalgunj Medical College.

[11] Arca M. Alterations of intestinal lipoprotein metabolism in diabetes mellitus and metabolic syndrome. Atherosclerosis Supplements.

[12] Castro-Caringal J, Mendoza E, Mercado-Asis LB. Correlation of postprandial lipemia with postprandial hyperglycemia and poor glycemic control among patients with type 2 diabetes mellitus. Philippine Journal of Internal Medicine. 2015;**53**(4):1-4

[13] Nakamura A, Monma Y, Kajitani S, Noda K, Nakajima S, Endo H, et al. Effect of glycemic state on postprandial hyperlipidemia and hyperinsulinemia with coronary artery disease. Heart and

[14] Asiam M, Aggarwal S, Sharnma KK,

Vessels. 2016;**31**(9):1446-1455

[15] Rivellese A, De Natale C, Di Lucrezia M, Lidia P, Ciro L, Sylvana C, et al. Exogenous and endogenous postprandial lipid

Galay V, Madhu SV. Postprandial hypertriglyceridemia predicts development of insulin resistance, glucose in tolerance and type 2 DM. PLoS One. 2016;**11**(1):e0145730

2015;**13**:21-24

2015;**17**:12-16

[2] Katsuyuki N, Takamitsu N, Yoshiharu T, Takeaki N, et al. Postprandial lipoprotein metabolism: VLDL vs chylomicrons. Clinica Chimica Acta.

[3] Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose sweetened, beverages increase visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. The Journal of Clinical Investigation.

[4] So T, Mercado-Asis LB, Zacarias MB, et al. A comparison of dose response postprandial lipid profile of healthy filipino subjects after an oral fat challenge test of varying fat contents. Philippine Journal of Internal Medicine.

[5] Gabriel FS, Samson C, Abejuela Z,

Sicat-Gabriel PR, Sumpio JP, Zacarias MB, et al. Post prandial effect of orlistat on the peaking of lipid level after sequential high fat meals. International Journal of Endocrinology and Metabolism.

[6] Abejuela ZR, Macaballug AG, Sumpio JP, Zacarias MB, Mercado-Asis LB. Orlistat abolishes postprandial lipid peaking. International Journal of Endocrinology and Metabolism.

[7] Rosenson RS, Helenowski IB, Tangney CC. Heterogeneous post prandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy. Cardiovascular Drugs and Therapy. 2010;**24**:439-447

2012;**10**(2):458-463

2009;**3**:179-186

compared with non-fasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;**298**:309-316

[31] Kats D, Sharrett A, Ginsberg H, Nambi V, Ballantyne C, Hoogeveen R, et al. Postprandial lipemia and the risk of coronary heart disease and stroke: The Atherosclerosis Risk in Communities (ARIC) Study. BMJ Open Diabetes Research and Care. 2017;**5**:e000335

[32] Jellinger P, Handelsman Y, Rosenblit P, Bloomgarden Z, Fonseca V, Garber A, et al. American association of clinical endocrinologists and American college of endocrinologist guidelines for management of dyslipidemia and prevention of cardiovascular disease. CPG for managing dyslipidemia and prevention of CVD. Endocrine Practice. 2017;**23**(Suppl 2)

[33] White K, Moorthy M, Akinkuolie A, Demier O, Ridker P, Cook N, et al. Identifying an optimal cutpoint value for the diagnosis of hypertriglyceridemia in the nonfasting state. Clinical Chemistry. 2015;**61**(9):1156-1163

[34] Samson CE, Galia AL, Llave KI, Zacarias, MB, Mercado-Asis LB. Postprandial peaking and plateauing of triglycerides and VLDL in patients with underlying cardiovascular diseases despite treatment. International Journal of Endocrinology and Metabolism. 2012;**10**:587-593

[35] Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Senman LJ, et al. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. The American Journal of Cardiology. 2004;**93**(1):31-39

[36] Cavallero E, Dachet C, Assadolahi F, Martin C, Navarro N, Ansquer JC, et al. Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load in patients with Type 2 DM and optimal glucose control. Atherosclerosis. 2003;**166**:151

[37] Ooi TC, Cousins M, Ooi DS, Nakajima K, Edwards AL. Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia. Atherosclerosis. 2004;**172**:375

[38] Turker I, Demirag NG, Tanaci N, Tutar N, Kirbas I. Effects of orlistat plus diet on postprandial lipemia and brachial artery reactivity in normolipidemic, obese women with normal glucose tolerance: A prospective, randomized, controlled study. Current Therapeutic Research, Clinical and Experimental. 2006;**67**(3):159-173

[39] Bozetto G, Annuzzi A, Della Corte G, Patti L, Cipriano B, Mangione A, et al. Ezetimibe beneficially influences fasting and postprandial triglyceride-rich lipoproteins in type 2 diabetes. Atherosclerosis. 2011;**217**(1):142-148

[40] Yunoki K, Nakamura N, Miyoshi T, Enko K, Kohno K, Morita H, et al. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction. Atherosclerosis. 2011;**217**(2):486-491

**97**

Section 3

Special Topics in

the Management of

Dyslipidemia

Section 3

Special Topics in the Management of Dyslipidemia

*Dyslipidemia*

2017;**5**:e000335

2017;**23**(Suppl 2)

2015;**61**(9):1156-1163

2012;**10**:587-593

2004;**93**(1):31-39

[34] Samson CE, Galia AL, Llave KI, Zacarias, MB,

compared with non-fasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;**298**:309-316

[36] Cavallero E, Dachet C, Assadolahi F, Martin C, Navarro N, Ansquer JC, et al. Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load in patients with Type 2 DM and optimal glucose control. Atherosclerosis.

[37] Ooi TC, Cousins M, Ooi DS, Nakajima K, Edwards AL. Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia. Atherosclerosis.

[38] Turker I, Demirag NG, Tanaci N, Tutar N, Kirbas I. Effects of orlistat plus diet on postprandial lipemia and brachial artery reactivity in normolipidemic, obese women with normal glucose tolerance: A prospective, randomized, controlled study. Current Therapeutic Research, Clinical and Experimental. 2006;**67**(3):159-173

[39] Bozetto G, Annuzzi A, Della Corte G, Patti L, Cipriano B, Mangione A, et al. Ezetimibe beneficially influences fasting and postprandial triglyceride-rich lipoproteins in type 2 diabetes. Atherosclerosis. 2011;**217**(1):142-148

[40] Yunoki K, Nakamura N, Miyoshi T, Enko K, Kohno K, Morita H, et al. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction. Atherosclerosis. 2011;**217**(2):486-491

2003;**166**:151

2004;**172**:375

[31] Kats D, Sharrett A, Ginsberg H, Nambi V, Ballantyne C, Hoogeveen R, et al. Postprandial lipemia and the risk of coronary heart disease and stroke: The Atherosclerosis Risk in Communities (ARIC) Study. BMJ Open Diabetes Research and Care.

[32] Jellinger P, Handelsman Y,

Rosenblit P, Bloomgarden Z, Fonseca V, Garber A, et al. American association of clinical endocrinologists and American college of endocrinologist guidelines for management of dyslipidemia and prevention of cardiovascular disease. CPG for managing dyslipidemia and prevention of CVD. Endocrine Practice.

[33] White K, Moorthy M, Akinkuolie A, Demier O, Ridker P, Cook N, et al. Identifying an optimal cutpoint value for the diagnosis of hypertriglyceridemia in the

nonfasting state. Clinical Chemistry.

Mercado-Asis LB. Postprandial peaking and plateauing of triglycerides and VLDL in patients with underlying cardiovascular diseases despite treatment. International Journal of Endocrinology and Metabolism.

[35] Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Senman LJ, et al. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. The American Journal of Cardiology.

**96**

**99**

such as ginger and turmeric.

**Chapter 6**

**Abstract**

of Dyslipidemia

*Abdullah Glil Alkushi*

Alternative Natural Management

In hypercholesterolemic patients, besides therapeutic treatments, alternative treatments can be used such as lifestyle changes, e.g. avoiding smoking, regular exercise, and consuming a diet rich in fiber and low in trans saturated and saturated fats. There are also certain plant products, such as the gum residue guggulipid, that are used in India as a traditional medicine to reduce blood cholesterol levels. Similarly, red yeast rice and rice bran oil have been observed to reduce elevated cholesterol levels. Other herbal products have also been investigated for their role in lowering cholesterol levels, as well as various other herbs and spices such as ginger and turmeric. Another herbal remedy available for reducing high cholesterol levels is the leaf extract of *Cynara scolymus*, commonly known as artichoke thistle. *Cynara cardunculus* var. *scolymus*, or globe artichoke, is mainly cultivated as a food crop. It has an important effect on reducing plasma cholesterol and low-density lipoprotein levels.

Hypercholesterolemia (HC) is defined as the increase in the levels of cholesterol in the blood. As per the recommendation of the expert panel of the National Cholesterol Education Program, desirable blood cholesterol levels should be <200 mg/dL. Levels ranging between 200 and 239 mg/dL are considered as borderline for cholesterol levels, and individuals with blood cholesterol levels above 240 mg/dL are considered hypercholesterolemic [1]. HC occurs due to both environmental and genetic factors [2]. According to familial HC, environmental factors mainly include obesity and diets rich in saturated fats, whereas genetic factors comprise the additive effects of several genes or defects in a single gene [3–5]. Elevated cholesterol levels in the blood not only cause coronary heart disease but can also lead to stroke and damage to the brain [6, 7]. High cholesterol has also been linked to peripheral vascular disease, in which fat is deposited mainly in the arteries that lead to the legs and feet [8]. HC is also linked to type 2 diabetes and hypertension [9, 10]. In hypercholesterolemic patients, besides therapeutic treatments, alternative treatments can be used such as lifestyle changes, e.g. avoiding smoking, regular exercise, and consuming a diet high in fiber and low in trans saturated and saturated fats. Similarly, red yeast rice and rice bran oil have been observed to reduce elevated cholesterol levels. Other herbal products have also been investigated for their role in lowering cholesterol levels, as well as various other herbs and spices

**Keywords:** alternative medicine, lifestyle changes, natural plants,

Chinese medicine, vitamins and minerals

**1. Dyslipidemia and Lifestyle**

## **Chapter 6**

## Alternative Natural Management of Dyslipidemia

*Abdullah Glil Alkushi*

## **Abstract**

In hypercholesterolemic patients, besides therapeutic treatments, alternative treatments can be used such as lifestyle changes, e.g. avoiding smoking, regular exercise, and consuming a diet rich in fiber and low in trans saturated and saturated fats. There are also certain plant products, such as the gum residue guggulipid, that are used in India as a traditional medicine to reduce blood cholesterol levels. Similarly, red yeast rice and rice bran oil have been observed to reduce elevated cholesterol levels. Other herbal products have also been investigated for their role in lowering cholesterol levels, as well as various other herbs and spices such as ginger and turmeric. Another herbal remedy available for reducing high cholesterol levels is the leaf extract of *Cynara scolymus*, commonly known as artichoke thistle. *Cynara cardunculus* var. *scolymus*, or globe artichoke, is mainly cultivated as a food crop. It has an important effect on reducing plasma cholesterol and low-density lipoprotein levels.

**Keywords:** alternative medicine, lifestyle changes, natural plants, Chinese medicine, vitamins and minerals

#### **1. Dyslipidemia and Lifestyle**

Hypercholesterolemia (HC) is defined as the increase in the levels of cholesterol in the blood. As per the recommendation of the expert panel of the National Cholesterol Education Program, desirable blood cholesterol levels should be <200 mg/dL. Levels ranging between 200 and 239 mg/dL are considered as borderline for cholesterol levels, and individuals with blood cholesterol levels above 240 mg/dL are considered hypercholesterolemic [1]. HC occurs due to both environmental and genetic factors [2]. According to familial HC, environmental factors mainly include obesity and diets rich in saturated fats, whereas genetic factors comprise the additive effects of several genes or defects in a single gene [3–5]. Elevated cholesterol levels in the blood not only cause coronary heart disease but can also lead to stroke and damage to the brain [6, 7]. High cholesterol has also been linked to peripheral vascular disease, in which fat is deposited mainly in the arteries that lead to the legs and feet [8]. HC is also linked to type 2 diabetes and hypertension [9, 10].

In hypercholesterolemic patients, besides therapeutic treatments, alternative treatments can be used such as lifestyle changes, e.g. avoiding smoking, regular exercise, and consuming a diet high in fiber and low in trans saturated and saturated fats. Similarly, red yeast rice and rice bran oil have been observed to reduce elevated cholesterol levels. Other herbal products have also been investigated for their role in lowering cholesterol levels, as well as various other herbs and spices such as ginger and turmeric.

#### *Dyslipidemia*

Another herbal remedy is the leaf extract of *Cynara scolymus*, commonly known as artichoke thistle. *Cynara cardunculus* var. *scolymus*, or globe artichoke, is mainly cultivated as a food crop. It has important effects in reducing plasma cholesterol and low-density lipoprotein (LDL) levels. Also, many vitamins and minerals help to reduce and control fat and cholesterol levels.

These will be discussed in this chapter.

#### **1.1 Lifestyle changes**

One of the most important things in the natural treatments of dyslipidemia is to reduce body weight and take regular exercise [11], which will help to regulate blood cholesterol [12] and decrease the high risk of developing cardiovascular diseases, especially coronary heart disease [13].

#### **1.2 Stopping smoking**

This is important in controlling high blood cholesterol, decreasing the risk of coronary heart disease, and improving high-density lipoprotein (HDL) cholesterol [14]. The mechanism of cigarette smoking will have an effect on lipid profile and enhance oxidation of plasma LDL, which leads to endothelial function impairment.

#### **1.3 Alcohol intake**

Alcohol has adverse effects on cholesterol and lipid levels, including raising serum triglyceride and HDL cholesterol levels. It has a minimum effect on LDL cholesterol but has effects on the body, including hepatic toxicity, cardiomyopathy, impaired reflexes, and psychosocial problems [15].

#### **1.4 Exercise**

Exercise is important in reducing the chance of developing heart disease. It is also important to reduce body weight, which can lead to reduced levels of fat and cholesterol [11].

Physical activity and exercise can be an important factor to improve cholesterol levels, increase HDL, and reduce LDL and triglycerides [16].

Aerobic exercise can generally improve lipid profile [17].

Moderate intensity aerobic exercise and an increase in physical activity in healthy people for more than 30 minutes for 5 days a week are important to maintain low LDL, cholesterol, and triglyceride levels, as well as increase HDL levels [18, 19].

In dyslipidemia especially in older or disabled individuals, increasing physical activity for more than 30 minutes for 5 days a week, moderate-intensity aerobic exercise [19], and high-intensity resistance exercises can all reduce LDL and triglycerides and increase HDL [20].

The beneficial effects of regular physical activity and exercise on cholesterol levels are important in the management of dyslipidemia and can lead to reducing the risks of heart attacks, strokes, and coronary heart disease.

#### **2. Food that should be avoided**

1.Food containing too much sugar and carbohydrates, which stimulate the liver to produce more cholesterol, should be avoided.

**101**

**3.3 Garlic**

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

diseases.

**3. Food and dyslipidemia**

**3.1 Dietary fiber intake**

serum cholesterol levels.

blood cholesterol levels.

generally unaffected [21].

• Docosahexaenoic acid (DHA)

• Eicosapentaenoic acid (EPA)

**3.2 Omega-3**

cholesterol [22–24].

2.Hydrogenated and trans fats increase cholesterol and the risk of cardiovascular

3.Red meat and animal products increase the risk of dyslipidemia.

Foods that help to decrease dyslipidemia are shown in **Tables 1** and **2**.

Dietary fiber (DF) intake provides many health benefits. However, the average fiber intake for US children and adults is less than half of the recommended levels. Individuals with high intakes of DF appear to be at significantly lower risk for developing coronary heart disease, stroke, hypertension, diabetes, obesity, and certain gastrointestinal diseases. Increasing fiber intake lowers blood pressure and

The effect of dietary soluble fiber on serum cholesterol levels has been extensively documented and promoted. The main mechanisms for the cholesterollowering effects of water-soluble and -insoluble DFs include binding and excretion of bile acids (BAs) in the small intestine. The cholesterol-reducing effect of water-insoluble DF, such as lignin or citric fiber, is rather low compared to water-soluble DF and is mainly based on direct binding of BAs. In the small intestine the BAs are bound to the insoluble DF and excreted from the enterohepatic circulation together with the undigested DF, which results in a lowering of

In addition, soluble fibers are known to bind to BAs in the small intestine, thereby removing them from the body and reducing the rate of BA recycling. The loss of BAs in the stool stimulates the liver to increase cholesterol uptake from the circulation to replenish the BA supply. As a result, concentrations of serum total and LDL cholesterol are reduced, while HDL cholesterol and triglycerides are

Omega-3 fatty acids are important in reducing triglycerides and non-HDL

Reducing triglycerides and cholesterol helps to reduce atherosclerosis [25–28]. Using omega-3 fatty acids has benefits in metabolic abnormality associated with

Garlic (*Allium sativum*) belongs to onion genes. It used as an herb medication for various diseases. It has major roles in decreasing risk factors of cardiovascular

Omega-3 fatty acids are presented in two formulas:

non-alcoholic fatty liver in patients with hyperlipidemia [29].

diseases like high blood pressure and high serum lipids [30–33].


## **3. Food and dyslipidemia**

*Dyslipidemia*

**1.1 Lifestyle changes**

**1.2 Stopping smoking**

impairment.

**1.4 Exercise**

cholesterol [11].

erides and increase HDL [20].

**2. Food that should be avoided**

**1.3 Alcohol intake**

reduce and control fat and cholesterol levels. These will be discussed in this chapter.

especially coronary heart disease [13].

impaired reflexes, and psychosocial problems [15].

levels, increase HDL, and reduce LDL and triglycerides [16]. Aerobic exercise can generally improve lipid profile [17].

the risks of heart attacks, strokes, and coronary heart disease.

to produce more cholesterol, should be avoided.

Another herbal remedy is the leaf extract of *Cynara scolymus*, commonly known as artichoke thistle. *Cynara cardunculus* var. *scolymus*, or globe artichoke, is mainly cultivated as a food crop. It has important effects in reducing plasma cholesterol and low-density lipoprotein (LDL) levels. Also, many vitamins and minerals help to

One of the most important things in the natural treatments of dyslipidemia is to reduce body weight and take regular exercise [11], which will help to regulate blood cholesterol [12] and decrease the high risk of developing cardiovascular diseases,

This is important in controlling high blood cholesterol, decreasing the risk of coronary heart disease, and improving high-density lipoprotein (HDL) cholesterol [14]. The mechanism of cigarette smoking will have an effect on lipid profile and enhance oxidation of plasma LDL, which leads to endothelial function

Alcohol has adverse effects on cholesterol and lipid levels, including raising serum triglyceride and HDL cholesterol levels. It has a minimum effect on LDL cholesterol but has effects on the body, including hepatic toxicity, cardiomyopathy,

Exercise is important in reducing the chance of developing heart disease. It is also important to reduce body weight, which can lead to reduced levels of fat and

Physical activity and exercise can be an important factor to improve cholesterol

Moderate intensity aerobic exercise and an increase in physical activity in healthy people for more than 30 minutes for 5 days a week are important to maintain low LDL, cholesterol, and triglyceride levels, as well as increase HDL levels [18, 19]. In dyslipidemia especially in older or disabled individuals, increasing physical activity for more than 30 minutes for 5 days a week, moderate-intensity aerobic exercise [19], and high-intensity resistance exercises can all reduce LDL and triglyc-

The beneficial effects of regular physical activity and exercise on cholesterol levels are important in the management of dyslipidemia and can lead to reducing

1.Food containing too much sugar and carbohydrates, which stimulate the liver

**100**

Foods that help to decrease dyslipidemia are shown in **Tables 1** and **2**.

## **3.1 Dietary fiber intake**

Dietary fiber (DF) intake provides many health benefits. However, the average fiber intake for US children and adults is less than half of the recommended levels. Individuals with high intakes of DF appear to be at significantly lower risk for developing coronary heart disease, stroke, hypertension, diabetes, obesity, and certain gastrointestinal diseases. Increasing fiber intake lowers blood pressure and serum cholesterol levels.

The effect of dietary soluble fiber on serum cholesterol levels has been extensively documented and promoted. The main mechanisms for the cholesterollowering effects of water-soluble and -insoluble DFs include binding and excretion of bile acids (BAs) in the small intestine. The cholesterol-reducing effect of water-insoluble DF, such as lignin or citric fiber, is rather low compared to water-soluble DF and is mainly based on direct binding of BAs. In the small intestine the BAs are bound to the insoluble DF and excreted from the enterohepatic circulation together with the undigested DF, which results in a lowering of blood cholesterol levels.

In addition, soluble fibers are known to bind to BAs in the small intestine, thereby removing them from the body and reducing the rate of BA recycling. The loss of BAs in the stool stimulates the liver to increase cholesterol uptake from the circulation to replenish the BA supply. As a result, concentrations of serum total and LDL cholesterol are reduced, while HDL cholesterol and triglycerides are generally unaffected [21].

## **3.2 Omega-3**

Omega-3 fatty acids are presented in two formulas:


Omega-3 fatty acids are important in reducing triglycerides and non-HDL cholesterol [22–24].

Reducing triglycerides and cholesterol helps to reduce atherosclerosis [25–28].

Using omega-3 fatty acids has benefits in metabolic abnormality associated with non-alcoholic fatty liver in patients with hyperlipidemia [29].

## **3.3 Garlic**

Garlic (*Allium sativum*) belongs to onion genes. It used as an herb medication for various diseases. It has major roles in decreasing risk factors of cardiovascular diseases like high blood pressure and high serum lipids [30–33].

#### *Dyslipidemia*


#### **Table 1.**

*Foods and herbals and their effects on lipid profiles.*


#### **Table 2.**

*Vitamins and minerals and their effects on lipid profiles.*

Garlic reduces cholesterol, LDL, and triglyceride levels by inhibiting cholesterol biosynthesis in the liver and LDL oxidation [34–38].

There are a few side effects associated with using garlic such as allergic dermatitis [39] and its interference with oral anticoagulant drugs [39].

#### **3.4 Read yeast rice**

Red yeast rice is a product of rice and is found in China and many Asian countries where it is used as a traditional medicine [40, 41].

**103**

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

emia, have four beneficial characteristics:

seed, and folium nelumbinis.

Radix polygoni multiflori.

**3.6 Artichoke**

hypercholesteremia) [41, 43].

**3.5 Chinese medicine**

Biochemically it contains polyketides, unsaturated fatty acids, phytosterols, pigments, and monacolins [41, 42]. It lowers cholesterol by inhibiting 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is the rate-limiting step for cholesterol synthesis in the liver. This component, especially monacolins, is chemically similar to lovastatin (a drug used to treat

Traditional Chinese medicine (TCM) has been used in clinical practice for many centuries. Chinese medicine has shown good effects for human health and treating many diseases. Recently, TCM has shown a beneficial effect for treating dyslipidemia; however, its mechanism remains unclear or totally unknown. Many studies on dyslipidemia with a single Chinese herb showed that TCM can improve phlegm, dampness, and blood stasis syndromes in patients with hyperlipidemia, therefore it has a beneficial effect for lowering hyperlipidemia monomers or effective extracts [44–46]. One study [46] showed that Chinese herbs, which have effects on hyperlipid-

1.Clearing heat and removing toxicity, for example, Radix et Rhizoma Rhei, Rhizoma Polygoni Cuspidati, Semen Cassia, Coptis chinensis, Scutellaria

2.Promoting blood circulation and removing blood stasis, for example, Fructus crataegi, red yeast rice, Rhizoma, Radix *Salvia miltiorrhizae*, and Turmerone.

3.Eliminating dampness and phlegm, for example, Rhizoma Alismatis, plantain

4.Increasing body energy, for example, Radix Astragali, Radix Ginseng, and

Another herbal remedy available for reducing high cholesterol levels is the leaf extract of *Cynara scolymus*, commonly known as artichoke thistle. *Cynara cardunculus* var. *scolymus*, or globe artichoke, is mainly cultivated as a food crop. It is a perennial plant that is largely native to the Mediterranean region in Southern Europe and Northern Africa, and the Canary Islands. In addition to food, artichoke is used in tea and liqueur preparation. Studies on the medicinal properties of artichoke have been continuing over the last six decades. Several in vitro and in vivo studies have investigated the effect of artichoke leaf extract (ALE), especially cymarine, in reducing plasma cholesterol levels [47–50]. Along with cymarine, the antiatherosclerotic effect of luteolin-rich artichoke extract reduces LDL oxidation in a dosedependent manner [51]. A dose-dependent inhibition of cholesterol biosynthesis,

In addition to in vitro and in vivo studies, randomized controlled studies have assessed the effects of the oral administration of ALE in hypercholesterolemic patients. Bundy et al. assessed the effect of ALE on plasma lipid levels and general well-being in healthy individuals with mild to moderate HC [53]. The participants of the study received 1280 mg of ALE daily (four tablets of 320 mg) for 12 weeks. The majority of participants were females, and almost 90% of them were more than 40 years old. The plasma cholesterol levels were found to be reduced by 4.2%

using ALE, was also shown in primary-cultured rat hepatocytes [52].

baicalensis, Gynostemma pentaphyllum, and Radix Puerariae.

Biochemically it contains polyketides, unsaturated fatty acids, phytosterols, pigments, and monacolins [41, 42]. It lowers cholesterol by inhibiting 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is the rate-limiting step for cholesterol synthesis in the liver. This component, especially monacolins, is chemically similar to lovastatin (a drug used to treat hypercholesteremia) [41, 43].

## **3.5 Chinese medicine**

*Dyslipidemia*

**Table 1.**

**102**

**Table 2.**

**3.4 Read yeast rice**

Garlic reduces cholesterol, LDL, and triglyceride levels by inhibiting cholesterol

Lipoic acid Mineral Lowers LDL and protects against cholesterol oxidation

There are a few side effects associated with using garlic such as allergic dermati-

Red yeast rice is a product of rice and is found in China and many Asian coun-

biosynthesis in the liver and LDL oxidation [34–38].

*Vitamins and minerals and their effects on lipid profiles.*

tries where it is used as a traditional medicine [40, 41].

tis [39] and its interference with oral anticoagulant drugs [39].

Chromium Mineral Increases HDL level Choline Mineral Controls HDL level

**Name Type Effects on lipid profile**

**Plant name Type Effects on lipid profile**

Red yeast rice Food Lowers cholesterol level Chinese medicine Herbal Lowers hyperlipidemia Artichoke Food Lowers cholesterol level Fenugreek Herbal Lowers cholesterol level

Ginger Food Lowers cholesterol level

Dietary fiber Food Lowers LDL and cholesterol levels Omega-3 Food Lowers cholesterol and triglyceride levels Garlic Food Lowers cholesterol and triglyceride levels

Gum residue guggulipid Herbal Lowers LDL and cholesterol levels

Vitamin D Fat-soluble vitamin Reduces the risk of arterial blockage Magnesium Mineral Protects against LDL oxidation Manganese Mineral Protects against LDL oxidation

Selenium Mineral Protects against dangerous lipoproteins Copper Mineral Protects against dangerous lipoproteins Coenzyme Q10 Mineral Protects against dangerous lipoproteins

Inositol Mineral Lowers LDL and triglyceride levels

Carnitine Mineral Lowers LDL and triglyceride levels

Zinc Mineral Protects against dangerous lipoproteins and promotes HDL

Lowers LDL, cholesterol, and triglyceride levels

Lowers LDL, cholesterol, and triglyceride levels

Protects against LDL oxidation

vitamin

vitamin

vitamin

Vitamin B3 (niacin) Water-soluble

*Foods and herbals and their effects on lipid profiles.*

Vitamin B5 Water-soluble

Vitamin C Water-soluble

Traditional Chinese medicine (TCM) has been used in clinical practice for many centuries. Chinese medicine has shown good effects for human health and treating many diseases. Recently, TCM has shown a beneficial effect for treating dyslipidemia; however, its mechanism remains unclear or totally unknown. Many studies on dyslipidemia with a single Chinese herb showed that TCM can improve phlegm, dampness, and blood stasis syndromes in patients with hyperlipidemia, therefore it has a beneficial effect for lowering hyperlipidemia monomers or effective extracts [44–46].

One study [46] showed that Chinese herbs, which have effects on hyperlipidemia, have four beneficial characteristics:


### **3.6 Artichoke**

Another herbal remedy available for reducing high cholesterol levels is the leaf extract of *Cynara scolymus*, commonly known as artichoke thistle. *Cynara cardunculus* var. *scolymus*, or globe artichoke, is mainly cultivated as a food crop. It is a perennial plant that is largely native to the Mediterranean region in Southern Europe and Northern Africa, and the Canary Islands. In addition to food, artichoke is used in tea and liqueur preparation. Studies on the medicinal properties of artichoke have been continuing over the last six decades. Several in vitro and in vivo studies have investigated the effect of artichoke leaf extract (ALE), especially cymarine, in reducing plasma cholesterol levels [47–50]. Along with cymarine, the antiatherosclerotic effect of luteolin-rich artichoke extract reduces LDL oxidation in a dosedependent manner [51]. A dose-dependent inhibition of cholesterol biosynthesis, using ALE, was also shown in primary-cultured rat hepatocytes [52].

In addition to in vitro and in vivo studies, randomized controlled studies have assessed the effects of the oral administration of ALE in hypercholesterolemic patients. Bundy et al. assessed the effect of ALE on plasma lipid levels and general well-being in healthy individuals with mild to moderate HC [53]. The participants of the study received 1280 mg of ALE daily (four tablets of 320 mg) for 12 weeks. The majority of participants were females, and almost 90% of them were more than 40 years old. The plasma cholesterol levels were found to be reduced by 4.2%

#### *Dyslipidemia*

in the group administered ALE, whereas they increased by 1.9% in the placebo group. No significant difference in LDL cholesterol, HDL cholesterol, or triglycerides was observed between the groups. Englisch et al. conducted a similar study among 18–70-year-old hypercholesterolemic patients [54]. In addition to treatment with cholesterol-reducing drugs, participants were prohibited from antibiotic treatment. The intervention group received 1800 mg of ALE for 6 weeks. Total cholesterol levels were reduced by 18.5% in the group administered with ALE as compared to a 8.6% reduction in the placebo group. In addition to atherosclerosis, HC can affect organs such as kidneys. Studies in rats have shown that cholesterol can increase the incidence of glomerulosclerosis, and in vitro cell culture studies using human glomerular cells revealed the possible mechanisms that are involved in lipid-influenced glomerular damage [55]. Another study showed that treating HC in obese rats reduced their glomerular injuries [56]. Similar observations have also been made in studies with humans. Individuals with high triglycerides or a lecithin–cholesterol acyltransferase deficiency gradually developed renal failure due to glomerulosclerosis [57].

*C. cardunculus* leaf extract (CCL) not only has cholesterol-reducing capacity but also reduces blood glucose levels and repairs impaired kidney function and damage. These findings are significant particularly because HC results in further complications such as diabetes and kidney damage, both of which can be treated effectively with artichoke [50].

The hypercholesterolemic properties of artichoke involve inhibition of the enzyme HMG-CoA reductase. By lowering blood cholesterol levels and improving lipid profile, experts believe that artichoke can reduce the risks of arteriosclerosis and coronary heart disease and found that both CCL and *C. cardunculus* pulp extract.

decrease the concentration of the respective enzymes (an increase in levels of aspartate transaminase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) are indicators of liver dysfunction), hence serving hepatoprotective and regenerating effects [58]. Thus, it was concluded that artichoke has a beneficial effect on cardiovascular and liver disease.

#### **3.7 Fenugreek seeds**

Fenugreek (*Trigonella foenumgraecum*) has an effect on cholesterol and blood sugar. It is a good source of dietary fiber and has beneficial effects on decreasing cholesterol levels in blood and the liver [59, 60].

The mechanism of the lipid-lowering effect of fenugreek seeds is due to the presence of 4-hydroxyisoleucine, a branched chain amino acid [61], and its action on adipocytes and liver cells, which leads to decreased triglycerides, cholesterol, and LDL [62, 63].

#### **3.8 Gum residue guggulipid**

A gum resin of the tree *Commiphora mukul*, used for the management of obesity and lipid disorders, is centuries old [64]. The extract of this gum resin, designated guggulipid, has lipid-lowering effects in normal and hyperlipidemic animals (rats, rabbits, and monkeys) [65, 66].

In humans, many studies of the effect of gum resin gumsome in response to guggul treatment were observed in of patients in India [67].

In the United States, studies showed that 18% of patients showed a response to guggulipid treatment, with a decrease in LDL levels of more than 5% [68].

Variations in the results of clinical studies are due to many factors such as ethnic and genetic backgrounds, dietary restraints, and lifestyle [69].

**105**

**4.7 Zinc**

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

Ginger (*Zingiber officinale*) is a traditional natural plant, which has many characteristics such as decreasing lipid levels, antiplatelet aggregation, and antioxidant and anticarcinogenic qualities [70]. Several studies show that ginger can lower high cholesterol levels in animals. In humans a few study results showed the effects of using ginger in patients with high cholesterol and in the treatment of

Niacin is a water-soluble vitamin. It effectively lowers the atherogenic lipoprotein(a) by decreasing the rate of synthesis in the liver and lowering the level of cholesterols as well as triglycerides [72, 73]. It is important in reducing the

Vitamin B5 is a water-soluble vitamin, which is also called pantothenic acid. It is important in the synthesis of coenzyme A, as well as lowering LDL metabolism and

Vitamin C is a water-soluble vitamin and is essential for repairing tissues and enzyme production. It has a role in lipid metabolism, protects LDL from oxidation,

Vitamin D is a fat-soluble vitamin and has an important function in the body, including calcium homeostasis and suppressing foam cell formation, which reduces the risk of arterial blockage [78, 79] therefore reducing cardiovascular disease

Manganese is a cofactor to the antioxidant superoxide dismutase that repairs

Zinc protects against dangerous lipoproteins that lead to vascular inflammation

and plaque formation. It also controls the gene that makes HDL [84, 85].

and lowers atherosclerosis and lipoprotein(a) in some people [76, 77].

Magnesium protects LDL from being oxidized [80, 81].

damage to blood vessels caused by oxidized LDL [82, 83].

**3.9 Ginger**

dyslipidemia [71].

**4.2 Vitamin B5**

**4.3 Vitamin C**

**4.4 Vitamin D**

problems.

**4.5 Magnesium**

**4.6 Manganese**

**4. Vitamins and minerals**

incidence of cardiovascular disease.

reducing triglycerides [74, 75].

**4.1 Vitamin B3 (niacin)**

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

### **3.9 Ginger**

*Dyslipidemia*

due to glomerulosclerosis [57].

effect on cardiovascular and liver disease.

cholesterol levels in blood and the liver [59, 60].

artichoke [50].

pulp extract.

**3.7 Fenugreek seeds**

**3.8 Gum residue guggulipid**

rabbits, and monkeys) [65, 66].

in the group administered ALE, whereas they increased by 1.9% in the placebo group. No significant difference in LDL cholesterol, HDL cholesterol, or triglycerides was observed between the groups. Englisch et al. conducted a similar study among 18–70-year-old hypercholesterolemic patients [54]. In addition to treatment with cholesterol-reducing drugs, participants were prohibited from antibiotic treatment. The intervention group received 1800 mg of ALE for 6 weeks. Total cholesterol levels were reduced by 18.5% in the group administered with ALE as compared to a 8.6% reduction in the placebo group. In addition to atherosclerosis, HC can affect organs such as kidneys. Studies in rats have shown that cholesterol can increase the incidence of glomerulosclerosis, and in vitro cell culture studies using human glomerular cells revealed the possible mechanisms that are involved in lipid-influenced glomerular damage [55]. Another study showed that treating HC in obese rats reduced their glomerular injuries [56]. Similar observations have also been made in studies with humans. Individuals with high triglycerides or a lecithin–cholesterol acyltransferase deficiency gradually developed renal failure

*C. cardunculus* leaf extract (CCL) not only has cholesterol-reducing capacity but also reduces blood glucose levels and repairs impaired kidney function and damage. These findings are significant particularly because HC results in further complications such as diabetes and kidney damage, both of which can be treated effectively with

The hypercholesterolemic properties of artichoke involve inhibition of the enzyme HMG-CoA reductase. By lowering blood cholesterol levels and improving lipid profile, experts believe that artichoke can reduce the risks of arteriosclerosis and coronary heart disease and found that both CCL and *C. cardunculus*

decrease the concentration of the respective enzymes (an increase in levels of aspartate transaminase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) are indicators of liver dysfunction), hence serving hepatoprotective and regenerating effects [58]. Thus, it was concluded that artichoke has a beneficial

Fenugreek (*Trigonella foenumgraecum*) has an effect on cholesterol and blood sugar. It is a good source of dietary fiber and has beneficial effects on decreasing

The mechanism of the lipid-lowering effect of fenugreek seeds is due to the presence of 4-hydroxyisoleucine, a branched chain amino acid [61], and its action on adipocytes and liver cells, which leads to decreased triglycerides, cholesterol, and LDL [62, 63].

A gum resin of the tree *Commiphora mukul*, used for the management of obesity and lipid disorders, is centuries old [64]. The extract of this gum resin, designated guggulipid, has lipid-lowering effects in normal and hyperlipidemic animals (rats,

In humans, many studies of the effect of gum resin gumsome in response to

guggulipid treatment, with a decrease in LDL levels of more than 5% [68].

In the United States, studies showed that 18% of patients showed a response to

Variations in the results of clinical studies are due to many factors such as ethnic

guggul treatment were observed in of patients in India [67].

and genetic backgrounds, dietary restraints, and lifestyle [69].

**104**

Ginger (*Zingiber officinale*) is a traditional natural plant, which has many characteristics such as decreasing lipid levels, antiplatelet aggregation, and antioxidant and anticarcinogenic qualities [70]. Several studies show that ginger can lower high cholesterol levels in animals. In humans a few study results showed the effects of using ginger in patients with high cholesterol and in the treatment of dyslipidemia [71].

## **4. Vitamins and minerals**

## **4.1 Vitamin B3 (niacin)**

Niacin is a water-soluble vitamin. It effectively lowers the atherogenic lipoprotein(a) by decreasing the rate of synthesis in the liver and lowering the level of cholesterols as well as triglycerides [72, 73]. It is important in reducing the incidence of cardiovascular disease.

## **4.2 Vitamin B5**

Vitamin B5 is a water-soluble vitamin, which is also called pantothenic acid. It is important in the synthesis of coenzyme A, as well as lowering LDL metabolism and reducing triglycerides [74, 75].

## **4.3 Vitamin C**

Vitamin C is a water-soluble vitamin and is essential for repairing tissues and enzyme production. It has a role in lipid metabolism, protects LDL from oxidation, and lowers atherosclerosis and lipoprotein(a) in some people [76, 77].

#### **4.4 Vitamin D**

Vitamin D is a fat-soluble vitamin and has an important function in the body, including calcium homeostasis and suppressing foam cell formation, which reduces the risk of arterial blockage [78, 79] therefore reducing cardiovascular disease problems.

#### **4.5 Magnesium**

Magnesium protects LDL from being oxidized [80, 81].

#### **4.6 Manganese**

Manganese is a cofactor to the antioxidant superoxide dismutase that repairs damage to blood vessels caused by oxidized LDL [82, 83].

#### **4.7 Zinc**

Zinc protects against dangerous lipoproteins that lead to vascular inflammation and plaque formation. It also controls the gene that makes HDL [84, 85].

## **4.8 Selenium**

Selenium prevents postprandial change in lipoproteins, which makes them easy to oxidize and become harmful [86, 87].

## **4.9 Copper**

Many copper-dependent enzymes affect lipoprotein metabolism that build up fats and cholesterol in arteries [88–90].

## **4.10 Coenzyme Q10**

Coenzyme Q10 lowers lipoprotein(a) and improves dyslipidemia medicine [91, 92].

## **4.11 Chromium**

Chromium increases HDL levels and cooperates with niacin (B3) for dyslipidemia [93–95].

## **4.12 Choline**

Choline controls HDL metabolism due to the enzyme lecithin cholesterol acyltransferase that has beneficial effects on lipoprotein metabolism [96, 97].

## **4.13 Inositol**

Inositol lowers LDL levels, especially in patients with metabolic syndrome. It also lowers triglyceride levels [98–100].

## **4.14 Lipoic acid**

Lipoic acid lowers LDL levels and protects against oxidized cholesterol [101, 102].

## **4.15 Carnitine**

Carnitine lowers triglycerides, LDL, and the atherogenic lipoprotein(a) by transporting fatty acids into cells so that they can be used as energy [103–105].

## **5. Conclusion**

Besides pharmacological treatments for HC, using alternative treatments may help to increase the effectiveness of drugs. Alternative treatments can help to alter sedentary lifestyles and include exercise, stopping smoking, and eating a number of foods (omega-3, garlic, red yeast rice), herbs (Chinese medicine), vitamins (B, B5, C, and D), and many minerals.

**107**

**Author details**

Saudi Arabia

Abdullah Glil Alkushi

provided the original work is properly cited.

\*Address all correspondence to: dr.alkushi@gmail.com

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah,

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

*Dyslipidemia*

**4.8 Selenium**

**4.9 Copper**

**4.10 Coenzyme Q10**

**4.11 Chromium**

emia [93–95].

**4.12 Choline**

**4.13 Inositol**

**4.14 Lipoic acid**

**4.15 Carnitine**

**5. Conclusion**

C, and D), and many minerals.

to oxidize and become harmful [86, 87].

fats and cholesterol in arteries [88–90].

also lowers triglyceride levels [98–100].

Selenium prevents postprandial change in lipoproteins, which makes them easy

Many copper-dependent enzymes affect lipoprotein metabolism that build up

Coenzyme Q10 lowers lipoprotein(a) and improves dyslipidemia medicine [91, 92].

Chromium increases HDL levels and cooperates with niacin (B3) for dyslipid-

Choline controls HDL metabolism due to the enzyme lecithin cholesterol acyl-

Inositol lowers LDL levels, especially in patients with metabolic syndrome. It

Lipoic acid lowers LDL levels and protects against oxidized cholesterol [101, 102].

Carnitine lowers triglycerides, LDL, and the atherogenic lipoprotein(a) by transporting fatty acids into cells so that they can be used as energy [103–105].

Besides pharmacological treatments for HC, using alternative treatments may help to increase the effectiveness of drugs. Alternative treatments can help to alter sedentary lifestyles and include exercise, stopping smoking, and eating a number of foods (omega-3, garlic, red yeast rice), herbs (Chinese medicine), vitamins (B, B5,

transferase that has beneficial effects on lipoprotein metabolism [96, 97].

**106**

## **Author details**

Abdullah Glil Alkushi Department of Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

\*Address all correspondence to: dr.alkushi@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[22] Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. Journal of Cardiovascular Risk.

[23] Pownall HJ, Brauchi D, Kilinc C, et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of highdensity and low-density lipoproteins. Atherosclerosis. 1999;**143**(2):285-297

[24] Maki KC, Orloff DG, Nicholls SJ, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clinical Therapeutics.

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of exercise on plasma lipoproteins. The New England Journal of Medicine. 2002;**347**(19):1483-1492

[18] Aadahl M, Kjaer M, Jørgensen T. Associations between overall physical activity level and cardiovascular risk factors in an adult population. European Journal of Epidemiology. 2007;**22**(6):369-378

[19] Fett C, Fett W, Marchini J. Circuit weight training vs jogging in metabolic risk factors of overweight/obese women. Arquivos Brasileiros de Cardiologia. 2009;**93**(5):519-525

[20] Lira F, Yamashita A, Uchida M, et al. Low and moderate, rather than high intensity strength exercise induces benefit regarding plasma lipid profile. Diabetology and Metabolic Syndrome. 2010;**2**:31

[21] Osfor MMH, Ashsh AM, ElSawy NA, Qusty NFH, Alkushi AG. Effect of wheat bran consumption on serum lipid profile of hypercholesterolemia patients residence in Holly Makah. Asian Journal of Natural & Applied Sciences. 2016;**5**(1):1-9

[22] Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. Journal of Cardiovascular Risk. 1997;**4**(5-6):385-391

[23] Pownall HJ, Brauchi D, Kilinc C, et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of highdensity and low-density lipoproteins. Atherosclerosis. 1999;**143**(2):285-297

[24] Maki KC, Orloff DG, Nicholls SJ, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clinical Therapeutics. 2013;**35**(9):1400-1411

[25] Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, et al. Lossoffunction mutations in APOC3 and risk of ischemic vascular disease. The New England Journal of Medicine. 2014;**371**(1):32-41

[26] TG and HDL Working Group of the Exome. Sequencing Project NHLaBI. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. The New England Journal of Medicine. 2014;**371**(1):22-31

[27] Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk: New insights from human genetics. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;**35**(2):e3-e9

[28] Dewey FE, Gusarova V, O'Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. The New England Journal of Medicine. 2016;**374**(12):1123-1133

[29] Qin Y, Zhou Y, Chen S-H, et al. Fish oil supplements lower serum lipids and glucose in correlation with a reduction in plasma fibroblast growth factor 21 and prostaglandin E2 in nonalcoholic fatty liver disease associated with hyperlipidemia: A randomized clinical trial. PLoS One. 2015;**10**(7):e0133496. DOI: 10.1371/journal.pone.0133496. Herder C, editor

[30] Ackermann RT, Mulrow CD, Ramirez G. Garlic shows promise for improving some cardiovascular risk factors. Archives of Internal Medicine. 2001;**161**(6):813

[31] Qidwai W, Ashfaq T. Role of garlic usage in cardiovascular disease prevention: An evidence-based approach. Evidence-Based Complementary and Alternative Medicine. 2013;**2013**:1-9. Article ID 125649

[32] Khoo YSK, Aziz Z. Garlic supplementation and serum cholesterol:

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*Dyslipidemia*

**References**

1988;**148**:36-69

[1] Goodman DS, Hulley SB, Clark LT, et al. expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. The expert panel. Archives of Internal Medicine.

in pediatrics. Pediatric Endocrinology Reviews. 2008;**5**(Suppl 2):727-738

[11] National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Bethesda, Md: National Cholesterol Education Program, National Institutes of Health, National Heart, Lung, and Blood Institute; 1993. DHSS Publication

[10] Ivanovic B, Tadic M. Hypercholesterolemia and hypertension: Two sides of the same coin. American Journal of Cardiovascular Drugs. 2015;**15**:403-414

No. (NIH) 93-3095:5

[12] Yeshurun D, Gotto AM Jr. Hyperlipidemia: Perspectives in diagnosis and treatment. Southern Medical Journal. 1995;**88**:379-391

[13] The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. Lipid Research Clinics Program. JAMA. 1984;**251**:351-364

[14] Adam D, Gepner M, Megan E. Effect of smoking and smoking cessation on lipid and lipoprotein: Outcomes from a randomized clinical trial. American Heart Journal. 2011;**161**(1):145-151

[15] Ahmed SM, Clasen ME, Donnelly JF. Management of dyslipidemia in adults. American Family Physician.

[16] Ferguson MA, Alderson NL, Trost SG, et al. Effects of four different single exercise sessions on lipids, lipoproteins, and lipoprotein lipase. Journal of Applied Physiology.

[17] Kraus W, Houmard J, Duscha B, et al. Effects of the amount and intensity

1998;**57**(9):2192-2204

1998;**85**(3):1169-1174

[2] Bhatnagar D, Soran H, Durrington PN. Hypercholesterolaemia and its management. BMJ. 2008;**337**:a993

hypercholesterolemia. Journal of Lipid

[4] Grundy SM. George Lyman Duff Memorial Lecture. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease.

Arteriosclerosis and Thrombosis.

[5] Sniderman AD, Tsimikas S, Fazio S. The severe hypercholesterolemia phenotype: Clinical diagnosis,

management, and emerging therapies. Journal of the American College of Cardiology. 2014;**63**:1935-1947

[6] Clark LT. Cholesterol and heart disease: Current concepts in pathogenesis and treatment. Journal of the National Medical Association.

[7] Navi BB, Segal AZ. The role of cholesterol and statins in stroke. Current

Cardiology Reports. 2009;**11**:4-11

[9] Kwiterovich PO. Primary and

secondary disorders of lipid metabolism

Medicine. 1997;**2**:227-230

[8] Cooke JP. The pathophysiology of peripheral arterial disease: Rational targets for drug intervention. Vascular

1991;**11**:1619-1635

1986;**78**:743-751

[3] Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, et al. Familial defective apolipoprotein B-100: A mutation of apolipoprotein B that causes

Research. 1990;**31**:1337-1349

A meta-analysis. Journal of Clinical Pharmacy and Therapeutics. 2009;**34**(2):133-145

[33] Osamor PE, Owumi BE. Complementary and alternative medicine in the management of hypertension in an urban Nigerian community. BMC Complementary and Alternative Medicine. 2010;**10**(1):36

[34] Zhang XH, Lowe D, Giles P. A randomized trial of the effects of garlic oil upon coronary heart disease risk factors in trained male runners. Blood Coagulation & Fibrinolysis. 2001;**12**(1):67-74

[35] Lau BHS. Suppression of LDL oxidation by garlic compounds is a possible mechanism of cardiovascular health benefit. The Journal of Nutrition. 2006;**136**(3):765-768

[36] Duda G, Suliburska J, Pupek-Musialik D. Effects of short-term garlic supplementation on lipid metabolism and antioxidant status in hypertensive adults. Pharmacological Reports. 2008;**60**(2):163

[37] Zeng T, Zhang CL, Zhao XL. The roles of garlic on the lipid parameters: A systematic review of the literature. Critical Reviews in Food Science and Nutrition. 2013;**53**(3):215-230

[38] Jahan F, Nanjib K, Qidwai W. Role of garlic in dyslipidemia: An evidence based review. Scientific Journal of Biological Sciences. 2015;**4**(5):36-42

[39] Steiner M, Khan AH, Holbert D, Lin RI. A double-blind crossover study in moderately hypercholesterolaemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. The American Journal of Clinical Nutrition. 1996;**64**:866-870

[40] Burke FM. Red yeast rice for the treatment of dyslipidemia. Current Atherosclerosis Reports. 2015;**17**(4):495 [41] Francini-Pesenti F et al. Red yeast rice in the long-term treatment of hypercholesterolemia. A single-center experience. Acta Scientific Agriculture. 2017;**1**(3):16-18

[42] Patel S. Functional food red yeast rice (RYR) for metabolic syndrome amelioration: A review on pros and cons. World Journal of Microbiology and Biotechnology. 2016;**32**(5):2035-2042

[43] Zhang Z et al. Cytotoxic monacolins from red yeast rice, a Chinese medicine and food. Food Chemistry. 2016;**202**:262-268

[44] Shi HX, Li QH. Research progress of traditional Chinese medicine treatment of hyperlipidemia. Journal of Medical Forum. 2007;**28**(10):123-124

[45] Jiang JG. The clinical study progress of Chinese herbal medicine for hyperlipidemia. Journal of Practical Traditional Chinese Medicine. 2008;**24**(9):614-615

[46] Guo M, Liu Y, Gao ZY, Shi DZ. Chinese herbal medicine on dyslipidemia: Progress and perspective. Evidence-based Complementary and Alternative Medicine. 2014;**2014**:1-11

[47] Wojcicki J, Winter S. Effect of preparation Cynarex on the blood serum lipids level of the workers exposed to the chronic action of carbon disulphide. Medycyna Pracy. 1975;**26**:213-217

[48] Wójcicki J. Effect of 1,5-dicaffeylquinic acid (cynarine) on cholesterol levels in serum and liver of acute ethanol-treated rats. Drug and Alcohol Dependence. 1978;**3**:143-145

[49] Wojcicki J, Samochowiec L, Kosmider K. Influence of an extract from artichoke (*Cynara scolymus* L.) on the level of lipids in serum of aged men. Herba Polonica. 1981;**27**:265-268

**111**

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

> [58] Header EA, ElSawy NA, Alkushi AG. Biological effect of Cynara

2017;**11**(2):41-49

1993;**1240**:1249

2015;**4**(7):997-1000

2012;**11**:6

2000;**10**:353-358

2014;**24**(8):539-542

1997;**73**:909-928

cardunculus on liver and heart status for hypercholesterolemic rats. Australian Journal of Basic and Applied Sciences.

[59] Nadkarni KM. Trigonella foenum graecum: Indian materia. Médica.

[60] Kumar K, Kumar S, Datta A, Bandyopadhyay A. Effect of fenugreek seeds on glycemia and dyslipidemia in patients with type 2 diabetes mellitus. International Journal of Medical Science and Public Health.

[61] Belaid Nouira Y, Bakhta H, Bouaziz M. Study on the lipid profile and the parieto-temporal lipid peroxidation in AlCl3 mediated neurotoxicity: the modulatory effect of the fenugreek seeds. Lipids in Health and Disease.

[62] Jetle L, Harvey L, Eugeni K, Leven SN. The 4-hydroxy isoleucine plant-derived treatment for metabolic syndrome. Current opinion treatment for the metabolic syndrome. Current Opinion in Investigational Drugs.

[63] Sharma MS, Choudhary PR. Hypolipidemic effect of fenugreek seeds and its comparison with

[64] Dev S. Ethnotherapeutics and modern drug development. The

[65] Satyavati GV. Gum guggul (Commiphora mukul)—The success story of an ancient insight leading to a modern discovery. The Indian Journal of Medical Research. 1988;**87**:327-335

atorvastatin on experimentally induced hyperlipidemia. Journal of the College of Physicians and Surgeons–Pakistan.

potential of Ayurveda. Current Science.

[50] Alkushi AG. Biological effect of Cynara cardunculus on kidney status of hypercholesterolemic rats. Pharmacognosy Magazine.

[51] Brown JE, Rice-Evans CA. Luteolinrich artichoke extract protects low density lipoprotein from oxidation in vitro. Free Radical Research.

2017;**13**:S430-S436

1998;**29**:247-255

1998;**286**:1122-1128

2008;**15**:668-675

[52] Gebhardt R. Inhibition of cholesterol biosynthesis in primary cultured rat hepatocytes by artichoke

(*Cynara scolymus* L.) extracts. The Journal of Pharmacology and Experimental Therapeutics.

[53] Bundy R, Walker AF, Middleton RW, Wallis C, Simpson HC. Artichoke leaf extract (Cynara scolymus) reduces

plasma cholesterol in otherwise healthy hypercholesterolemic adults: A randomized, double blind placebo controlled trial. Phytomedicine.

[54] Englisch W, Beckers C, Unkauf M, Ruepp M, Zinserling V. Efficacy of artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittel-

[55] Gröne EF, Walli AK, Gröne HJ, Miller B, Seidel D. The role of lipids in nephrosclerosis and glomerulosclerosis.

Forschung. 2000;**50**:260-265

Atherosclerosis. 1994;**107**:1-13

[56] Kasiske BL, O'Donnell MP, Cleary MP, Keane WF. Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney International. 1988;**33**:667-672

[57] Samuelsson O, Mulec H, Knight-Gibson C, Attman PO, Kron B, Larsson R, et al. Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency. Nephrology, Dialysis, Transplantation. 1997;**12**:1908-1915

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

[50] Alkushi AG. Biological effect of Cynara cardunculus on kidney status of hypercholesterolemic rats. Pharmacognosy Magazine. 2017;**13**:S430-S436

*Dyslipidemia*

2009;**34**(2):133-145

2001;**12**(1):67-74

2006;**136**(3):765-768

2008;**60**(2):163

[33] Osamor PE, Owumi BE. Complementary and alternative medicine in the management of hypertension in an urban Nigerian community. BMC Complementary and Alternative Medicine. 2010;**10**(1):36

[34] Zhang XH, Lowe D, Giles P. A randomized trial of the effects of garlic oil upon coronary heart disease risk factors in trained male runners. Blood Coagulation & Fibrinolysis.

[35] Lau BHS. Suppression of LDL oxidation by garlic compounds is a possible mechanism of cardiovascular health benefit. The Journal of Nutrition.

[36] Duda G, Suliburska J, Pupek-Musialik D. Effects of short-term garlic supplementation on lipid metabolism and antioxidant status in hypertensive adults. Pharmacological Reports.

[37] Zeng T, Zhang CL, Zhao XL. The roles of garlic on the lipid parameters: A systematic review of the literature. Critical Reviews in Food Science and Nutrition. 2013;**53**(3):215-230

[38] Jahan F, Nanjib K, Qidwai W. Role of garlic in dyslipidemia: An evidence based review. Scientific Journal of Biological Sciences. 2015;**4**(5):36-42

[39] Steiner M, Khan AH, Holbert D, Lin RI. A double-blind crossover study in moderately hypercholesterolaemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. The American Journal of Clinical Nutrition. 1996;**64**:866-870

[40] Burke FM. Red yeast rice for the treatment of dyslipidemia. Current Atherosclerosis Reports. 2015;**17**(4):495

A meta-analysis. Journal of Clinical Pharmacy and Therapeutics.

[41] Francini-Pesenti F et al. Red yeast rice in the long-term treatment of hypercholesterolemia. A single-center experience. Acta Scientific Agriculture.

[42] Patel S. Functional food red yeast rice (RYR) for metabolic syndrome amelioration: A review on pros and cons. World Journal of Microbiology and Biotechnology.

from red yeast rice, a Chinese medicine and food. Food Chemistry.

Forum. 2007;**28**(10):123-124

[45] Jiang JG. The clinical study progress of Chinese herbal medicine for hyperlipidemia. Journal of Practical

Traditional Chinese Medicine.

[46] Guo M, Liu Y, Gao ZY, Shi DZ. Chinese herbal medicine on dyslipidemia: Progress and perspective. Evidence-based Complementary and Alternative Medicine. 2014;**2014**:1-11

[47] Wojcicki J, Winter S. Effect of preparation Cynarex on the blood serum lipids level of the workers exposed to the chronic action of carbon disulphide. Medycyna Pracy.

1,5-dicaffeylquinic acid (cynarine) on cholesterol levels in serum and liver of acute ethanol-treated rats. Drug and Alcohol Dependence. 1978;**3**:143-145

[49] Wojcicki J, Samochowiec L, Kosmider K. Influence of an extract from artichoke (*Cynara scolymus* L.) on the level of lipids in serum of aged men.

Herba Polonica. 1981;**27**:265-268

2008;**24**(9):614-615

1975;**26**:213-217

[48] Wójcicki J. Effect of

[43] Zhang Z et al. Cytotoxic monacolins

[44] Shi HX, Li QH. Research progress of traditional Chinese medicine treatment of hyperlipidemia. Journal of Medical

2017;**1**(3):16-18

2016;**32**(5):2035-2042

2016;**202**:262-268

**110**

[51] Brown JE, Rice-Evans CA. Luteolinrich artichoke extract protects low density lipoprotein from oxidation in vitro. Free Radical Research. 1998;**29**:247-255

[52] Gebhardt R. Inhibition of cholesterol biosynthesis in primary cultured rat hepatocytes by artichoke (*Cynara scolymus* L.) extracts. The Journal of Pharmacology and Experimental Therapeutics. 1998;**286**:1122-1128

[53] Bundy R, Walker AF, Middleton RW, Wallis C, Simpson HC. Artichoke leaf extract (Cynara scolymus) reduces plasma cholesterol in otherwise healthy hypercholesterolemic adults: A randomized, double blind placebo controlled trial. Phytomedicine. 2008;**15**:668-675

[54] Englisch W, Beckers C, Unkauf M, Ruepp M, Zinserling V. Efficacy of artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittel-Forschung. 2000;**50**:260-265

[55] Gröne EF, Walli AK, Gröne HJ, Miller B, Seidel D. The role of lipids in nephrosclerosis and glomerulosclerosis. Atherosclerosis. 1994;**107**:1-13

[56] Kasiske BL, O'Donnell MP, Cleary MP, Keane WF. Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney International. 1988;**33**:667-672

[57] Samuelsson O, Mulec H, Knight-Gibson C, Attman PO, Kron B, Larsson R, et al. Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency. Nephrology, Dialysis, Transplantation. 1997;**12**:1908-1915

[58] Header EA, ElSawy NA, Alkushi AG. Biological effect of Cynara cardunculus on liver and heart status for hypercholesterolemic rats. Australian Journal of Basic and Applied Sciences. 2017;**11**(2):41-49

[59] Nadkarni KM. Trigonella foenum graecum: Indian materia. Médica. 1993;**1240**:1249

[60] Kumar K, Kumar S, Datta A, Bandyopadhyay A. Effect of fenugreek seeds on glycemia and dyslipidemia in patients with type 2 diabetes mellitus. International Journal of Medical Science and Public Health. 2015;**4**(7):997-1000

[61] Belaid Nouira Y, Bakhta H, Bouaziz M. Study on the lipid profile and the parieto-temporal lipid peroxidation in AlCl3 mediated neurotoxicity: the modulatory effect of the fenugreek seeds. Lipids in Health and Disease. 2012;**11**:6

[62] Jetle L, Harvey L, Eugeni K, Leven SN. The 4-hydroxy isoleucine plant-derived treatment for metabolic syndrome. Current opinion treatment for the metabolic syndrome. Current Opinion in Investigational Drugs. 2000;**10**:353-358

[63] Sharma MS, Choudhary PR. Hypolipidemic effect of fenugreek seeds and its comparison with atorvastatin on experimentally induced hyperlipidemia. Journal of the College of Physicians and Surgeons–Pakistan. 2014;**24**(8):539-542

[64] Dev S. Ethnotherapeutics and modern drug development. The potential of Ayurveda. Current Science. 1997;**73**:909-928

[65] Satyavati GV. Gum guggul (Commiphora mukul)—The success story of an ancient insight leading to a modern discovery. The Indian Journal of Medical Research. 1988;**87**:327-335

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[71] Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. The Journal of Nutrition. 2000;**130**:1124-1131

[72] Seed M, O'Connor B, Perombelon N, et al. The effects of nicotinic acid and acipimox on lipoprotein (a) concentration and turnover. Atherosclerosis. 1993;**101**:61-68

[73] Kostner K, Gupta S. Niacin: A lipid polypill? Expert Opinion on Pharmacotherapy. 2008;**9**:2911-2920 [74] McRae M. Treatment of hyperlipoproteinemia with pantethine: A review and analysis of efficacy and tolerability. Nutrition Research. 2005;**25**:319-333

[75] Rumberger J, Napolitano J, Azmumano I, et al. Pantethine, a derivative of vitamin B(5) used as a nutritional supplement, favorably alters low-density lipoprotein cholesterol metabolism in low- to moderatecardiovascular risk North American subjects: A triple-blinded placebo and diet-controlled investigation. Nutrition Research. 2011;**31**:608-615

[76] Woollard K, Loryman C, Meredith E, et al. Effects of oral vitamin C on monocyte: Endothelial cell adhesion in healthy subjects. Biochemical and Biophysical Research Communications. 2002;**294**:1161-1168

[77] Shariat S, Mostafavi S, Khakpour F. Antioxidant effects of vitamins C and E on the low density lipoprotein oxidation mediated by myeloperoxidase. Iranian Biomedical Journal. 2013;**17**:22-28

[78] Riek A, Oh J, Bernal-Mizrachi C. Vitamin D regulates macrophage cholesterol metabolism in diabetes. The Journal of Steroid Biochemistry and Molecular Biology. 2010;**121**:430-433

[79] Guasch A, Bulló M, Rabassa A, et al. Plasma vitamin D and parathormone are associated with obesity and atherogenic dyslipidemia: A cross-sectional study. Cardiovascular Diabetology. 2012;**11**:149

[80] Sherer Y, Bitzur R, Cohen H, et al. Mechanisms of action of antiatherogenic effect of magnesium: Lessons from a mouse model. Magnesium Research. 2001;**14**:173-179

[81] Maier J. Low magnesium and atherosclerosis: An evidence-based link. Molecular Aspects of Medicine. 2003;**24**:137-146

**113**

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

> in copper-deficient rats. Biological Trace Element Research. 2001;**80**:221-229

[90] DiSilverstro R, Joesph E, Zhang W, et al. A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular

health. Metabolism. 2012;**61**:

[91] Langsjoen P, Langsjoen A. The clinical use of HMG CoA reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications. BioFactors.

[92] Cicero A, Derosa G, Miconi A, et al. Possible role of ubiquinone in the treatment of massive hypertriglyceridemia resistant to PUFA and fibrates. Biomedicine & Pharmacotherapy. 2005;**59**:312-317

[93] Press R, Geller J, Evans G. The effect of chromium picolinate on serum cholesterol apolipoprotein fractions in human subjects. The Western Journal of

[94] Sealls W, Penque B, Elmendorf J. Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia—Brief report. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;**31**:1139-1140

[95] Sundaram B, Singhal K, Sandhir R. Anti-atherogenic effect of chromium picolinate in streptozotocin-induced experimental diabetes. Journal of

phosphatidylcholine biosynthesis in the regulation of lipoprotein homeostasis. Current Opinion in Lipidology.

Lecithin:cholesterol acyltransferase:

Diabetes. 2013;**5**:43-50

[96] Vance D. Role of

2008;**19**:229-234

[97] Kunnen S, Van Eck M.

Medicine. 1990;**152**:41-45

1242-1246

2003;**18**:101-111

[82] Takabe W, Li R, Ai L, et al. Oxidized low-density lipoproteinactivated c-Jun NH2-terminal kinase regulates manganese superoxide dismutase ubiquitination: Implication for mitochondrial redox status and apoptosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;**30**:436-441

[83] Perrotta I, Perrotta E, Sesti S, Cassese M and Mazzulla S, et al. MnSOD expression in human atherosclerotic plaques: An immunohistochemical and ultrastructural study. Cardiovascular Pathology. 2013;**22**:428-437. Epub ahead

[84] Wu J, Wu Y, Reaves S, et al. Apolipoprotein A-I gene expression is regulated by cellular zinc status in hep G2 cells. The American Journal of Physiology. 1999;**277**:C537-C544

[85] Shen H, MacDonald R,

2007;**137**:2339-2345

2007;**17**:649-656

2011;**143**:310-319

Bruemmer D, et al. Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone. The Journal of Nutrition.

[86] Natella F, Fidale M, Tubaro F, et al. Selenium supplementation prevents the increase in atherogenic electronegative LDL (LDL minus) in the postprandial

phase. Nutrition, Metabolism, and Cardiovascular Diseases.

[87] Kaur H, Bansal M. Studies on scavenger receptors under experimental hypercholesterolemia: Modulation on selenium supplementation. Biological Trace Element Research.

[88] Hamilton I, Gilmore W, Strain J. Marginal copper deficiency and atherosclerosis. Biological Trace Element Research. 2000;**78**:179-189

[89] Wildman R, Mao S. Tissue-specific alteration in lipoprotein lipase activity

of print

*Alternative Natural Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.82430*

*Dyslipidemia*

1990;**22**:37-44

2007;**25**:375-390

[66] Singh K, Chander R, Kapoor NK. Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats. Pharmacological Research.

[74] McRae M. Treatment of

[75] Rumberger J, Napolitano J, Azmumano I, et al. Pantethine, a derivative of vitamin B(5) used as a nutritional supplement, favorably alters low-density lipoprotein cholesterol metabolism in low- to moderatecardiovascular risk North American subjects: A triple-blinded placebo and diet-controlled investigation. Nutrition

Research. 2011;**31**:608-615

2002;**294**:1161-1168

2013;**17**:22-28

[76] Woollard K, Loryman C, Meredith E, et al. Effects of oral vitamin C on monocyte: Endothelial cell adhesion in healthy subjects. Biochemical and Biophysical Research Communications.

[77] Shariat S, Mostafavi S, Khakpour F. Antioxidant effects of vitamins C and E on the low density lipoprotein oxidation mediated by myeloperoxidase.

Iranian Biomedical Journal.

[78] Riek A, Oh J, Bernal-Mizrachi C. Vitamin D regulates macrophage cholesterol metabolism in diabetes. The Journal of Steroid Biochemistry and Molecular Biology. 2010;**121**:430-433

[79] Guasch A, Bulló M, Rabassa A, et al. Plasma vitamin D and parathormone are associated with obesity and atherogenic dyslipidemia: A cross-sectional study. Cardiovascular Diabetology. 2012;**11**:149

[80] Sherer Y, Bitzur R, Cohen H, et al. Mechanisms of action of antiatherogenic effect of magnesium: Lessons from a mouse model.

[81] Maier J. Low magnesium and atherosclerosis: An evidence-based link. Molecular Aspects of Medicine.

2003;**24**:137-146

Magnesium Research. 2001;**14**:173-179

2005;**25**:319-333

hyperlipoproteinemia with pantethine: A review and analysis of efficacy and tolerability. Nutrition Research.

[67] Deng R. Therapeutic effects of guggul and its constituent guggulsterone: Cardiovascular

benefits. Cardiovascular Drug Reviews.

[68] Szapary PO, Wolfe ML, Bloedon LT, et al. Gugulipid for the treatment of hypercholesterolemia: A randomized controlled trial. Journal of the American Medical Association. 2003;**290**:765-772

[69] Ramachandran C, Nair SM, Quirrin

[70] Ellen RL, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. The American Journal

[71] Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. The Journal of Nutrition.

[72] Seed M, O'Connor B, Perombelon N, et al. The effects of nicotinic acid and acipimox on lipoprotein (a) concentration and turnover. Atherosclerosis. 1993;**101**:61-68

[73] Kostner K, Gupta S. Niacin: A lipid polypill? Expert Opinion on Pharmacotherapy. 2008;**9**:2911-2920

K-W, Melnick SJ. Hypolipidemic effects of a proprietary Commiphora Mukul gum resin extract and medium-

chain triglyceride preparation (GU-MCT810). Journal of Evidence-Based Complementary & Alternative

Medicine. 2013;**18**(4):248-256

of Cardiology. 1998;**81**:60-65

2000;**130**:1124-1131

**112**

[82] Takabe W, Li R, Ai L, et al. Oxidized low-density lipoproteinactivated c-Jun NH2-terminal kinase regulates manganese superoxide dismutase ubiquitination: Implication for mitochondrial redox status and apoptosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;**30**:436-441

[83] Perrotta I, Perrotta E, Sesti S, Cassese M and Mazzulla S, et al. MnSOD expression in human atherosclerotic plaques: An immunohistochemical and ultrastructural study. Cardiovascular Pathology. 2013;**22**:428-437. Epub ahead of print

[84] Wu J, Wu Y, Reaves S, et al. Apolipoprotein A-I gene expression is regulated by cellular zinc status in hep G2 cells. The American Journal of Physiology. 1999;**277**:C537-C544

[85] Shen H, MacDonald R, Bruemmer D, et al. Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone. The Journal of Nutrition. 2007;**137**:2339-2345

[86] Natella F, Fidale M, Tubaro F, et al. Selenium supplementation prevents the increase in atherogenic electronegative LDL (LDL minus) in the postprandial phase. Nutrition, Metabolism, and Cardiovascular Diseases. 2007;**17**:649-656

[87] Kaur H, Bansal M. Studies on scavenger receptors under experimental hypercholesterolemia: Modulation on selenium supplementation. Biological Trace Element Research. 2011;**143**:310-319

[88] Hamilton I, Gilmore W, Strain J. Marginal copper deficiency and atherosclerosis. Biological Trace Element Research. 2000;**78**:179-189

[89] Wildman R, Mao S. Tissue-specific alteration in lipoprotein lipase activity

in copper-deficient rats. Biological Trace Element Research. 2001;**80**:221-229

[90] DiSilverstro R, Joesph E, Zhang W, et al. A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health. Metabolism. 2012;**61**: 1242-1246

[91] Langsjoen P, Langsjoen A. The clinical use of HMG CoA reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications. BioFactors. 2003;**18**:101-111

[92] Cicero A, Derosa G, Miconi A, et al. Possible role of ubiquinone in the treatment of massive hypertriglyceridemia resistant to PUFA and fibrates. Biomedicine & Pharmacotherapy. 2005;**59**:312-317

[93] Press R, Geller J, Evans G. The effect of chromium picolinate on serum cholesterol apolipoprotein fractions in human subjects. The Western Journal of Medicine. 1990;**152**:41-45

[94] Sealls W, Penque B, Elmendorf J. Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia—Brief report. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;**31**:1139-1140

[95] Sundaram B, Singhal K, Sandhir R. Anti-atherogenic effect of chromium picolinate in streptozotocin-induced experimental diabetes. Journal of Diabetes. 2013;**5**:43-50

[96] Vance D. Role of phosphatidylcholine biosynthesis in the regulation of lipoprotein homeostasis. Current Opinion in Lipidology. 2008;**19**:229-234

[97] Kunnen S, Van Eck M. Lecithin:cholesterol acyltransferase: Old friend or foe in atherosclerosis? Journal of Lipid Research. 2012;**53**:1783-1799

[98] Jariwalla R. Inositol hexaphosphate (IP6) as an anti-neoplastic and lipidlowering agent. Anticancer Research. 1999;**19**:3699-3702

[99] Maeba R, Hara H, Ishikawa H, et al. Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome. Journal of Nutritional Science and Vitaminology. 2008;**54**:196-202

[100] Minozzi M, Nordio M, Pajalich R. The combined therapy myo-inositol plus D-chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. European Review for Medical and Pharmacological Sciences. 2013;**17**:537-540

[101] Zhang Y, Han P, Wu N, He B, Lu Y, Li S, et al. Amelioration of lipid abnormalities by α-lipoic acid through antioxidative and anti-inflammatory effects. Obesity (Silver Spring). 2011;**19**(8):1647-1653

[102] Harding S, Rideout T, Jones P. Evidence for using alpha-lipoic acid in reducing lipoprotein and inflammatory related atherosclerotic risk. Journal of Dietary Supplements. 2012;**9**:116-127

[103] Sirtori C, Calabresi L, Ferrara S, et al. L-carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutrition, Metabolism, and Cardiovascular Diseases. 2000;**10**:247-251

[104] Derosa G, Cicero AF, Gaddi A, Mugellini A, Ciccarelli L, Fogari R. The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients

with type 2 diabetes mellitus. Clinical Therapeutics. 2003; **25**(5):1429-1439

[105] Malaguarnera M, Vacante M, Avitabile T, et al. L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes. The American Journal of Clinical Nutrition. 2009;**89**:71-76

**115**

**Chapter 7**

**Abstract**

*Joseph M. Keenan*

management of this health problem.

**1. Background: early niacin trials**

**Keywords:** niacin, nicotinic acid, HDL-C, Lp(a), niacin formulations

Niacin or vitamin B3 comes in two forms, nicotinamide and nicotinic acid (NA), but only NA has lipid management benefits. The recommended daily allowance of vitamin B3 for nutritional benefit is only 20–30 mg/day, but the dose needed for lipid benefits is much higher and depends on whether one is using immediate-release (IRNA) 3000–6000 mg/day or extended-release (ERNA) 1000–2000 mg/day formulations [1, 2]. The lipid benefits of NA were discovered serendipitously in the 1940–1950s when mega-doses of vitamins were being used in the management of mental health disorders. It was noted that high doses of NA lowered total cholesterol significantly. It was at that same time that elevated cholesterol was found to be associated with increased risk of cardiovascular disease (CVD) that led to the early trials of NA for management of dyslipidemia. Investigators in those early studies did not know what the mechanism of action of NA was but they were impressed that not only did NA lower total cholesterol by 20+%, but also specifically lowered beta lipoprotein cholesterol (LDL-C), raised alpha lipoprotein cholesterol (HDL-C), and lowered triglycerides (TG) [3, 4].

The Role of Niacin in the

Management of Dyslipidemia

Niacin or nicotinic acid has been used for the management of dyslipidemia for over 50 years, and it is the first medication that has been shown to reduce both coronary disease events and mortality. It is unique among the various lipid therapies in that it can not only reduce all of atherogenic lipid fractions (total cholesterol, low-density lipoprotein, very low-density lipoprotein, non-HDL lipoproteins, and triglycerides), but is also the most effective agent for raising high-density lipoprotein (specifically Apolipoprotein A-1). It is also the only lipid therapy that can lower lipoprotein (a). Niacin also has non-lipid benefits that improve vascular health and reduce atherogenesis. Niacin therapy was initially hampered by a high incidence of side effects, especially flushing, but this has largely been overcome by extended-release formulations and dosing and administering properly. Despite the failure of two recent clinical trials to show benefit of combining niacin with statins, there are many trials that support using niacin as monotherapy or in combination with other lipid agents including statins. Niacin is also the cheapest lipid agent available, and with the epidemic of cardiovascular disease in the world, it offers great value in the population-wide

## **Chapter 7**

*Dyslipidemia*

Old friend or foe in atherosclerosis?

with type 2 diabetes mellitus. Clinical Therapeutics. 2003;

[105] Malaguarnera M, Vacante M, Avitabile T, et al. L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes. The American Journal of Clinical

Nutrition. 2009;**89**:71-76

**25**(5):1429-1439

[98] Jariwalla R. Inositol hexaphosphate (IP6) as an anti-neoplastic and lipidlowering agent. Anticancer Research.

[99] Maeba R, Hara H, Ishikawa H, et al. Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome. Journal of Nutritional Science and Vitaminology.

[100] Minozzi M, Nordio M, Pajalich R. The combined therapy myo-inositol plus D-chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. European Review for Medical and Pharmacological Sciences.

[101] Zhang Y, Han P, Wu N, He B, Lu Y, Li S, et al. Amelioration of lipid abnormalities by α-lipoic acid through antioxidative and anti-inflammatory effects. Obesity (Silver Spring).

[102] Harding S, Rideout T, Jones

[103] Sirtori C, Calabresi L, Ferrara S, et al. L-carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutrition, Metabolism,

and Cardiovascular Diseases.

[104] Derosa G, Cicero AF, Gaddi A, Mugellini A, Ciccarelli L, Fogari R. The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients

2000;**10**:247-251

P. Evidence for using alpha-lipoic acid in reducing lipoprotein and inflammatory related atherosclerotic risk. Journal of Dietary Supplements. 2012;**9**:116-127

Journal of Lipid Research.

2012;**53**:1783-1799

1999;**19**:3699-3702

2008;**54**:196-202

2013;**17**:537-540

2011;**19**(8):1647-1653

**114**

## The Role of Niacin in the Management of Dyslipidemia

*Joseph M. Keenan*

### **Abstract**

Niacin or nicotinic acid has been used for the management of dyslipidemia for over 50 years, and it is the first medication that has been shown to reduce both coronary disease events and mortality. It is unique among the various lipid therapies in that it can not only reduce all of atherogenic lipid fractions (total cholesterol, low-density lipoprotein, very low-density lipoprotein, non-HDL lipoproteins, and triglycerides), but is also the most effective agent for raising high-density lipoprotein (specifically Apolipoprotein A-1). It is also the only lipid therapy that can lower lipoprotein (a). Niacin also has non-lipid benefits that improve vascular health and reduce atherogenesis. Niacin therapy was initially hampered by a high incidence of side effects, especially flushing, but this has largely been overcome by extended-release formulations and dosing and administering properly. Despite the failure of two recent clinical trials to show benefit of combining niacin with statins, there are many trials that support using niacin as monotherapy or in combination with other lipid agents including statins. Niacin is also the cheapest lipid agent available, and with the epidemic of cardiovascular disease in the world, it offers great value in the population-wide management of this health problem.

**Keywords:** niacin, nicotinic acid, HDL-C, Lp(a), niacin formulations

### **1. Background: early niacin trials**

Niacin or vitamin B3 comes in two forms, nicotinamide and nicotinic acid (NA), but only NA has lipid management benefits. The recommended daily allowance of vitamin B3 for nutritional benefit is only 20–30 mg/day, but the dose needed for lipid benefits is much higher and depends on whether one is using immediate-release (IRNA) 3000–6000 mg/day or extended-release (ERNA) 1000–2000 mg/day formulations [1, 2]. The lipid benefits of NA were discovered serendipitously in the 1940–1950s when mega-doses of vitamins were being used in the management of mental health disorders. It was noted that high doses of NA lowered total cholesterol significantly. It was at that same time that elevated cholesterol was found to be associated with increased risk of cardiovascular disease (CVD) that led to the early trials of NA for management of dyslipidemia. Investigators in those early studies did not know what the mechanism of action of NA was but they were impressed that not only did NA lower total cholesterol by 20+%, but also specifically lowered beta lipoprotein cholesterol (LDL-C), raised alpha lipoprotein cholesterol (HDL-C), and lowered triglycerides (TG) [3, 4].

It became evident at that time that high cholesterol was not only associated with increased risk of CVD, but also diet and lifestyle interventions were usually not adequate to reduce cholesterol levels. This led to a large clinical trial, The Coronary Drug Project, that was a head to head trial of the cholesterol lowering agents available then (Thyroxine, Estrogen-two forms, Clofibrate and IRNA). The study was conducted from 1969 to 1975 and had five treatment arms and a large placebo arm totaling 8341 subjects [5]. The thyroxine and both estrogen treatment arms were terminated early due to lack of benefit and the clofibrate arm had some lipid improvements that failed to show reduction in coronary events. The IRNA arm not only demonstrated significant improvements in clinically important lipid fractions (total cholesterol, LDL-C, HDL-C, and TG) but, more importantly, it had a significant decrease in coronary events compared to placebo group. In addition, long-term (15 years) follow-up showed 11% decrease in mortality in the IRNA group compared to the placebo [6]. The only negative aspect of the Coronary Drug Project was the high incidence of flushing (>60%) in the IRNA treatment group. The immediate-release formulation of NA was used in that study, and, even though the majority of subjects were able to develop some level of tolerance, 8% had to drop out due to flushing.

## **2. NA mechanism of action**

Nicotinic acid offers multiple clinical benefits to the lipid profile but the most unique and important is its ability to raise HDL-C. The 2017 Guidelines on the Management of Dyslipidemia list low HDL-C and a major risk factor for coronary disease because of important role of HDL-C in reverse cholesterol transport [7]. No agent is more potent at raising HDL-C than NA. NA not only NA raises HDL-C but also selectively prevents liver catabolism of apolipoprotein A-1, which is the key HDL lipoprotein needed for reverse cholesterol transport [8]. Thus NA increases both the capacity and the efficiency of HDL-C cholesterol transport. The liver is the site of synthesis of TG, very low-density lipoprotein (VLDL), lipoprotein (a) (Lp(a)), and LDL-C, and NA attaches to and antagonizes the hydroxycarboxylic acid-2 receptor of hepatocytes. This inhibits a hepatic microsomal enzyme (diacylglycerol acyltransferase-2) that is necessary for the final step in the production of those lipids [8]. Not only does NA reduce the beta lipoproteins that make up LDL-C,


**117**

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

risk factor for coronary disease [7].

with controls [9] (**Table 1**).

**3. Side effects of NA**

but also more specifically NA reduces the small dense LDL-C particles that are most atherogenic. Furthermore, NA is one of the best agents to lower TG and is the only medication that significantly lowers Lp(a), which is also a significant independent

In addition, in vitro research using human aortic endothelial cells has demonstrated impressive non-lipid benefits of NA in reducing risk of coronary disease. Researchers found that: (1) NA inhibits vascular inflammation by reducing reactive oxygen species, (2) NA reduces LDL-C oxidation making it less atherogenic, and (3) NA reduces vascular adhesion molecules and monocyte chemo-attractant protein-1, which decreases the attachment of monocytes and macrophages to the vascular wall, a key element in early atherogenesis [8]. An animal study demonstrated an additional non-lipid effect of NA, which is a neuroprotective benefit following stroke. The study involved inducing a stroke by middle cerebral artery occlusion in rats. Rats induced with NA within 2 hours of occlusion had a reduced volume of brain tissue damage and improved the functional recovery compared

Despite its many benefits, NA utilization can be hampered by a number of adverse side effects. The good news is virtually all NA side effects are reversible, and most can be minimized or eliminated by appropriate dosing and administration. The most common side effect is flushing and that is more common with IRNA and the initial doses of ERNA. Flushing is caused by release of prostaglandin D2 and prostaglandin E2 from Langerhans cells in the skin and macrophages [8]. In most persons, this flushing response can be minimized by proper dosing and administration (discussed later). William Parsons Jr., a co-investigator in the Coronary Drug Project and an early proponent of NA, was quite disappointed that many clinicians never learned "how to do" niacin resulting in higher dropout rates in NA therapy than that was warranted. This led him to writing a book, "Cholesterol Control Without a Diet! The Niacin Solution" for both lay and professional persons in an

Another side effect that is sometimes seen with ERNA therapy (but almost never with IRNA) is impaired liver function. This is due to methyl group depletion in the hepatocytes, secondary to the metabolic amidization in the liver of NA to nicotinamide [8]. This problem was shown to be preventable or reversible in most cases without loss of lipid benefit in studies using wax-matrix ERNA (WM-ERNA; Endur-Acin by Endurance Products Inc.) by either dose reduction or methyl group supplementation with methionine [11, 12]. Hepatic transaminase levels should be monitored during NA therapy. Modest transaminase level increases are acceptable, but NA dose

reduction should be implemented if levels approach 2–3 times normal limits.

Increased blood glucose levels with NA therapy had raised concerns about its use in persons with diabetes or impaired glucose tolerance (metabolic syndrome). Blood glucose should be monitored in patients on NA treatment but that concern has been largely dismissed by the results from clinical trials. A controlled trial using WM-ERNA in non-diabetics showed only a 1% rise in baseline glucose levels at 6 weeks that returned to baseline by 6 months [13]. The AIM-HIGH trial that used polygel ERNA (PG-ERNA; Niaspan, AbbVie Inc.) specifically recruited persons with low HDL-C and high TG (metabolic syndrome or MS) found a 5% rise initially from baseline glucose levels that returned to baseline over 2 years, and there was no difference in the development of diabetes in the two treatment groups [14]. A post-hoc analysis of the Coronary Drug Project (that used IRNA) found that the subgroup of

effort to educate all on proper NA administration [10].

initiators)


#### *Ref. [7–9].*

#### **Table 1.**

*Summary of niacin lipid and non-lipid cardiovascular benefits.*

but also more specifically NA reduces the small dense LDL-C particles that are most atherogenic. Furthermore, NA is one of the best agents to lower TG and is the only medication that significantly lowers Lp(a), which is also a significant independent risk factor for coronary disease [7].

In addition, in vitro research using human aortic endothelial cells has demonstrated impressive non-lipid benefits of NA in reducing risk of coronary disease. Researchers found that: (1) NA inhibits vascular inflammation by reducing reactive oxygen species, (2) NA reduces LDL-C oxidation making it less atherogenic, and (3) NA reduces vascular adhesion molecules and monocyte chemo-attractant protein-1, which decreases the attachment of monocytes and macrophages to the vascular wall, a key element in early atherogenesis [8]. An animal study demonstrated an additional non-lipid effect of NA, which is a neuroprotective benefit following stroke. The study involved inducing a stroke by middle cerebral artery occlusion in rats. Rats induced with NA within 2 hours of occlusion had a reduced volume of brain tissue damage and improved the functional recovery compared with controls [9] (**Table 1**).

## **3. Side effects of NA**

*Dyslipidemia*

**116**

**Lipid benefits**


drop out due to flushing.

**2. NA mechanism of action**


**Non-lipid benefits**

initiators)

*Ref. [7–9].*

**Table 1.**





*Summary of niacin lipid and non-lipid cardiovascular benefits.*


It became evident at that time that high cholesterol was not only associated with increased risk of CVD, but also diet and lifestyle interventions were usually not adequate to reduce cholesterol levels. This led to a large clinical trial, The Coronary Drug Project, that was a head to head trial of the cholesterol lowering agents available then (Thyroxine, Estrogen-two forms, Clofibrate and IRNA). The study was conducted from 1969 to 1975 and had five treatment arms and a large placebo arm totaling 8341 subjects [5]. The thyroxine and both estrogen treatment arms were terminated early due to lack of benefit and the clofibrate arm had some lipid improvements that failed to show reduction in coronary events. The IRNA arm not only demonstrated significant improvements in clinically important lipid fractions (total cholesterol, LDL-C, HDL-C, and TG) but, more importantly, it had a significant decrease in coronary events compared to placebo group. In addition, long-term (15 years) follow-up showed 11% decrease in mortality in the IRNA group compared to the placebo [6]. The only negative aspect of the Coronary Drug Project was the high incidence of flushing (>60%) in the IRNA treatment group. The immediate-release formulation of NA was used in that study, and, even though the majority of subjects were able to develop some level of tolerance, 8% had to

Nicotinic acid offers multiple clinical benefits to the lipid profile but the most unique and important is its ability to raise HDL-C. The 2017 Guidelines on the Management of Dyslipidemia list low HDL-C and a major risk factor for coronary disease because of important role of HDL-C in reverse cholesterol transport [7]. No agent is more potent at raising HDL-C than NA. NA not only NA raises HDL-C but also selectively prevents liver catabolism of apolipoprotein A-1, which is the key HDL lipoprotein needed for reverse cholesterol transport [8]. Thus NA increases both the capacity and the efficiency of HDL-C cholesterol transport. The liver is the site of synthesis of TG, very low-density lipoprotein (VLDL), lipoprotein (a) (Lp(a)), and LDL-C, and NA attaches to and antagonizes the hydroxycarboxylic acid-2 receptor of hepatocytes. This inhibits a hepatic microsomal enzyme (diacylglycerol acyltransferase-2) that is necessary for the final step in the production of those lipids [8]. Not only does NA reduce the beta lipoproteins that make up LDL-C,


Despite its many benefits, NA utilization can be hampered by a number of adverse side effects. The good news is virtually all NA side effects are reversible, and most can be minimized or eliminated by appropriate dosing and administration. The most common side effect is flushing and that is more common with IRNA and the initial doses of ERNA. Flushing is caused by release of prostaglandin D2 and prostaglandin E2 from Langerhans cells in the skin and macrophages [8]. In most persons, this flushing response can be minimized by proper dosing and administration (discussed later). William Parsons Jr., a co-investigator in the Coronary Drug Project and an early proponent of NA, was quite disappointed that many clinicians never learned "how to do" niacin resulting in higher dropout rates in NA therapy than that was warranted. This led him to writing a book, "Cholesterol Control Without a Diet! The Niacin Solution" for both lay and professional persons in an effort to educate all on proper NA administration [10].

Another side effect that is sometimes seen with ERNA therapy (but almost never with IRNA) is impaired liver function. This is due to methyl group depletion in the hepatocytes, secondary to the metabolic amidization in the liver of NA to nicotinamide [8]. This problem was shown to be preventable or reversible in most cases without loss of lipid benefit in studies using wax-matrix ERNA (WM-ERNA; Endur-Acin by Endurance Products Inc.) by either dose reduction or methyl group supplementation with methionine [11, 12]. Hepatic transaminase levels should be monitored during NA therapy. Modest transaminase level increases are acceptable, but NA dose reduction should be implemented if levels approach 2–3 times normal limits.

Increased blood glucose levels with NA therapy had raised concerns about its use in persons with diabetes or impaired glucose tolerance (metabolic syndrome). Blood glucose should be monitored in patients on NA treatment but that concern has been largely dismissed by the results from clinical trials. A controlled trial using WM-ERNA in non-diabetics showed only a 1% rise in baseline glucose levels at 6 weeks that returned to baseline by 6 months [13]. The AIM-HIGH trial that used polygel ERNA (PG-ERNA; Niaspan, AbbVie Inc.) specifically recruited persons with low HDL-C and high TG (metabolic syndrome or MS) found a 5% rise initially from baseline glucose levels that returned to baseline over 2 years, and there was no difference in the development of diabetes in the two treatment groups [14]. A post-hoc analysis of the Coronary Drug Project (that used IRNA) found that the subgroup of

#### *Dyslipidemia*

subjects with MS had comparable reduction in coronary events and long-term mortality to the other subjects in the IRNA treatment group [15]. The consensus is that the benefits of treating lipid risk factors in persons with MS or diabetes outweighs any modest increase that NA treatment may cause to insulin resistance.

There are a number of less common side effects with NA treatment most of which are manageable without discontinuing therapy. Gastrointestinal upset can occur in some individuals and may be due to increased acid production on NA treatment. This is usually managed by splitting the daily dose and taking it with meals. Acid blocking agents may also help. Hyperuricemia may also occur with NA treatment and uric acid levels should be monitored routinely along with blood glucose levels and liver function tests. Nicotinuric acid is a by-product of liver metabolism of NA and can complete with renal excretion of uric acid causing levels to rise. The clinician must decide whether the continued use of NA would require additional management of uric acid levels is worth the lipid benefits. Increased homocysteine levels can occur with NA treatment and these should also be monitored routinely during NA therapy. Hyper-homocysteinemia is also a risk factor for cardiovascular disease that can be managed by folic acid supplementation. Some persons may experience a rash with flushing that usually clears with the development of tolerance, and in a rare instance, a darkened patch of skin may occur (acanthosis nigricans). All of these side effects are completely resolvable/reversible by discontinuing NA if other management of the side effect is unsuccessful.

## **4. Selecting appropriate patients for NA therapy**

As described above, the pleiotropic benefits of NA treatment make it an excellent choice for mixed dyslipidemias. One of the most prevalent forms of mixed dyslipidemia that is uniquely suited to NA treatment is MS (low HDL-C, high TG). A study of prevalence of MS in the United States showed 34% of all adults and 55% of persons over the age of 60 has MS [16]. An 8 year prospective study of cardiovascular risk (Framingham) in 3323 middle-aged adults in the United States found the risk of developing CVD over that 8 year period for persons with MS was 34% for men and 16% for women [17]. An epidemiology study of the prevalence of MS in European countries found it as high as 71.7% of adults in some countries and MS-associated CVD prevalence as high as 52% [18]. Thus, the prevalence and the high risk of CVD with MS make this a very large population of persons who would benefit from NA therapy, especially those persons with normal or modest elevations of LDL-C.

The problem of treating MS with NA as monotherapy is achieving the LDL-C goal for that person. Since cardiovascular risk assessment views MS as the equivalent of having a prior coronary event the LDL-C goal is usually more aggressive (e.g.70 mg/dl) and that can be difficult to achieve on NA alone. A meta-analysis in 2010 of NA studies using NA alone or in combination with other agents showed a 26% reduction in coronary events. In addition, they showed a decrease in coronary atherosclerosis in 92% of persons treated with NA, as well as a reduction in carotid intimal thickness of 17 mm per year of NA treatment [2]. Most of these studies were conducted prior to the introduction of statins for lipid management. The compliment of the lipid benefits of NA and the effective LDL-C lowering benefit of statin drugs led to clinical trials using PG-ERNA with statins which did demonstrate broad improvement of lipid profiles (decreased LDL-C, TG, Lp(a), and increased HDL-C) [19, 20]. Modeling of lipid therapy from these studies indicated that an ERNA with a statin would produce optimal lipid values for reducing coronary disease [21].

**119**

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

The early success in lipid profile improvement of combination trials of PG-ERNA/statin led to the development of two very large clinical trials of combination PG-ERNA/statin therapy that were intended to demonstrate conclusively the benefit of combined treatment on the reduction of cardiovascular events and mortality (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/ High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study—Treatment of HDL to Reduce the Incidence of Vascular Events [HPS-2 THRIVE]) [22, 23]. The much-anticipated results of those trials were very disappointing and not only failed to demonstrate reduction in vascular events but also appeared to show increased adverse events and side effects with that combination. Critics of these two trials pointed out major design flaws in both studies that raise serious questions about the validity of any conclusions drawn from study results. The AIM-HIGH trial was terminated early because of what was thought to be an increase in cerebrovascular accidents in the PG-ERNA/statin treatment group, which in later analysis was found to be an artifact [22]. The main conclusion of the AIM-HIGH trial was that the combined PG-ERNA/statin treatment group did not show a decrease in cardiovascular events. This, in fact, was not true for the subgroup who were in the highest tertile of baseline TG and the lowest tertile of baseline HDL-C, both lipid fractions that benefitted from the NA addition to treatment [24]. Another AIM-HIGH post-hoc analysis of remnant lipoproteins and HDL-C2 showed that the PG-ERNA/statin treatment group did demonstrate improvements that could confer benefit in prevention of cardiovascular events, but perhaps this was not able to be demonstrated because of early termination [25]. Others also point out that the Coronary Drug Project took 6 years to demonstrate a reduction in coronary events with NA therapy, so the failure of AIM-HIGH and HPS-2 THRIVE to demonstrate the same may have been due to early termination of these studies [26]. Also, one of the lipid benefits of adding NA to a statin is the additional lowering of LDL-C which did occur in the AIM-HIGH trial. However, this benefit was muted since the control group had a second LDL-C lowering drug (ezetimibe) added to their treatment to

match any LDL-C lowering by NA in the treatment group [22].

achieve lipid goals and desired clinical endpoints [26].

The HPS-2 THRIVE trial was actually PG-ERNA in combination with Laropiprant, a prostaglandin DP1 receptor inhibitor that reduces the NA flushing side effect, and together this combination was added to statin therapy. The investigators had no idea when designing the study that the PG-ERNA/Laropiprant combination would cause such an increase in myopathies especially in Chinese subjects. Of the 25,673 study subjects over 11,000 were Chinese, and their annual incidence of myopathy was 800% greater than that European subjects on the same treatment [27]. Critics of the HPS-2 THRIVE trial felt the addition of Laropiprant to the NA treatment group confounded the outcomes and thus they do not accept it as a legitimate study of the combination of NA and statin therapy [26]. The main conclusion of the HPS-2 THRIVE study was similar to the AIM-HIGH study; that is, the addition of NA to statin therapy did not improve cardiovascular outcomes, and, in fact, resulted in an increase in serious adverse effects [23]. Despite the design flaws in these large trials, the consensus is that adding NA to statin therapy in persons who are already at their LDL-C goal does not improve clinical outcomes. These two large studies raised serious questions about what is the appropriate combination therapy with statins in persons who have not reached their LDL-C goal. While this controversy still lingers, many feel the effectiveness of NA in reducing LDL-C (especially small dense LDL-C particles) as well as the other lipid benefits as shown in earlier studies continues to make NA an appropriate combination with statins to

Recent changes in recommendations of national cholesterol treatment guidelines in the United States have increased the number who are considered eligible to start

#### *The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

*Dyslipidemia*

subjects with MS had comparable reduction in coronary events and long-term mortality to the other subjects in the IRNA treatment group [15]. The consensus is that the benefits of treating lipid risk factors in persons with MS or diabetes outweighs

There are a number of less common side effects with NA treatment most of which are manageable without discontinuing therapy. Gastrointestinal upset can occur in some individuals and may be due to increased acid production on NA treatment. This is usually managed by splitting the daily dose and taking it with meals. Acid blocking agents may also help. Hyperuricemia may also occur with NA treatment and uric acid levels should be monitored routinely along with blood glucose levels and liver function tests. Nicotinuric acid is a by-product of liver metabolism of NA and can complete with renal excretion of uric acid causing levels to rise. The clinician must decide whether the continued use of NA would require additional management of uric acid levels is worth the lipid benefits. Increased homocysteine levels can occur with NA treatment and these should also be monitored routinely during NA therapy. Hyper-homocysteinemia is also a risk factor for cardiovascular disease that can be managed by folic acid supplementation. Some persons may experience a rash with flushing that usually clears with the development of tolerance, and in a rare instance, a darkened patch of skin may occur (acanthosis nigricans). All of these side effects are completely resolvable/reversible by discontinuing

As described above, the pleiotropic benefits of NA treatment make it an excellent choice for mixed dyslipidemias. One of the most prevalent forms of mixed dyslipidemia that is uniquely suited to NA treatment is MS (low HDL-C, high TG). A study of prevalence of MS in the United States showed 34% of all adults and 55% of persons over the age of 60 has MS [16]. An 8 year prospective study of cardiovascular risk (Framingham) in 3323 middle-aged adults in the United States found the risk of developing CVD over that 8 year period for persons with MS was 34% for men and 16% for women [17]. An epidemiology study of the prevalence of MS in European countries found it as high as 71.7% of adults in some countries and MS-associated CVD prevalence as high as 52% [18]. Thus, the prevalence and the high risk of CVD with MS make this a very large population of persons who would benefit from NA therapy, especially those

The problem of treating MS with NA as monotherapy is achieving the LDL-C goal for that person. Since cardiovascular risk assessment views MS as the equivalent of having a prior coronary event the LDL-C goal is usually more aggressive (e.g.70 mg/dl) and that can be difficult to achieve on NA alone. A meta-analysis in 2010 of NA studies using NA alone or in combination with other agents showed a 26% reduction in coronary events. In addition, they showed a decrease in coronary atherosclerosis in 92% of persons treated with NA, as well as a reduction in carotid intimal thickness of 17 mm per year of NA treatment [2]. Most of these studies were conducted prior to the introduction of statins for lipid management. The compliment of the lipid benefits of NA and the effective LDL-C lowering benefit of statin drugs led to clinical trials using PG-ERNA with statins which did demonstrate broad improvement of lipid profiles (decreased LDL-C, TG, Lp(a), and increased HDL-C) [19, 20]. Modeling of lipid therapy from these studies indicated that an ERNA with a statin would produce optimal lipid values for reducing

any modest increase that NA treatment may cause to insulin resistance.

NA if other management of the side effect is unsuccessful.

**4. Selecting appropriate patients for NA therapy**

persons with normal or modest elevations of LDL-C.

**118**

coronary disease [21].

The early success in lipid profile improvement of combination trials of PG-ERNA/statin led to the development of two very large clinical trials of combination PG-ERNA/statin therapy that were intended to demonstrate conclusively the benefit of combined treatment on the reduction of cardiovascular events and mortality (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/ High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study—Treatment of HDL to Reduce the Incidence of Vascular Events [HPS-2 THRIVE]) [22, 23]. The much-anticipated results of those trials were very disappointing and not only failed to demonstrate reduction in vascular events but also appeared to show increased adverse events and side effects with that combination. Critics of these two trials pointed out major design flaws in both studies that raise serious questions about the validity of any conclusions drawn from study results. The AIM-HIGH trial was terminated early because of what was thought to be an increase in cerebrovascular accidents in the PG-ERNA/statin treatment group, which in later analysis was found to be an artifact [22]. The main conclusion of the AIM-HIGH trial was that the combined PG-ERNA/statin treatment group did not show a decrease in cardiovascular events. This, in fact, was not true for the subgroup who were in the highest tertile of baseline TG and the lowest tertile of baseline HDL-C, both lipid fractions that benefitted from the NA addition to treatment [24]. Another AIM-HIGH post-hoc analysis of remnant lipoproteins and HDL-C2 showed that the PG-ERNA/statin treatment group did demonstrate improvements that could confer benefit in prevention of cardiovascular events, but perhaps this was not able to be demonstrated because of early termination [25]. Others also point out that the Coronary Drug Project took 6 years to demonstrate a reduction in coronary events with NA therapy, so the failure of AIM-HIGH and HPS-2 THRIVE to demonstrate the same may have been due to early termination of these studies [26]. Also, one of the lipid benefits of adding NA to a statin is the additional lowering of LDL-C which did occur in the AIM-HIGH trial. However, this benefit was muted since the control group had a second LDL-C lowering drug (ezetimibe) added to their treatment to match any LDL-C lowering by NA in the treatment group [22].

The HPS-2 THRIVE trial was actually PG-ERNA in combination with Laropiprant, a prostaglandin DP1 receptor inhibitor that reduces the NA flushing side effect, and together this combination was added to statin therapy. The investigators had no idea when designing the study that the PG-ERNA/Laropiprant combination would cause such an increase in myopathies especially in Chinese subjects. Of the 25,673 study subjects over 11,000 were Chinese, and their annual incidence of myopathy was 800% greater than that European subjects on the same treatment [27]. Critics of the HPS-2 THRIVE trial felt the addition of Laropiprant to the NA treatment group confounded the outcomes and thus they do not accept it as a legitimate study of the combination of NA and statin therapy [26]. The main conclusion of the HPS-2 THRIVE study was similar to the AIM-HIGH study; that is, the addition of NA to statin therapy did not improve cardiovascular outcomes, and, in fact, resulted in an increase in serious adverse effects [23]. Despite the design flaws in these large trials, the consensus is that adding NA to statin therapy in persons who are already at their LDL-C goal does not improve clinical outcomes. These two large studies raised serious questions about what is the appropriate combination therapy with statins in persons who have not reached their LDL-C goal. While this controversy still lingers, many feel the effectiveness of NA in reducing LDL-C (especially small dense LDL-C particles) as well as the other lipid benefits as shown in earlier studies continues to make NA an appropriate combination with statins to achieve lipid goals and desired clinical endpoints [26].

Recent changes in recommendations of national cholesterol treatment guidelines in the United States have increased the number who are considered eligible to start

statin therapy (absolute risk of cardiac event >7.5% over 10 years) to over 50 million persons [28]. The rate of statin intolerance (stopping therapy) in general population cholesterol intervention is 18–20% or about 10 million persons (statin intolerant) in the United States who are candidates for other lipid therapy interventions [29]. This represents another large target group that is appropriate for NA therapy since none of the other agents available have abroad range of lipid and non-lipid benefits for prevention of CVD [8, 26]. Some have suggested that proprotein-convertase subtilisin/kexin type 9 (PCSK-9) inhibitors be used when statin intolerance is encountered. At a cost of \$15,000/year for PCSK-9 inhibitors and an estimated incremental cost of \$330,000 per quality-adjusted life-years (QALYs), this option is very limited [30].

Perhaps the largest group of persons who would be logical candidates for NA lipid therapy globally are those whose risk scores indicate need to initiate lipid treatment but either they, individually, or their health system cannot afford statin treatment. Cardiovascular disease has grown at epidemic rates in developing countries and those countries account for over 80% of all cardiovascular deaths annually [31]. Using microsimulation modeling, analysts recently demonstrated that initiating statin therapy at the recommended 7.5% risk threshold would be an incremental cost-effectiveness ratio of \$37,000 per QALYs gained [32]. This may be considered cost-effective in a developed country, but in a developing country this is prohibitive. Not only does NA have the broadest profile of lipid and non-lipid benefits for coronary disease/mortality reduction, it is also the cheapest available lipid lowering agent. Thus, it makes sense as a public health strategy for developing countries to initiate population level of lipid therapy intervention with NA monotherapy adding other agents as needed, and reserve initiation with statin therapy to the subset of persons with high/very high risk status.

Persons with isolated dyslipidemic fractions such as low HDL-C, or high TG are also reasonable candidates for NA therapy and NA is the only agent at present that can significantly lower Lp(a). A meta-analysis of clinical trials specifically targeting hypertriglyceridemia (two trials were NA monotherapy, one NA with fibrates) showed significant reduction in coronary events especially if high TG was associated with low HDL-C [33]. A meta-analysis of clinical trials of NA to lower Lp(a) showed significant reductions of 22–24%, and a case report of NA with a statin showed a dramatic 88% reduction [34, 35].

## **5. Choosing an NA formulation**

The early clinical trials of NA used immediate-release formulations with good lipid results but many of those trials had unacceptably high drop-out rates due to flushing [36]. In an effort to reduce the flushing side effects, sustained-release NA formulations were developed. These did reduce flushing but continuous/ sustained exposure of the liver to NA resulted in a high incidence of impaired liver function [36]. Researchers found that an intermediate (between immediate and sustained) or ERNA provided the best reduction in flushing side effects and also reduced the liver issues encountered with the more sustained-release formulations [36]. Another formulation that was made popular by its "no flush" claim is inositol hexanicotinate (six molecules of niacin attached to inositol). There are many NA products available on-line and over-the-counter that claim to be extended-release preparations but most of them have not been studied for safety, efficacy, and side effects in controlled clinical trials. Poon conducted an *in vitro* dissolution study of 19 non-prescription NA products comparing them to 1 prescription PG-ERNA product (Niaspan) [37]. He found wide variation in dissolution rates suggesting the *in vivo* NA release from these products would difficult to predict.

**121**

**Figure 1.**

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

*(WMER) and 500 mg dose of inositol hexanicotinate (IHN).*

In selecting an NA product for clinical use, it is best to stay with products that have demonstrated safety and efficacy in clinical trials. The PG-ERNA, Niaspan, is the only NA formulation that has been approved by the US Food and Drug Administration for lipid therapy and is the standard by which other NA products are measured. It is by far the most extensively tested NA formulation having been used in both monotherapy and combined therapy with other agents including the AIM-HIGH and HPS-2 THRIVE studies. It has consistently demonstrated the desired lipid benefits and has typically had a total drop-out rate of 18–19% (9–10% due to flushing intolerance and 8–9% due to other adverse effects) [38]. Another polygel extended-release NA product, Slo-Niacin (Upsher-Smith Inc.) has also been extensively tested in clinical trials and was used in a large Veteran's Administration NA interchange study. Veterans who were on Niaspan (5321 subjects) were switched to Slo-Niacin and followed for 2 years. The results showed comparable safety/side effects and lipid benefits and Slo-Niacin had even greater lowering of TG [39]. A third NA product that uses a wax-matrix for its extended-release formulation is Endur-Acin (Endurance Products Inc). Endur-Acin has demonstrated comparable if not better lipid results compared the PG-ERNAs and it has exceptional safety and side effect rates with an average total drop-out rate of only 3–8% for 4 clinical trials totaling more than 400 subjects [11, 13, 40, 41]. Since age is one of the strongest non-lipid risk factors for CVD, it is worth noting that a post-hoc analysis of one of the Endur-Acin trials showed that older persons enjoyed even better lipid results than younger persons with no increase in side effects or drop-out rates [42]. The only clinical trial testing inositol NA as monotherapy showed its claim of "no flush" is a scam. In a head to head comparison trial with wax-matrix NA (Endur-Acin) that included pharmacokinetics of both agents, wax-matrix NA demonstrated an optimal extended-release and absorption curve over 8 hours and inositol NA had a flat line absorption curve demonstrating no bioavailability at all [41] (See **Figure 1**).

*Mean blood levels (ng/ml) over 8 hours of NA after single dose of 500 mg of wax-matrix nicotinic acid* 

**6. NA dosing and administration: "How to do" niacin**

Guidelines recommend determining the patients risk score for likelihood of a coronary event in the next 10 years and discussing treatment options and goals before initiating treatment. Initiation of NA therapy also should be preceded by

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

#### **Figure 1.**

*Dyslipidemia*

persons with high/very high risk status.

showed a dramatic 88% reduction [34, 35].

**5. Choosing an NA formulation**

statin therapy (absolute risk of cardiac event >7.5% over 10 years) to over 50 million persons [28]. The rate of statin intolerance (stopping therapy) in general population cholesterol intervention is 18–20% or about 10 million persons (statin intolerant) in the United States who are candidates for other lipid therapy interventions [29]. This represents another large target group that is appropriate for NA therapy since none of the other agents available have abroad range of lipid and non-lipid benefits for prevention of CVD [8, 26]. Some have suggested that proprotein-convertase subtilisin/kexin type 9 (PCSK-9) inhibitors be used when statin intolerance is encountered. At a cost of \$15,000/year for PCSK-9 inhibitors and an estimated incremental cost of \$330,000 per quality-adjusted life-years (QALYs), this option is very limited [30]. Perhaps the largest group of persons who would be logical candidates for NA lipid therapy globally are those whose risk scores indicate need to initiate lipid treatment but either they, individually, or their health system cannot afford statin treatment. Cardiovascular disease has grown at epidemic rates in developing countries and those countries account for over 80% of all cardiovascular deaths annually [31]. Using microsimulation modeling, analysts recently demonstrated that initiating statin therapy at the recommended 7.5% risk threshold would be an incremental cost-effectiveness ratio of \$37,000 per QALYs gained [32]. This may be considered cost-effective in a developed country, but in a developing country this is prohibitive. Not only does NA have the broadest profile of lipid and non-lipid benefits for coronary disease/mortality reduction, it is also the cheapest available lipid lowering agent. Thus, it makes sense as a public health strategy for developing countries to initiate population level of lipid therapy intervention with NA monotherapy adding other agents as needed, and reserve initiation with statin therapy to the subset of

Persons with isolated dyslipidemic fractions such as low HDL-C, or high TG are also reasonable candidates for NA therapy and NA is the only agent at present that can significantly lower Lp(a). A meta-analysis of clinical trials specifically targeting hypertriglyceridemia (two trials were NA monotherapy, one NA with fibrates) showed significant reduction in coronary events especially if high TG was associated with low HDL-C [33]. A meta-analysis of clinical trials of NA to lower Lp(a) showed significant reductions of 22–24%, and a case report of NA with a statin

The early clinical trials of NA used immediate-release formulations with good lipid results but many of those trials had unacceptably high drop-out rates due to flushing [36]. In an effort to reduce the flushing side effects, sustained-release NA formulations were developed. These did reduce flushing but continuous/ sustained exposure of the liver to NA resulted in a high incidence of impaired liver function [36]. Researchers found that an intermediate (between immediate and sustained) or ERNA provided the best reduction in flushing side effects and also reduced the liver issues encountered with the more sustained-release formulations [36]. Another formulation that was made popular by its "no flush" claim is inositol hexanicotinate (six molecules of niacin attached to inositol). There are many NA products available on-line and over-the-counter that claim to be extended-release preparations but most of them have not been studied for safety, efficacy, and side effects in controlled clinical trials. Poon conducted an *in vitro* dissolution study of 19 non-prescription NA products comparing them to 1 prescription PG-ERNA product (Niaspan) [37]. He found wide variation in dissolution rates suggesting the

*in vivo* NA release from these products would difficult to predict.

**120**

*Mean blood levels (ng/ml) over 8 hours of NA after single dose of 500 mg of wax-matrix nicotinic acid (WMER) and 500 mg dose of inositol hexanicotinate (IHN).*

In selecting an NA product for clinical use, it is best to stay with products that have demonstrated safety and efficacy in clinical trials. The PG-ERNA, Niaspan, is the only NA formulation that has been approved by the US Food and Drug Administration for lipid therapy and is the standard by which other NA products are measured. It is by far the most extensively tested NA formulation having been used in both monotherapy and combined therapy with other agents including the AIM-HIGH and HPS-2 THRIVE studies. It has consistently demonstrated the desired lipid benefits and has typically had a total drop-out rate of 18–19% (9–10% due to flushing intolerance and 8–9% due to other adverse effects) [38]. Another polygel extended-release NA product, Slo-Niacin (Upsher-Smith Inc.) has also been extensively tested in clinical trials and was used in a large Veteran's Administration NA interchange study. Veterans who were on Niaspan (5321 subjects) were switched to Slo-Niacin and followed for 2 years. The results showed comparable safety/side effects and lipid benefits and Slo-Niacin had even greater lowering of TG [39]. A third NA product that uses a wax-matrix for its extended-release formulation is Endur-Acin (Endurance Products Inc). Endur-Acin has demonstrated comparable if not better lipid results compared the PG-ERNAs and it has exceptional safety and side effect rates with an average total drop-out rate of only 3–8% for 4 clinical trials totaling more than 400 subjects [11, 13, 40, 41]. Since age is one of the strongest non-lipid risk factors for CVD, it is worth noting that a post-hoc analysis of one of the Endur-Acin trials showed that older persons enjoyed even better lipid results than younger persons with no increase in side effects or drop-out rates [42]. The only clinical trial testing inositol NA as monotherapy showed its claim of "no flush" is a scam. In a head to head comparison trial with wax-matrix NA (Endur-Acin) that included pharmacokinetics of both agents, wax-matrix NA demonstrated an optimal extended-release and absorption curve over 8 hours and inositol NA had a flat line absorption curve demonstrating no bioavailability at all [41] (See **Figure 1**).

## **6. NA dosing and administration: "How to do" niacin**

Guidelines recommend determining the patients risk score for likelihood of a coronary event in the next 10 years and discussing treatment options and goals before initiating treatment. Initiation of NA therapy also should be preceded by

baseline check of lipids, blood glucose, hemoglobin A1C, uric acid, homocysteine, and liver transaminases to be sure the patient is an appropriate candidate. If you are primarily targeting low HDL-C with NA therapy, the most effective formulation is IRNA. Even though that form of NA has the highest rate of flushing it can be minimized in most persons by proper dosing and administration: (1) initiating therapy at a low dose (250–500 mg) and gradually increasing over 1–2 weeks to allow tolerance to develop, (2) giving aspirin with the dose of NA to block the prostaglandin response, and (3) giving the NA dose with meals to slow the rate of absorption. The Coronary Drug Project using IRNA had only an 8% drop-out rate due to flushing. Typically, IRNA dosing is advanced to at least 3000 mg/day for optimal HDL-C response but can be increased to as high as 6000 mg/day in divided doses with meals to reach goals as tolerated. Lipids and blood chemistries should be rechecked at 6 weeks and monitored at 6 week intervals until targeted dose has been reached. If chemistries remain within normal limits (liver transaminases acceptable up to three times, the upper limit of normal) then monitoring interval can be extended to 3 months once targeted dose has been reached. For most persons whose liver function tests approach/exceed three times the upper limit of normal, simply reduce dosage by half and recheck tests in 2 weeks. They are most likely sensitive to the amidization metabolism of NA in the liver and are becoming depleted of methyl groups. They will usually continue to have excellent lipid results at the lower dose and will also benefit from a diet rich in "methyl donor" foods (kale, berries, fish, nuts, etc.) or taking a methionine supplement. In the Endur-Acin versus inositol clinical trial six persons on Endur-Acin had dose reduction due to liver enzyme elevations, yet all had a good lipid response and five were able to reach their LDL-C goal [41]. If additional lipid lowering agents are needed, follow up can be adjusted to take into consideration monitoring that added agent or any possible interactions of agents.

For essentially all other NA lipid therapies (other than isolated low HDL-C), ERNA is better tolerated and more effective for the other lipid fractions. Initiating dosing for ERNA therapy is essentially the same as IRNA as listed above. Most of the PG-ERNA studies have used one time/day dosing at bedtime with a small snack for two reasons: (1) convenience (and it can be given at the time a statin is supposed to be given) and (2) to match the time of peak hepatic lipid synthesis. The PG-ERNAs (Niaspan and Slo-Niacin) also have a somewhat higher rate of flushing than the WM-ERNA (Endur-Acin) so giving it in a near fasting state may also reduce the chance of early breakdown of the polygel capsule that might happen with the increased peristaltic activity of a meal. Critics of the bedtime NA dosing used in the AIM-HIGH and HPS-2 THRIVE studies, however, point out that dosing NA in a fasting or near fasting state causes a drop in non-esterified fatty acids. This in turn can inadvertently cause a transient drop in blood glucose triggering release of epinephrine and hepatic gluconeogenesis which might have caused some of the negative results found in those studies [26]. Also, persons taking any ERNA should be cautioned to avoid consuming a hot beverage with dosing since that can accelerate NA release and risk flushing.

In targeting appropriate patients for NA lipid therapy, it is helpful to know what lipid changes to expect for typical dosing of NA. Increases in HDL-C are typically in the +12 to +22% range with an IRNA dose of 3000 mg or an ERNA (Niaspan, Slo-Niacin, Endur-Acin) dose of 1500–2000 mg with IRNA and Niaspan being toward the better response end. Decreases in LDL-C for those agents are typically in the −12 to −26% with Endur-Acin toward the better response end. Decreases in TG are typically −10 to −15% and Lp(a) about −18 to −22% [11, 43–45]. Knowing the patients baseline lipid/chemistry levels and their 10 year coronary risk score can help in choosing an NA agent and dosing strategy. A person with isolated low HDL-C would be a good candidate for IRNA or possibly Niaspan if they do not tolerate the

**123**

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

the rest of your life can be a substantial expense.

**7. Conclusion**

flushing with IRNA. A person with MS, since they are considered higher risk for a coronary event (lower LDL-C goals), might do well to start on Endur-Acin and get the extra LDL-C benefit. In a clinical trial using Endur-Acin in persons with mild to moderate dyslipidemia 78% of persons with 0–1 cardiac risk factor and 44% of persons with 2 or more risk factors were able to get to their LDL-C goal along with the additional NA benefits in other lipid fractions [41]. A person whose baseline chemistries suggest glucose intolerance might best be placed on mealtime dosing to avoid reactive hypoglycemia and epinephrine release, and, of course, anyone with pre-existing liver function issues would best be started on IRNA. Management of side effects and adverse events from NA therapy are covered above (**side effects of NA**). Despite the bad press from the AIM-HIGH and HPS-2 THRIVE studies, NA has been used successfully with virtually every class of lipid lowering agent especially statins. With the possible exception of adding NA therapy to a person who is already at their LDL-C goal on statins, providers should feel comfortable adding

other agents to NA or NA to other agents to achieve lipid goals [46, 47].

Last but not least in considering NA for lipid therapy is the cost. There are many very inexpensive NAs available in pharmacies, health supplement stores, and on-line, all claiming to lower cholesterol. But the patient should be advised to stay with those products that have been proven safe and effective in clinical trials, and specifically to avoid the NAs that claim "no flush" (inositol hexanicotinate) that have been proven "no benefit". Endur-Acin (WM-ERNA) and Slo-Niacin (PG-ERNA) are available on-line for only \$8–9.00 USD/month for treatment (www. endur.com; www.slo-niacin.com). Niaspan is available only by prescription and is more expensive as are generic statins which are about 5–6 times more expensive. The cost may not be a big issue for persons with full drug coverage health insurance. But for others, even those with a co-pay, taking a medication that you will need for

Nicotinic acid is the first dyslipidemia medication to reduce both CVD events and mortality. No other lipid medication has the breadth of lipid and non-lipid benefits for managing CVD risk. Specifically, NA is the best agent for raising HDL-C, one of the best agents for lowering TG and the only medication that can significantly lower Lp(a). This is in addition to ability of NA to significantly lower LDL-C, and non-HDL-C. Unique non-lipid benefits include reduction of LDL-C oxidation and other oxidative species as well as prevention of inflammatory adhesion molecules in the vascular intima all of which are associated with atherogenesis. The initial clinical experience with IRNA was hampered by fairly high rates of flushing intolerance, but this has been largely overcome by the development of ERNA and attention to proper dosing and administration. Initial clinical trials of NA as monotherapy and in combination with other agents (statins, fibrates, and bile acid sequestrants) all showed significant lipid benefits. Two very large clinical trials (AIM-HIGH, and HPS-2 THRIVE) that were intended to confirm the benefits of NA/statin combined therapy had very disappointing results. Unfortunately, despite significant design flaws in these two studies, their results have led to widespread discontinuance of NA, both in combination with statins and even NA monotherapy. The real conclusion that seems supported by the two large clinical trials is that adding NA to statin treatment when a person is already at their LCL-C goal probably does not add benefit. But to disregard all of the prior positive NA studies and the fact that these large trials had serious design flaws is unfair judgment of NA. In fact, a 2013 meta-analysis

#### *The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

*Dyslipidemia*

agent or any possible interactions of agents.

dosing since that can accelerate NA release and risk flushing.

baseline check of lipids, blood glucose, hemoglobin A1C, uric acid, homocysteine, and liver transaminases to be sure the patient is an appropriate candidate. If you are primarily targeting low HDL-C with NA therapy, the most effective formulation is IRNA. Even though that form of NA has the highest rate of flushing it can be minimized in most persons by proper dosing and administration: (1) initiating therapy at a low dose (250–500 mg) and gradually increasing over 1–2 weeks to allow tolerance to develop, (2) giving aspirin with the dose of NA to block the prostaglandin response, and (3) giving the NA dose with meals to slow the rate of absorption. The Coronary Drug Project using IRNA had only an 8% drop-out rate due to flushing. Typically, IRNA dosing is advanced to at least 3000 mg/day for optimal HDL-C response but can be increased to as high as 6000 mg/day in divided doses with meals to reach goals as tolerated. Lipids and blood chemistries should be rechecked at 6 weeks and monitored at 6 week intervals until targeted dose has been reached. If chemistries remain within normal limits (liver transaminases acceptable up to three times, the upper limit of normal) then monitoring interval can be extended to 3 months once targeted dose has been reached. For most persons whose liver function tests approach/exceed three times the upper limit of normal, simply reduce dosage by half and recheck tests in 2 weeks. They are most likely sensitive to the amidization metabolism of NA in the liver and are becoming depleted of methyl groups. They will usually continue to have excellent lipid results at the lower dose and will also benefit from a diet rich in "methyl donor" foods (kale, berries, fish, nuts, etc.) or taking a methionine supplement. In the Endur-Acin versus inositol clinical trial six persons on Endur-Acin had dose reduction due to liver enzyme elevations, yet all had a good lipid response and five were able to reach their LDL-C goal [41]. If additional lipid lowering agents are needed, follow up can be adjusted to take into consideration monitoring that added

For essentially all other NA lipid therapies (other than isolated low HDL-C), ERNA is better tolerated and more effective for the other lipid fractions. Initiating dosing for ERNA therapy is essentially the same as IRNA as listed above. Most of the PG-ERNA studies have used one time/day dosing at bedtime with a small snack for two reasons: (1) convenience (and it can be given at the time a statin is supposed to be given) and (2) to match the time of peak hepatic lipid synthesis. The PG-ERNAs (Niaspan and Slo-Niacin) also have a somewhat higher rate of flushing than the WM-ERNA (Endur-Acin) so giving it in a near fasting state may also reduce the chance of early breakdown of the polygel capsule that might happen with the increased peristaltic activity of a meal. Critics of the bedtime NA dosing used in the AIM-HIGH and HPS-2 THRIVE studies, however, point out that dosing NA in a fasting or near fasting state causes a drop in non-esterified fatty acids. This in turn can inadvertently cause a transient drop in blood glucose triggering release of epinephrine and hepatic gluconeogenesis which might have caused some of the negative results found in those studies [26]. Also, persons taking any ERNA should be cautioned to avoid consuming a hot beverage with

In targeting appropriate patients for NA lipid therapy, it is helpful to know what lipid changes to expect for typical dosing of NA. Increases in HDL-C are typically in the +12 to +22% range with an IRNA dose of 3000 mg or an ERNA (Niaspan, Slo-Niacin, Endur-Acin) dose of 1500–2000 mg with IRNA and Niaspan being toward the better response end. Decreases in LDL-C for those agents are typically in the −12 to −26% with Endur-Acin toward the better response end. Decreases in TG are typically −10 to −15% and Lp(a) about −18 to −22% [11, 43–45]. Knowing the patients baseline lipid/chemistry levels and their 10 year coronary risk score can help in choosing an NA agent and dosing strategy. A person with isolated low HDL-C would be a good candidate for IRNA or possibly Niaspan if they do not tolerate the

**122**

flushing with IRNA. A person with MS, since they are considered higher risk for a coronary event (lower LDL-C goals), might do well to start on Endur-Acin and get the extra LDL-C benefit. In a clinical trial using Endur-Acin in persons with mild to moderate dyslipidemia 78% of persons with 0–1 cardiac risk factor and 44% of persons with 2 or more risk factors were able to get to their LDL-C goal along with the additional NA benefits in other lipid fractions [41]. A person whose baseline chemistries suggest glucose intolerance might best be placed on mealtime dosing to avoid reactive hypoglycemia and epinephrine release, and, of course, anyone with pre-existing liver function issues would best be started on IRNA. Management of side effects and adverse events from NA therapy are covered above (**side effects of NA**). Despite the bad press from the AIM-HIGH and HPS-2 THRIVE studies, NA has been used successfully with virtually every class of lipid lowering agent especially statins. With the possible exception of adding NA therapy to a person who is already at their LDL-C goal on statins, providers should feel comfortable adding other agents to NA or NA to other agents to achieve lipid goals [46, 47].

Last but not least in considering NA for lipid therapy is the cost. There are many very inexpensive NAs available in pharmacies, health supplement stores, and on-line, all claiming to lower cholesterol. But the patient should be advised to stay with those products that have been proven safe and effective in clinical trials, and specifically to avoid the NAs that claim "no flush" (inositol hexanicotinate) that have been proven "no benefit". Endur-Acin (WM-ERNA) and Slo-Niacin (PG-ERNA) are available on-line for only \$8–9.00 USD/month for treatment (www. endur.com; www.slo-niacin.com). Niaspan is available only by prescription and is more expensive as are generic statins which are about 5–6 times more expensive. The cost may not be a big issue for persons with full drug coverage health insurance. But for others, even those with a co-pay, taking a medication that you will need for the rest of your life can be a substantial expense.

## **7. Conclusion**

Nicotinic acid is the first dyslipidemia medication to reduce both CVD events and mortality. No other lipid medication has the breadth of lipid and non-lipid benefits for managing CVD risk. Specifically, NA is the best agent for raising HDL-C, one of the best agents for lowering TG and the only medication that can significantly lower Lp(a). This is in addition to ability of NA to significantly lower LDL-C, and non-HDL-C. Unique non-lipid benefits include reduction of LDL-C oxidation and other oxidative species as well as prevention of inflammatory adhesion molecules in the vascular intima all of which are associated with atherogenesis. The initial clinical experience with IRNA was hampered by fairly high rates of flushing intolerance, but this has been largely overcome by the development of ERNA and attention to proper dosing and administration. Initial clinical trials of NA as monotherapy and in combination with other agents (statins, fibrates, and bile acid sequestrants) all showed significant lipid benefits. Two very large clinical trials (AIM-HIGH, and HPS-2 THRIVE) that were intended to confirm the benefits of NA/statin combined therapy had very disappointing results. Unfortunately, despite significant design flaws in these two studies, their results have led to widespread discontinuance of NA, both in combination with statins and even NA monotherapy. The real conclusion that seems supported by the two large clinical trials is that adding NA to statin treatment when a person is already at their LCL-C goal probably does not add benefit. But to disregard all of the prior positive NA studies and the fact that these large trials had serious design flaws is unfair judgment of NA. In fact, a 2013 meta-analysis

of prior NA trials of both monotherapy and NA combined with other agents (included the Aim-High trial) showed that NA reduced risk of any CVD event by 34% and specifically major coronary event by 25% [48]. A similar meta-analysis of statin trials showed a 22 and 27% risk reduction for the same endpoints, respectively [49]. The obvious preference for statins when initialing lipid therapy is based on its effectiveness in lowering LDL-C, the prime lipid target in CVD risk reduction. But the NA trial with Endur-Acin showed that in a population with mild to moderate dyslipidemia, 50% or more of persons can reach their LDL-C goal with NA monotherapy and enjoy the additional lipid and non-lipid CVD benefits of NA therapy. Also, a recent study designed to evaluate the effects on atherogenic factors (lipid and non-lipid) when ERNA is added to statin therapy in MS patients showed an impressive array of positive benefits [50]. So, providers should continue to value its use in the many dyslipidemia patients who are appropriate for NA therapy and learn "how to do" NA for optimal results.

## **Author details**

Joseph M. Keenan Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, Minnesota, USA

\*Address all correspondence to: keena001@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**125**

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

> [8] Kamanna VS, Kashyap ML. Mechanism of action of niacin. The American Journal of Cardiology. 2008;**101**(8A):20B-26B. DOI: 10.1016/j.

> [9] Shehadah A, Chen J, Zacharek A, Cui Y, Ion M, Roberts C, et al. Niaspan treatment induces neuroprotection after stroke. Neurobiology of Disease.

[10] Parsons WB Jr. Cholesterol Control Without Diet! The Niacin Solution

[11] Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang ZQ. Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia. Archives of Internal Medicine.

[12] Aronov DM. The role of nicotinic acid in the treatment of atherosclerosis

[13] Keenan JM, Wenz JB, Ripsin CM, Huang Z, McCaffrey DJ. A clinical trial of oat bran and niacin in the treatment of hyperlipidemia. The Journal of Family Practice. 1992;**34**(3):313-319

[14] Goldberg RB, Bittner VA, Dunbar RL, et al. Effects of extended-release niacin added to simvastatin/ezetimibe on glucose and insulin values in AIM-HIGH. The American Journal of Medicine. 2016;**129**(7):753.E13-753.E22

[15] Canner PL, Furberg CD, McGovern ME. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the coronary drug project). The American Journal of Cardiology. 2006;**97**(4):477-479. Epub 2005

Dec 21

and atherogenic dyslipidemia. Kliniceskaia Meditsina. 1996;**74**(9):

amjcard.2008.02.029

2010;**40**(1):277-283

1991;**151**(7):1424-1432

48-52 Review. Russian

[1] Institute of Medicine. Dietary Reference Intakes for Thiamin,

[2] Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis.

[3] Altshul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry and Biophysics.

[4] Parsons WB Jr, Flinn JH. Reduction of serum cholesterol levels and beta-lipoprotein

cholesterol levels by nicotinic acid. A.M.A. Archives of Internal Medicine.

[5] Berge KG, Canner PL. Coronary drug project: Experience with niacin. Coronary drug project research group. European Journal of Clinical Pharmacology. 1991;**40**(Suppl 1):

[6] Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in coronary drug project patients: Longterm benefit with niacin. Journal of the American College of Cardiology.

[7] Jellinger PS, Handelsman Y, Rosenblit

PD, Bloomgarden ZT. American association of clinical endocrinologists and American college of endocrinology

guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocrine Practice. 2017;**23**(Suppl 2):1-87

2010;**210**(2):353-361

1955;**54**:558-559

1959;**103**(5):783-790

1986;**8**(6):1245-1255

S49-S51

Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press; 1998.

**References**

pp. 123-149

*The Role of Niacin in the Management of Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.81725*

## **References**

*Dyslipidemia*

**124**

**Author details**

Joseph M. Keenan

Minneapolis, Minnesota, USA

provided the original work is properly cited.

\*Address all correspondence to: keena001@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Family Medicine and Community Health, University of Minnesota,

of prior NA trials of both monotherapy and NA combined with other agents (included the Aim-High trial) showed that NA reduced risk of any CVD event by 34% and specifically major coronary event by 25% [48]. A similar meta-analysis of statin trials showed a 22 and 27% risk reduction for the same endpoints, respectively [49]. The obvious preference for statins when initialing lipid therapy is based on its effectiveness in lowering LDL-C, the prime lipid target in CVD risk reduction. But the NA trial with Endur-Acin showed that in a population with mild to moderate dyslipidemia, 50% or more of persons can reach their LDL-C goal with NA monotherapy and enjoy the additional lipid and non-lipid CVD benefits of NA therapy. Also, a recent study designed to evaluate the effects on atherogenic factors (lipid and non-lipid) when ERNA is added to statin therapy in MS patients showed an impressive array of positive benefits [50]. So, providers should continue to value its use in the many dyslipidemia patients who are appropriate for NA therapy and learn "how to do" NA for optimal results.

[1] Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press; 1998. pp. 123-149

[2] Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. 2010;**210**(2):353-361

[3] Altshul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry and Biophysics. 1955;**54**:558-559

[4] Parsons WB Jr, Flinn JH. Reduction of serum cholesterol levels and beta-lipoprotein cholesterol levels by nicotinic acid. A.M.A. Archives of Internal Medicine. 1959;**103**(5):783-790

[5] Berge KG, Canner PL. Coronary drug project: Experience with niacin. Coronary drug project research group. European Journal of Clinical Pharmacology. 1991;**40**(Suppl 1): S49-S51

[6] Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in coronary drug project patients: Longterm benefit with niacin. Journal of the American College of Cardiology. 1986;**8**(6):1245-1255

[7] Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT. American association of clinical endocrinologists and American college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocrine Practice. 2017;**23**(Suppl 2):1-87

[8] Kamanna VS, Kashyap ML. Mechanism of action of niacin. The American Journal of Cardiology. 2008;**101**(8A):20B-26B. DOI: 10.1016/j. amjcard.2008.02.029

[9] Shehadah A, Chen J, Zacharek A, Cui Y, Ion M, Roberts C, et al. Niaspan treatment induces neuroprotection after stroke. Neurobiology of Disease. 2010;**40**(1):277-283

[10] Parsons WB Jr. Cholesterol Control Without Diet! The Niacin Solution

[11] Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang ZQ. Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia. Archives of Internal Medicine. 1991;**151**(7):1424-1432

[12] Aronov DM. The role of nicotinic acid in the treatment of atherosclerosis and atherogenic dyslipidemia. Kliniceskaia Meditsina. 1996;**74**(9): 48-52 Review. Russian

[13] Keenan JM, Wenz JB, Ripsin CM, Huang Z, McCaffrey DJ. A clinical trial of oat bran and niacin in the treatment of hyperlipidemia. The Journal of Family Practice. 1992;**34**(3):313-319

[14] Goldberg RB, Bittner VA, Dunbar RL, et al. Effects of extended-release niacin added to simvastatin/ezetimibe on glucose and insulin values in AIM-HIGH. The American Journal of Medicine. 2016;**129**(7):753.E13-753.E22

[15] Canner PL, Furberg CD, McGovern ME. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the coronary drug project). The American Journal of Cardiology. 2006;**97**(4):477-479. Epub 2005 Dec 21

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**129**

proven.

**Chapter 8**

**Abstract**

*Olta Tafaj Reddy*

very effective at lowering LDL-C.

**1. Introduction**

vascular disease [2].

**Keywords:** dyslipidemia, PCSK9 inhibitors, ezetimibe, LDL-C

Novel Therapies for Dyslipidemia

Multiple studies have shown a strong correlation between low-density lipoprotein cholesterol (LDL-C) concentration and development as well as progression of atherosclerosis and cardiovascular disorders. Thus, the decrease of the LDL-C burden through lifestyle modification and/or pharmacological interventions unanimously demonstrated a decrease in cardiovascular events and mortality. To date, statins are considered the cornerstone of lipid-lowering therapy. The Cholesterol Treatment Trialists' (CTT) Collaboration has shown consistency of treatment benefits across a wide patient population. However, new data are now revealing that a considerate patient population failed to achieve lipid goals solely on statins and a significant percentage cannot tolerate treatment. Therefore, extensive work has recently been done in generating novel LDL-C-lowering agents that would act through mechanisms different from statins. Among others, monoclonal antibodies to protein convertase subtilisin/kexin type 9 (PCSK9) and ezetimibe seem particularly promising. Both PCSK9 monoclonal antibodies and ezetimibe have shown to be well tolerated and

Cardiovascular disease (CVD), which includes coronary heart disease (CHD)

Under certain circumstances, non-statin medications like ezetimibe and PCSK9 inhibitors are found to be useful particularly in combination with statin therapy. Clinical trials pertaining to these novel therapies have shown great benefits with significant LDL-C-lowering potential and decrease in cardiovascular risk. These agents are generally well tolerated, but long-term safety and cost remain to be

and strokes, is considered as a number one cause of morbidity and mortality worldwide. Together with hypertension, dyslipidemia is among the most prevalent risk factors leading to CVD. Thus, treatment of dyslipidemia is crucial in reducing CVD events and the morbidity and mortality associated with them. Studies in the last decade have confirmed a causal relationship between low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular diseases (ASCVD) [1]. LDL-C can be lowered by diet restriction and lifestyle changes or by various lipid-lowering therapies, among which statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) are currently considered the cornerstone medication. Based on the 2018 guidelines published by the American College of Cardiology (ACC) and the American Heart Association (AHA), multiple recommendations have been made for patients with or at risk of developing cardio-

## **Chapter 8**

*Dyslipidemia*

in the management of hyperlipidemia. Metabolism. 1998;**47**:1097-1104

[45] Morgan JM, Capuzzi DM, Guyton JR, Centor RM, Goldberg R, Robbins DC, et al. Treatment effect of Niaspan, a controlled-release niacin, in patients with hypercholesterolemia: A placebo-controlled trial. Journal of Cardiovascular Pharmacology and Therapeutics. 1996;**1**(3):195-202

[46] Vogt A, Kassner U, Hostalek U, Steinhagen-Thiessen E. Prolongedrelease nicotinic acid for the

management of dyslipidemia: An update including results from the NAUTILUS study. Vascular Health and Risk Management. 2007;**3**(4):467-479

[47] Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, et al. The ARBITER 6-HALTS trial (arterial biology for the investigation of the treatment effects of reducing cholesterol 6-HDL and LDL treatment strategies in atherosclerosis): Final results and the impact of medication adherence, dose, and treatment duration. Journal of the American College of Cardiology.

2010;**55**(24):2721-2726

2013;**61**(4):440-446

Lancet. 2010;**376**:1670-1681

[48] Lavigne PM, Karas RH. The

current state of niacin in cardiovascular disease prevention: A systematic review and meta-regression. Journal of the American College of Cardiology.

[49] Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomized trials.

[50] Adiels M, Chapman MJ, Robillard P, et al. Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis. Journal of Clinical Lipidology.

**128**

2018;**12**:810-821
