**3.2 Hypertriglyceridemia and related markers**

The function of TG in the etiology of atherosclerosis has garnered limited attention in recent years, with most studies focusing on the benefits of raising HDL-C. Contemporary clinical and genetic evidence, on the other hand, suggests that TG, especially TRLs, and apoprotein C3, play essential roles in the etiology of atherosclerosis. Therefore, TG and TRLs are getting increasing attention and are becoming one of the therapeutic targets for lowering the risk of ASCVD [28].

TG is the main component in the structure of the TRL group including VLDL-C and chylomicrons which are synthesized in the liver and small intestine, respectively [29, 30]. The metabolism of TG and TRLs has the involvement of lipoprotein lipase (LPL) which is capable of activating the hydrolysis of the TG component in the core of TRLs into fatty acids. As a result, residual VLDL-C and residual chylomicrons are formed, which contain less TG and more cholesterol than normal TRLs [29, 31]. A portion of VLDL-C residues and residual chylomicrons are captured in the liver and neutralized by hepatic bile. The remainder is metabolized again by LPL or hepatic lipase enzymes, forming cholesterol-rich LDL-C [29, 30]. The residual LDL-C, VLDL-C, and residual chylomicrons are all cholesterol-rich lipoproteins and are classified as non-HDL [29, 32]. As with LDL-C, residual VLDL-C and chyplomicron molecules can be engulfed by macrophages in the vascular wall, which contributes to vascular inflammation and progression of atheromal. However, unlike LDL-C, the residual VLDL-C and chylomicron molecules do not require oxidation when participating in the process of atherosclerosis [29, 30]. Many factors impact the metabolism of TG and TRLs, with LPL playing a major role. The activity of the LPL enzyme has a direct effect on the concentration of TG and TRLs in the blood; for example, increasing LPL activity lowers TG and TRL concentrations while increasing VLDL-C molecules and residual chylomicrons, and vice versa (**Figure 1**).

The reduction in TG and TRLs metabolism leads to less cholesterol-rich lipoprotein concentrations and is expected to reduce the risk of atherosclerosis. However, intensive genetic and molecular biology studies of TG, TRLs and LPL all showed conflicting results. The first observational studies in the field of genetics related to TG, TRLs and LPL found that mutations that decrease TRLs metabolism were associated with atherosclerosis and coronary artery disease, whereas mutations TRLs metabolism enhancer had the opposite effect. Several mutations directly in the LPL enzyme associated with CVD risk have been observed including Gly188Glu, Asp91Asn and Asn291Ser substitution mutations. In which, the Gly188Glu substitution mutation in LPL can increase the risk of coronary heart disease 5 times higher than those without the mutation [33]. ApoC-II and ApoA-V loss-of-function mutations, both have been conveyed to increase blood TG, increase the risk of myocardial infarction and coronary artery disease, while mutations in the APOC3 gene - the gene that codes for Apo C-III - such as the RX 9 mutation and some other rare mutations give the opposite result [29, 34]. Most recently, ANGPTL4 mutations have appeared to reduce TG levels and reduced the risk of coronary artery disease. When conducting whole-chromosome studies on single-nucleotide polymorphisms (SNPs), susceptibility loci in the genomic regions encoding ApoC-III, ApoA-V, ANGPTL3, and ANGPTL4 were revealed to be associated with ASCVD, which lays the foundation for gene therapy to improve CV risk. In addition, there are

#### **Figure 1.**

*The center role of LDL-C and TRLs in the formation of atherosclerotic plaque. ANGPTL = angiopoietin like protein, HL = hepatic lipase, LPL = lipoprotein lipase.*

many other genetic studies with similar results regarding the role of TG in vascular events [29].

Due to the inverse correlation of HDL-C and TG, most of the previous epidemiological studies intimated the association between increased TG and atherosclerosis, which was explained by the lowering effect of HDL-C. However, there are studies that refute this view and provide strong evidence that TG is an independent factor affecting the risk of CV events. Furthermore, there appears to be a positive correlation between serum TG levels and mortality risk, even when adjusted for HDL-C and other factors [29].

With a few other CVD not caused by atherosclerosis, TG also showed a similar association. One study found that increase levels of TG and residual cholesterol molecules (total cholesterol minus LDL-C and HDL-C) were risks of aortic stenosis [35].

#### *3.2.1 Treatment of hypertriglyceridemia*

Because of the harmful effects of TG on the cardiovascular system, strategies to control TG levels were rapidly investigated to contribute to the control of CV risk in general population. Several epidemiological studies have indicated a reduction in the risk of CV events in subjects regularly consuming fish or foods rich in omega-3 fatty acid (EPA), which has been proved to reduce TG level [36–38]. However, studies testing natural EPA in subjects with ASCVD or heart failure or at high CV risk such as the ORIGIN study and most recently the STRENGTH study have showed no beneficial effect [39, 40]. Similarly, most trials of TG-lowering therapies have failed to improve CV risk. Until 2019, the REDUCE IT trial – a multicenter, double-blind, randomized, placebo-controlled study – was performed in statin-treated diabetic patients with CVD or other CV risk factors having TG levels between 135 and 499 mg/dl (1.52 to 5.63 mmol/L) and blood LDL-C levels between 41 and 100 mg/dl (1.06 to 2.59). mmol/L). There were one group treated with icosapent ethyl - a synthetic derivative of EPA with TG-lowering effects - and a placebo group. The results

#### *Residual Cardiovascular Risk Factors in Dyslipidemia DOI: http://dx.doi.org/10.5772/intechopen.100046*

concluded that in patients with elevated TG, the use of icosapent ethyl reduced significantly CV events [41]. In addition to TG-reducing effect, the CV benefits of icosapent ethyl are also attributed to its effects on the main mechanisms underlying the progression of atherosclerosis, such as reduced inflammation and anti-oxidation, which stabilize and even regress atherosclerotic plaques [42]. Up to now, icosapent ethyl is considered a potential drug to help eliminate the residual CV risk caused by hypertriglyceridemia (**Figure 2**).

Research on the effects of fibrates which is a potent TG-lowering agent on CVD was also conducted quite early. In 1975, clofibrate in combination with niacin showed no significant benefit in reducing the risk of CVD [43]. However, VA-HIT study compared the gemfibrozil-treated group with the placebo group in patients with blood HDL-C levels <40 mg/dL and blood LDL-C levels <140 mg/dL showed effects on lipid parameters: HDL-C levels increased by 6%, total cholesterol decreased by 4% and TG decreased by 31% compared to the placebo group. In addition, VA-HIT also uncovered that gemfibrozil reduced the risk of mortality from major vascular events such as coronary artery disease, myocardial infarction, and stroke by 24% [44]. However, in 2010, ACCORD trial on combination of fenofibrate and statin in type 2 diabetes showed no favorable results [45]. A multicenter meta-analysis examinining data from 18 studies of fibrates during 1950–2010 to further assess their impact on CVD revealed fibrates decreased the risk of major CV events by 10% and coronary events by 13% but did not lower the overall risk of stroke or mortality rate [46]. With these results, there is practically no clear evidence that fibrates are beneficial in improving the risk of CVD or vascular events.

Novel therapies of hypertriglyceridemia are being applied to achieve maximum efficacy while minimizing undesirable side effects. For example, AKCEA-APOCIII-LRx is targeted on inhibiting the synthesis of Apo C-III by hindering the mRNA that translates it. In healthy volunteers, clinical trials of the treatment revealed a reduction in the risk of CV events in the treated group, as well as acceptable tolerability [47].

Residual lipoprotein cholesterol (RLP-C) which has close relation with TG level has also recently been demonstrated to be a residual CV risk factor even in those

#### **Figure 2.**

*(A) The Kaplan–Meier event curves for the primary end point of CV events without death. There was a statistically significant difference in primary CV events in the icosapent ethyl group (17.2%) compared with the placebo group (22%), corresponding to an absolute between-group difference of 4.8 percentage points, hazard ratio, 0.75 (95% CI, 0.68–0.83) P < 0.001, NNT = 21 over a median follow-up of 4.9 years. (B) The Kaplan–Meier event curves for the secondary end point of CV events without death. There was a statistically significant difference in secondary CV events in the icosapent ethyl group (17.2%) compared with the placebo group (22%), corresponding to an absolute between-group difference of 3.6 percentage points, hazard ratio, 0.74 (95% CI, 0.65–0.83) P < 0.001, NNT = 28 over a median follow-up of 4.9 years. NNT = number needed to treat, Cl = confidence interval. Reproduced with permission from Deepak L. Bhatt, M.D., 2019 [41].*

with good LDL-C control. Elevated blood levels of RLP-C have been proved to predict coronary and other CV events [35, 48]. This is a new direction that need investigating in order to enhance the accuracy of assessing residual CV risk. In addition, more RLP-C intervention trials are required to demonstate the effect in CVD prophylaxis.

#### **3.3 Low HDL-C**

Research on the role of TG and TRLs in atherosclerotic disease are progressively providing conclusive evidence while trials to raise blood HDL-C levels have so far failed to show significant clinical benefit. This augments the possibility that the previously established causal link between higher HDL-C and a lower risk of vascular events is attributable to a comparable reduction in TG as HDL-C rises. The function of HDL-C in atherosclerosis-related CVD is still debatable nowadays.

There are several factors that contribute to HDL-C to protect blood vessels from atherosclerosis. The HDL-C molecule is responsible for cholesterol transfer from organs and peripheral blood vessels to the liver for biliary elimination. HDL-C also diminishes immune cell adherence and increases vasodilating process as well as inhibits platelet aggregation via prostacyclin. Prostacyclin modulation, in turn, aids in the breakdown of fibrin and thrombolysis in couple with decreasing inflammatory mediators and restoring vascular endothelial cell function. In addition, HDL-C is an inherent antioxidant involved in the preservation of blood vessels from oxidative damage [8, 49].

It is evident that HDL-C can prevent blood vessels from atherosclerosis. However, the role of HDL-C in lowering the overall risk of cardiovascular disease remains unknown. While epidemiological studies linked HDL-C to a lower risk of atherosclerotic CV events [50, 51], genetic study found that HDL-C had no effect on CV event risk [52, 53]. Indeed, when delving into a few gene mutations related to Scavenger receptor class B type 1 (SR-BI) and Cholesteryl ester transfer protein (CEPT) receptors - two components involved in HDL-C metabolism, these ones affect CV events differently. The pathway of HDL-C metabolism in the human body has the participation of SR-BI and CEPT receptors. When these two factors lose their function, the concentration of HDL-C in the blood will increase [54–56]. Studies in individuals with anomalies in the gene that cause loss of SR-BI receptor function have showed an increase in HDL-C levels but also an increased risk of CV events [55]. Nevertheless, studies of mutations that reduce function of CEPT showed irrelevant outcome. With the Ile405Val substitution alteration on CEPT, it is concluded that there was a decrease in CEPT activity and an increase in HDL-C regarding gender, but further an increased risk of ischemic heart disease in women but not in men [56]. Despite that, studies with other gene mutations such as TaqIB, I405V and -629C > A have clarified a reduced risk of coronary heart disease [57]. In 2009, a genetic study in different loci of the gene coding for CEPT, gave an explaination for this heterogeneity. There was an inverse association between HDL-C and the risk of cardiovascular events as a result of mutations; however, there are other alterations that do not demonstrate this correlation [8]. With achievements in functional decoding of HDL-C in terms of genes, researchers and clinical practitioners would assume the role of HDL-C in ASCVD will soon be clarified and become a state-of-art implement to assist in the treatment, prognosis, and prevention of CVD.

Since the role of HDL-C is uncertain, the use of the HDL-C measurement in clinical practice has been limited up until present. Due to the extreme prior belief that HDL-C is a favorable factor for lowering CVD risk, HDL-C was added to

SCORE – the CV risk assessment model – to create SCORE – HDL-C in European Society of Cardiology recommendations for the treatment of dyslipidemia [58, 59]. A study published in 2015 evaluated the predictive capacity of two models, SCORE - HDL-C and SCORE, and found that while the SCORE - HDL-C did not enhance CV mortality prognosis, it did lower the sensitivity of finding persons at high risk of CVD in the population [60].
