**2. Epidemiology**

Most large studies extending over the last 25 years suggested that the leading cause of atheroslerotic cardiovascular disease (ASCVD) is high LDL-C levels and this has been widely recognized and accepted [9, 11]. Furthermore, there is also growing evidence that increased levels of LDL-C and other ApoB containers, including very low density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL-C) and Lp(a), are directly related to the progression of ASCVD [12, 13]. In 2010, a multicenter study analyzing data from 26 randomized clinical trials in 2009 demonstrated that statins are effective in lowering LDL-C blood levels and controlling blood glucose levels. LDL-C at the recommended level is beneficial in reducing atherosclerotic CV events and CV mortality [14].

However, studies in recent years have revealed that control of plasma LDL-C concentrations is not the only goal of reducing the risk of CVD [15]. Based on the results of their study, Cannon et al. demonstrated an ongoing risk of major CV events after treatment with high doses of atorvastatin or pravastatin. The data signified that up to 26.3% in the atorvastatin-treated group and 22.4% in the pravastatin-treated group experienced a major CV event or death [16]. This evidence suggests that the goal of reducing the risk of CVD requires control not only of blood LDL-C levels but also of residual CV risk factors in other dyslipidemia, including TG and TRLs, HDL-C and Lp(a) [9].

## **3. Residual risk factors in dyslipidemia**

#### **3.1 Pathogenesis of atherosclerosis**

Atherosclerosis is a complex phenomenon that is involved by a number of factors. Firstly, when the vascular endothelial cell layer is injured, the synthesis of nitrite oxide (NO), a chemical that protects blood vessels, is reduced, while the production of oxidants rises [17, 18]. Infiltration of ApoBs including remnants of chylomicron, VLDL-C, IDL-C, LDL-C and Lp(a) into the endothelial layer. The ApoBs that are retained in the vessel wall oxidize, triggering a cascade of biological events that result in an inflammatory response [19, 20]. Furthermore, platelets are stimulated to cause chronic vascular inflammation which leads to leukocyte recruitment [21, 22]. Monocytes and neutrophils penetrate the endothelial layer into the arterial wall. Macrophages that have been differentiated from monocytes amplify lipid absorption and produce foam cells, which play a key role in the formation and instability of atherosclerotic plaques. T lymphocytes, mastocytes, and other inflammatory cells penetrate the lesion and help to continue the noxious inflammatory

response [20–24]. This process is also maintained and enhanced through signaling pathways such as MCP-1, M-CFS, GM-CFS [25–27]. As a result, the plaque ruptures and leads to clinical manifestations for example, myocardial infarction or stroke.
