**3.4 Lipoprotein (a)**

Lp(a) is made up of an LDL-C molecule covalently bound to an apolipoprotein (a) that is homologous to the coagulation factor plasminogen. It also includes an apolipoprotein B100 as it contains LDL-C. Therefore, Lp(a) has both atherogenic and thrombolytic properties [70, 71]. The ability of Lp(a) to permeate the artery wall has been demonstrated [72]. Lp(a) has been showed to increase thrombus development, inflammatory response, and foam cell production in both laboratory and animal investigations [73].

Many studies prove that Lp(a) is a factor affecting the morbidity and mortality of CVD [74, 75]. The INTERHEART study proclaimed that Lp(a) levels >50 mg/dL increased the risk of myocardial ischemia [76]. The effect of Lp(a) on CV risk was independent of other risk factors, including LDL-C levels [77, 78]. Thus, elevation of blood Lp(a) levels confers a residual CV risk in dyslipidemia, which is similar to the role of TG mentioned above. A large study of LPA genetic variants also showed an independent role for Lp(a) in relation to coronary events, despite low LDL-C levels with statin therapy [79]. To specify the role of Lp(a) in reducing the risk of CVD, a study compared blood levels of Lp(a) with the risk of CVD and LDL-C levels with CVD risk, the results showed that the clinical benefit of lowering Lp(a) was directly proportional to the reduction of Lp(a) levels. Specifically, a 101.5 mg/dL reduction in Lp(a) resulted in a clinically significant reduction in CVD risk similar to a 38.67 mg/dL reduction in LDL-C [80].

Among the factors affecting Lp(a) levels, PCSK9 is one that has been observed in clinical trials to reduce Lp(a) concentration [78]. The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in influencing Lp(a) levels was also confirmed in a survey of PCSK9 functional-affecting mutants, which explicated that overexpressed function mutations of PCSK9 increased the CV risk while the PCSK9 R46L mutation reduced its function, showing a reduced risk of aortic stenosis and myocardial infarction [81]. The reduction in CV risk is proportional to the level of Lp(a) in the blood as mentioned above. Therefore, PCSK9 inhibitors are a potential agent for reducing the incidence of vascular events through its effect on Lp(a).

#### *3.4.1 Treatment of high lipoprotein (a)*

The cornerstone of current potential drug development is the new evidence on the benefits of Lp(a) reduction on the risk of CV events and mortality. Only in the last three years have trials of drugs that reduce Lp(a), such as alirocumab and evolocumab, been conducted. ODYSSEY OUTCOMES was a large trial of alirocumab, the results of which showed that alirocumab reduced the total number of CV events and CV mortality in patients diagnosed with acute coronary syndrome (ACS) [81]. In 2020, the data from the ODYSSEY OUTCOMES trial were reanalyzed to determine the effect of baseline Lp(a) levels and the trend of alirocumab-induced change on Lp(a) and LDL-C, results showed that each 5 mg/dL reduction in Lp(a) was predictive of a 2.5% reduction in CV events. Therefore, Lp(a) should now be considered a therapeutic target, especially after ACS [82]. There was a tremendous advantage when comparing alirocumab or evolocumab with placebo or ezetimibe plus a statin in another trial; however, the benefit difference between the two groups was not significant when comparing the two groups utilizing the combination of ezetimibe and statin [83].

Currently, new therapies that selectively target Lp(a) are being developed. The APO(a)-LRx study is currently ongoing, but preliminary findings indicate that APO(a)-LRx has the potential to reduce Lp(a) levels and their effects by up to 80%, potentially lowering CV risk [84]. In addition, testing a monoclonal antibody that reduces blood Lp(a) levels has demonstrated promising in vitro data [85]. The results of these trials are eagerly awaited.

To date, more persuasive evidence has exhibited that TG and Lp(a) are independent CV risk factors, even with LDL-C, and should be considered as new therapeutic targets in the management of CVD. Meanwhile, the importance of HDL-C has decreased compared to the previous era. However, in-depth studies analyzing genes and blood HDL-C levels are two hypotheses that need to be further studied to clarify the role of HDL-C.
