**7. Conclusion**

*Management of Dyslipidemia*

that a reduction of 1 mmol/L of LDL-C is associated with a 20–25% reduction in the relative risk of major CV events including cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke [45]. Statins reduce the biosynthesis of cholesterol in the liver by competitively inhibiting the enzyme hydroxymethylglutaryl CoA (HMG-CoA) reductase, the rate-limiting step in the production of cholesterol. The reduction in intracellular cholesterol promotes up-regulation of LDL receptor (LDLR) at the surface of the hepatocytes, which in turn results in increased hepatic uptake of LDL from the blood, thereby lowering plasma concentrations of LDLand other ApoB-containing lipoprotein particles. The degree of LDL-C reduction is dose-dependent and varies between the different statins. A high intensity statin, on average, reduces LDL-C by >50%, while, moderate-intensity therapy is defined as the dose expected to reduce LDL-C by 30-50% [35]. Statins should be initiated with the highest tolerated dose to reach the LDL-C goal determined by the individual's risk category. There are abundant data supporting the concept of 'the lower LDL-C, the better' in the primary and secondary cardiovascular disease prevention. Statins are generally safe and well tolerated apart from myalgia which is the most commonly reported statin adverse effect, although its frequency is higher in everyday clinical practice than in RCTs [46]. However, due to low adherence to statin therapy or statin intolerance, many patients do not reach LDL-C target levels. Because the LDL-C targets suggested in guidelines, currently <1.4 mmol/L in patients with very-high CV risk, < 1.8 in patients with high CV risk and < 2.6 mmol/L in those with moderate CV risk respectively, are often not achieved, additional and more

Ezetimibe inhibits dietary and biliary cholesterol absorption by interacting with the Niemann-Pick C1-Like 1 protein (NPC1L1), thereby lowering the amount of cholesterol delivered to the liver. In response to reduced cholesterol delivery, the liver reacts by upregulating LDL receptor expression, which in turn leads to increased clearance of LDL from the blood. A large clinical trial evaluating the addition of ezetimibe to statins in patients with prior acute coronary syndrome found a 24% reduction in LDL-C levels and a 6.4% reduction in the relative risk of CV death, major coronary events, or nonfatal stroke at 7 years [47]. Statinezetimibe combination treatment is the first choice for managing elevated LDL-C in very-high-risk patients with high LDL-C unlikely to reach goal with a statin, and in

A new class of drugs, PCSK9 inhibitors, that targets a proprotein convertase subtilisin/kexin type 9 (PCSK9) is recommended by current guidelines for the secondary prevention of very high-risk individuals not at LDL-C goal despite maximally tolerated statin doses and ezetimibe [35]. This protein regulates plasma concentrations of LDL-C by interacting with LDL receptors on hepatocytes. After binding to an LDL receptor, PCSK9 directs it to lysosomal degradation. Consequently, it inhibits recycling of the receptor to the surface of the hepatocyte and delays catabolism of LDL particles [49]. Currently approved PCSK9 inhibitors are the human monoclonal antibodies, alirocumab and evolocumab. The mechanism of action relates to the reduction of the plasma level of PCSK9, which in turn results in decreased intracellular degradation and increased expression of LDL receptors at the cell surface and therefore in a reduction of circulating LDL-C levels [50]. Co-administration with statin treatment has a sound rationale because statins upregulate PCSK9. In clinical trials, PCSK9 inhibitors either alone or in combination with statins, and/or other lipid-lowering therapies have been shown to significantly reduce LDL-C levels on average by 60%, depending on dose. In contrast to statins, inhibiting PCSK9 with monoclonal antibodies also reduces Lp(a)

aggressive LDL-C lowering therapies are needed [35].

primary prevention familial hypercholesterolaemia patients [48].

**14**

plasma levels.

Dyslipidemias largely contribute to global cardiovascular disease burden. Consistent evidence from epidemiological and clinical studies, supports the key role of the circulating LDL-C and other apoB containing lipoproteins in the development of atherosclerosis. Therefore, reducing LDL-C and other ApoB-containing lipoproteins is a core component of lipid management for both the primary prevention of CVD and the secondary prevention of recurrent CV events. A major outstanding challenge is how best to implement use of evidence-based therapies in clinical practice, particularly statins and PCSK9 inhibitors. Understanding the important role that metabolic derangements play in the pathogenesis of atherosclerosis pave the way for stronger implementation of current guidelines for CVD risk assessment and prevention.
