**3. Approved indication**

*Management of Dyslipidemia*

and its appropriate use.

**2. Mechanism of action**

plasma concentrations [8].

limits up titration of statin therapy, or in some patients, even prevents the use of a small dose of statins. In order to obtain optimal ASCVD risk reduction, further lowering the LDL-C has been achieved with the use of ezetimibe, as well as the use

The PCSK9i: evolocumab and alirocumab, have shown promising results over the last several years, not only in major randomized landmark trials but also in clinical practice. These agents are one of the most efficacious antihyperlipidemic therapies and have shown to achieve a reduction in low density lipoprotein (LDL) by 50–65% [2, 3]. Two large outcomes trials [4, 5] have demonstrated that both evolocumab and alirocumab are effective in reducing major adverse cardiac events in high risk atherosclerotic cardiovascular disease (ASCVD) conditions. Most recent multi-society guidelines are endorsing the use of PCSK9i in patients at very high cardiovascular risk [6], which includes patients with familial hypercholesterolemia. A joint consensus statement from the European Society of Cardiology and European Atherosclerosis Society suggested that PCSK9i could be considered in patients with clinical ASCVD treated with maximal tolerated statin therapy and/or ezetimibe who have continued to have LDL-C > 100 mg/dL [7]. Despite all the available data supporting its efficacy and clinical benefits, the cost-effectiveness and economic value of PCSK9 inhibitors has been reported to be 'low value' as measured in quality adjusted age years. [6]. The guidelines have also felt that the economic value of PCSK9i would be improved by restricting its use to patients at high risk of ASCVD events, specifically initiating PCSK9i in high risk patients with LDL-C values >120, despite optimal lipid lowering therapy. In this article we describe the clinical use of PCSK9i in the current era

The proprotein convertase subtilisin/kexin-9 (PCSK9) is a serine protease, which has been found to be integral in the regulation of LDL-C plasma concentrations. The LDL receptors (LDL-R) present on hepatocytes are responsible for binding circulating LDL-C and removing them from plasma. In the absence of PCKS9, the LDL-C/LDL-R complex enters hepatocytes within the endosome and dissociates into LDL-C and LDL-R as a result of the acidic pH present in the endosome. The LDL-R is then recycled back to the hepatocyte surface, making it available to bind more LDL-C, thereby lowering the serum LDL-C concentration. In the presence of PCSK9, however, the LDL-C/LDL-R complex does not dissociate within the endosome, and the entire complex is marked for lysosomal degradation. Without LDL-R recycling, less LDL-C is removed from circulation, resulting in higher LDL-C

The clinical implications of PCSK9 have been demonstrated in both loss of function and gain of function mutations. A gain of function mutation was first discovered in two French families with familial hypercholesterolemia that was not associated with LDLR or APOB mutations [9]. The mutated allele created an overexpression of PCSK9, and subsequently elevated plasma LDL-C levels, with sequelae of significant hypercholesterolemia including tendinous xanthomas and risk of premature ASCVD in the fourth and fifth decade. While gain of mutation functions have been discovered in other cohorts in Utah, Norway and the United Kingdom, familial hypercholesterolemia secondary to PCKS9 gain of function mutations is uniquely rare [8]. However, this discovery provided insight to PCSK9 activity, and that overexpression of this protein results in excessive LDL-C in vivo. This discovery also provided the third locus for autosomal dominant familial

of proprotein convertase subtilisin/kexin type 9-inhibitors (PCSK9i).

**156**

The Food and Drug Administration (FDA) has approved alirocumab and evolocumab as "an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous Familial Hypercholesterolemia (FH) or clinical ASCVD who require additional lowering of LDL-C." Evolocumab is also indicated for treatment of homozygous FH and, based on the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, "to reduce the risk of myocardial infarction (MI), stroke, and coronary revascularization in adults with established CVD."
