**Abstract**

Atherosclerotic cardiovascular diseases (ASCVD) remain the number one cause of death and morbidity in the country. Elevated cholesterol/hyperlipidemia has been considered one of the major risk factors for ASCVD. Statins have been the main stay therapy for treating hyperlipidemia achieving remarkable clinical benefits; however; its inability to achieve the desired reduction in the low density lipoprotein cholesterol (LDL) in some people and the disabling side effects from it in others, has led to a search for an alternative therapy. One of the groundbreaking inventions in this field has been the advent of the proprotein convertase subtilisin/ kexin type 9 inhibitors (PCSK9i). These agents have similar efficacy to high intensity statins and at the same time are tolerated well with a low incidence of side effects. Based on the results from multiple large scale clinical outcome trials, this class of LDL-C lowering agents has been recommended as appropriate second-line agents, or as an alternative therapy in cases of significant statin intolerance, for patients with established ASCVD and suboptimal LDL levels. As evidence supporting their efficacy and safety continues to mount, use of PCSK9i is likely to keep expanding in the current ASCVD population. In this chapter we discuss the advent of PCSK9i, their clinical utility, and their appropriate use keeping in view the high drug cost and other barriers in prescribing them.

**Keywords:** proprotein convertase subtilisin/kexin type 9 (PCSK9i), hyperlipidemia, ASCVD, LDL-C, statins, evolocumab, alirocumab

## **1. Introduction**

Hyperlipidemia is a well-known and established cardiovascular risk factor, with a global prevalence of approximately 39% per a World Health Organization report from 2011 [1]. Cholesterol lowering therapy, specifically low-density lipoprotein (LDL) lowering therapy, has been shown to significantly reduce the prevalence of atherosclerotic cardiovascular disease (ASCVD). The management of hyperlipidemia has evolved greatly over the last thirty years. Since the development of commercially available statins in the 1980's, this class of medication has become the hallmark for treatment of hyperlipidemia, with multiple adjunct therapies emerging over the past decade. And while statins are substantially efficacious in lowering LDL-C, a portion of patients are not able to achieve their goal LDL-C on statins alone. Another subset of patients develop statin induced side effects which either

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

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 and its appropriate use.
