GAUSS-2, RUTHERFORD-2, LAPLACE-2, DESCARTES, and TESLA Part B: PCSK9 inhibitors gain momentum

INTRODUCTION Lowering of low density lipoprotein (LDL) cholesterol (LDL-C) has been shown to be associated with significant reduction of adverse cardiovascular (CV) events. The 2013 ACC/AHA guidelines recommend high-intensity statin therapy to lower LDL-C levels by$ 50% with no specific target goal for adults at high risk for atherosclerotic CV diseases, andmoderate-intensity statin therapy to lower LDL-C levels by 30% -,50% if a high-intensity statin is not tolerated. Furthermore, European and Canadian guidelines recommend LDL-C goal of less than 70 mg/dL (1.8 mmol/L) in patients at very high CV risk. Despite intensive statin therapy, many patients are unable to achieve the recommended target levels of LDL-C. In addition, statin-related adverse events have been reported in up to 10% to 20% of patients, and stains may be not tolerated by certain subgroups of patients. This highlights the need for additional LDL-C lowering drugs. Unfortunately and up till recently, currently available non-statin LDL-C lowering therapies are either weak (ezetimibe) or poorly tolerated (niacin, and bile acid sequestrants). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel serine protease protein (Fig. 1) produced predominantly in the liver, and plays a central role in regulating LDL-C concentrations. PCSK9 binds to hepatic LDL receptors, promotes their degradation, and reduces the ability of the liver to clear LDL-C from the blood (Fig. 2). Statin use also upregulates PCSK9 levels, therefore PCSK9 inhibiton may additionally or synergistically lower LDL-C with statins. Evolocumab (AMG145) – manufactured by Amgen is a fully human monoclonal antibody that binds to PCSK9 and inhibits its interaction with LDL receptors (Fig. 2). Evolocumab has taken the lead in the race with other PCSK9 inhibitors to be the first in a new class of LDL-C lowering drugs close to the market (Table 1). Many phase II trials have evaluated the efficacy of evolocumab -including the longer term (52 weeks) OSLER studyand yielded robust reduction of circulating LDL-C concentration. Data from several phase III studies have been recently released as a part of the PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulation) comprehensive program (Table 2). These trials serve to clarify the efficacy of evolocumab in different groups of patients, and are critically reviewed here with particular reference to their clinical utility, and their place in future clinical practice.