ABC | Volume 112, Nº4, April 2019

Review Article PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice Filipe Ferrari, 1, 2 R icardo Stein, 1,2,3,4, 6 Marcelo Trotte Motta, 5 E milio Hideyuki Moriguchi 1,6, 7 Programa de Pós-Graduação em Cardiologia e Ciências Cardiovasculares - Hospital de Clínicas de Porto Alegre (HCPA) - Universidade Federal do Rio Grande do Sul (UFRGS), 1 Porto Alegre, RS – Brazil Grupo de Pesquisa em Cardiologia do Exercício (CardioEx) - Hospital de Clínicas de Porto Alegre (HCPA) - Universidade Federal do Rio Grande do Sul (UFRGS), 2 Porto Alegre, RS – Brazil Faculdade de Medicina - Hospital de Clínicas de Porto Alegre - Universidade Federal do Rio Grande do Sul (UFRGS), 3 Porto Alegre, RS – Brazil Vitta Centro de Bem-Estar Físico, 4 Porto Alegre, RS – Brazil Universidade Estadual de Feira de Santana, 5 Feira de Santana, BA – Brazil Divisão de Medicina Interna - Hospital de Clínicas de Porto Alegre, 6 Porto Alegre, RS – Brazil Departamento de Medicina Interna - Escola de Medicina - Universidade Federal do Rio Grande do Sul (UFRGS), 7 Porto Alegre, RS – Brazil Keywords Cardiovascular Diseases/physiopathology; Coronary Artery Disease/mortality; Proprotein Convertase 9; Cholesterol, LDL; Lipoproteins; Anticholesteromic Agents. Mailing Address: Emilio Hideyuki Moriguchi • Universidade Federal do Rio Grande do Sul - Av. Paulo Gama, 110. Postal Code 90040-060, Farroupilha, Porto Alegre, RS – Brazil E-mail: emoriguchi@hcpa.edu.br Manuscript received September 23, 2018, revised manuscript October 28, 2018, accepted November 01, 2018 DOI: 10.5935/abc.20190029 Abstract Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed. Introduction Worldwide, cardiovascular diseases account for almost half of all deaths in people under 70. In Brazil, they were responsible for almost 30% of deaths in 2013. 1 In recent decades, mounting evidence has shown a close link between low-density lipoprotein (LDL) levels and incidence of coronary artery disease (CAD). 2,3 Inadequate hepatic uptake of LDL results in increased levels of circulating LDL, and consequent incidence of premature CAD. 4 The treatment of dyslipidemias involves a number of factors, and lifestyle changes should be part of all medical prescriptions for this purpose. Non-pharmacological interventions, such as starting a regular exercise program, not smoking or quitting smoking, and adopting a healthy diet can have a significant impact on lipid profile. However, a substantial number of patients need to add hypolipidemic drugs (e.g., statins, ezetimibe, fibrates) to the aforementioned measures to achieve recommended LDL goals. 5 Substantial advances in lipid-lowering drugs have been achieved in recent years. 6 When used appropriately, these agents play a preponderant role in preventing adverse cardiovascular (CV) outcomes. 7 Hypolipidemic therapy with statins has been shown to have an impact both for primary prevention of atherosclerosis in patients at high CV risk 8 and for secondary prevention. However, some patients do not reach desired LDL levels even at maximal doses of statins (whether as monotherapy or up to triple therapy) or even when ezetimibe is added to statin therapy; this results in an important residual risk of CV events. 9,10 Thus, the search for therapeutic alternatives that can reduce LDL more aggressively, aiming to achieve better outcomes, continues. Among recent developments, perhaps the most outstanding class of novel lipid-lowering agents are the proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). 11 PCSK9 is a protein that ultimately promotes the degradation of hepatic LDL receptors, leading to hypercholesterolemia. 6,7 The PCSK9i are monoclonal antibodies that increase the availability of LDL receptors. When PCSK9 is inhibited, there is greater uptake of LDL by their respective receptors present in hepatocytes, with reduction of serum and plasma levels of LDL (Figure 1). 12,13 An important point about the causal relationship between LDL levels and CV outcomes is the dose-response behavior observed. To the extent that high LDL levels increase CV risk, when LDL levels are reduced, so is the rate of adverse CV outcomes. For example, the JUPITER study demonstrated that use of a statin (rosuvastatin) for 2 years was able to protect patients substantially, especially in those with LDL levels were below 45 mg/dL. 14 453