ABC | Volume 112, Nº4, April 2019

Review Article Ferrari et al PCSK9 Inhibitors in Clinical Practice Arq Bras Cardiol. 2019; 112(4):453-460 plasma levels of PCSK9, 30,31 with the latter potentially raising levels by up to 25%. 31 This fact should be taken into account. Statins themselves may also increase the incidence of DM2. A meta-analysis including more than 91,000 patients followed up for 4 years found a 9% increase in the risk of DM2 with the use of statins. 32 In fact, data show that the gain in function in the LDL receptor gene is capable of impairing the insulin-secreting capacity of the pancreatic beta-cells. 33 Thus, it is only natural that upregulation of LDL receptors with the use of PCSK9i might induce a decline in insulin release, thus facilitating development of new-onset DM2. Following this reasoning, a meta-analysis that evaluated short-term therapy with PCSK9i (1.5 years) found a small, but significant increase in plasma glucose and glycated hemoglobin levels. Moreover, this increase was proportional to the reduction in LDL, but was not enough to cause an impact on the emergence of new cases of DM2. 34 The safety of PCSK9i therapy has also been assessed. In a pre-specified meta-analysis of the FOURIER trial, the efficacy and safety of evolocumab was investigated in patients with and without DM2, in addition to the effect of evolocumab on blood glucose and on the risk of developing DM2. 35 Of those individuals already living with DM2, 8,000 had available data and 25% were on insulin. Among patients without the disease, 38% had prediabetes and 22% were normoglycemic. Both groups were homogeneous in terms of statin therapy, with 70% on maximal doses. 35 Evolocumab therapy significantly reduced CV risk in both groups, and did not increase the risk of recent-onset DM2; there was no worsening in blood glucose levels. These data suggest that evolocumab therapy is safe and effective in patients with atherosclerotic disease. Furthermore, the number needed to prevent a primary CV event over a 3-year period among DM2 patients was only 37. Therefore, the use of PCSK9i in patients with atherosclerotic CV disease and DM2 can be particularly attractive from the point of view of cost-benefit. 35 Possible anti-inflammatory mechanisms and pleiotropic effects The potential for anti-inflammatory action by PCSK9i is unclear. Unlike therapy with statins, there is no evidence of a potential role of PCSK9i in reducing C-reactive protein (CRP) levels, especially when measured by high-sensitivity methods (hsCRP). Two recent meta-analyses that evaluated approximately 7,000 patients 36,37 did not confirm this hypothesis. Although the relationship between PCSK9 and carotid intima-media thickness in healthy patients is controversial, it may play a direct role in the inflammatory process, contributing to atherosclerotic disease through LDL-independent mechanisms. 38 Whether these monoclonal antibodies interact with other pathways to induce an anti-inflammatory response is still unclear, and warrants further investigation. The relationship between serum levels of PCSK9 and atherosclerotic plaque characteristics has also been studied. Virtual - histology intravascular ultrasound  (VH- IVUS ) was used to analyze 581 patients with CAD, 39 and higher levels of PCSK9 were found to be associated with a greater fraction and amount of central necrotic tissue in coronary atherosclerosis, independent of LDL levels and statin therapy. 39 Therefore, PCSK9 seems to play a role that goes far beyond regulation of LDL. In another sub-analysis of the FOURIER trial, 40 evolocumab acted effectively against initial inflammatory risk in 27,564 patients at high CV risk. It bears stressing that the relative benefit of therapy with this drug for the prevention of CV events was independent of baseline CRP levels. Although those patients with higher hsCRP levels exhibited greater susceptibility to CV events, they were also those who tended to derive the greatest absolute benefit from evolocumab therapy. 40 Evidence suggests that vascular smooth muscle cells produce higher amounts of PCSK9 compared to endothelial cells, especially in an inflammatory microenvironment. In those regions where there is lower shear stress (i.e., force of blood friction against the arterial intima), PCSK9 expression is increased in smooth-muscle cells. Moreover, oxidized LDL appears to be implicated in the regulation of PCSK9 expression by modulating the secretion of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF- α ). 41 Corroborating these findings, Ricci et al. 42 tested the hypothesis of a relationship between PCSK9 and pro-inflammatory effects in macrophages. The authors initially performed a series of experiments with macrophages derived from the human monocytes cell line THP-1, incubated with increasing concentrations of recombinant human PCSK9. A positive correlation was observed between levels of PCSK9 and inflammatory response in macrophages, inducing expression of TNF- α , IL-1, IL-6, as well as chemokines such as monocyte chemoattractant protein - 1  (MCP-1). In addition, an inflammatory response was observed when THP-1 macrophages were co-cultured with HepG2 cells overexpressing PCSK9. 42 This provides additional evidence of a pro-inflammatory effect of PCSK9. Recently, Bernelot Moens et al. 43 evaluated the responses to PCSK9i in monocytes (key mediators of the inflammatory process) of patients with FH who were not on statins due to muscle pain. Several pro-inflammatory andmigratory alterations were observed in these monocytes. After 6 months of treatment with PCSK9i, the migratory capacity of monocytes, their lipid content, and their inflammatory responsiveness decreased to levels observed in FH patients on stable statin therapy. The reduction in lipid content with the use of PCSK9i attenuated the pro-inflammatory phenotype of monocytes. 43 These findings are important, because they emphasize that other mediators beyond CRP are involved in inflammation. Finally, it should be emphasized that the PCSK9i agents have pleiotropic effects, and that their use may have other therapeutic actions, in addition to their already-established hypolipidemic activity. Safety In 2012, the U.S. Food and Drug Administration (FDA) issued an alert on the potential adverse effects of statin treatment. 44 Two years later, the FDA asked PCSK9i developers to assess possible adverse events of these drugs in different studies, with special attention to the emergence of new cases of cognitive deficit. 45 This recommendation was based on 456