key: cord-0992229-p563jsrb authors: Barkas, Fotios; Milionis, Haralampos; Anastasiou, Georgia; Liberopoulos, Evangelos title: Statins and PCSK9 inhibitors: What is their role in coronavirus disease 2019? date: 2020-12-09 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110452 sha: c78a91911a20e50c62716d66ee3025427a85178f doc_id: 992229 cord_uid: p563jsrb Statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors interfere with several pathophysiological pathways of coronavirus disease 2019 (COVID-19). Statins may have a direct antiviral effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inhibiting its main protease. Statin-induced up-regulation of angiotensin-converting enzyme 2 (ACE2) may also be beneficial, whereas cholesterol reduction might significantly suppress SARS-CoV-2 by either blocking its host-cell entry through the disruption of lipid rafts or by inhibiting its replication. Available human studies have shown beneficial effects of statins and PCSK9 inhibitors on pneumonia and sepsis. These drugs may act as immunomodulators in COVID-19 and protect against major complications, such as acute respiratory distress syndrome and cytokine release syndrome. Considering their antioxidative, anti-arrhythmic, antithrombotic properties and their beneficial effect on endothelial dysfunction, along with the increased risk of mortality of patients at high cardiovascular risk infected by SARS-CoV-2, statins and PCSK9 inhibitors might prove effective against the cardiovascular and thromboembolic complications of COVID-19. On the whole, randomized clinical trials are needed to establish routine use of statins and PCSK9 inhibitors in the treatment of SARS-CoV-2 infection. In the meantime, it is recommended that lipid-lowering therapy should not be discontinued in COVID-19 patients unless otherwise indicated. At the end of 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of a cluster of pneumonia cases in Wuhan, in the Hubei Province of China and finally declared as pandemic in February 2020.(1) Until 30 May 2020, a total of 5,775,043 cases of coronavirus disease 2019 (COVID-19) and 361,220 deaths were confirmed worldwide.(1) SARS-Cov-2 is a beta-coronavirus in the same subgenus as the severe acute respiratory syndrome (SARS) virus, using an identical receptor, namely angiotensin-converting enzyme 2 (ACE2), for cell entry. (2) Although the majority of SARS-CoV-2 infections are mild to moderate, 14% of patients develop severe disease (dyspnea, hypoxia, or >50% lung involvement on imaging within 24 to 48 hours) and 5% critical disease (respiratory failure, shock, multi-organ dysfunction). Mortality rates range from 0.9 to 12% depending on the population under study.(1, 3) Cardiovascular disease, diabetes, hypertension, dyslipidemia, chronic lung and kidney disease, cancer, obesity and smoking have all been associated with severe disease and increased mortality. (4, 5) SARS-CoV-2 infection has been associated with downregulation of ACE2 receptors and a cytokine storm characterized by increased release of interleukin (IL)-6, IL-10, granulocytecolony stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, and tumor necrosis factor (TNF)-α. (6) The activation of these pathways lead to COVID-19 major complications related with high mortality rates, such as acute respiratory distress syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis, as well as cardiovascular complications, including myocarditis, heart failure, myocardial infarction and arrhythmias. (3, (6) (7) (8) Coagulopathy and thromboembolic events, such as stroke, 4 pulmonary embolism and deep vein thromboses, have also been described in patients with 10) Currently, there are no well-established effective therapies to treat SARS-CoV-2. (11) Only dexamethasone has been shown to significantly reduce 28-day mortality in patients with critical COVID-19. (12, 13) Remdesivir, a novel nucleotide analogue, has been proposed in hospitalized patients with severe COVID-19 requiring low-flow supplemental oxygen, given the potential reduction in time to clinical improvement. (12) (13) (14) (15) (16) However, the World Health Organization recommends against the use of remdesivir. (13) The rapidly expanding knowledge regarding its virology points to a number of potential drug targets. A plethora of randomized trials investigate possible therapeutic options against COVID-19. (11) In this context, drugs used in every day clinical practice are being considered. As a matter of fact, there is evidence that statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors could interfere with several pathophysiological pathways in COVID-19 ( Figure) . The aim of the present review was to describe these pathways and evaluate the potential role of these drugs in the management of patients infected with SARS-CoV-2. Statin therapy has been previously described to reduce Ebola infectivity through the inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form in statin-treated cells. (17) Similarly, it has been argued that statins could reduce SARS-CoV-2 infectivity by inhibiting its main protease, which plays an important role in the proteolytic maturation and thus in virus replication 5 ( Figure) .(18) A recent experimental study showed that statins, particularly pitavastatin, had a binding affinity to SARS-CoV-2 main protease which was more potent than that of protease or polymerase inhibitors. (18) Considering that statins and inhibitors of the renin-angiotensin-aldosterone system (RAAS) up-regulate ACE2 receptors, (19) (22) Therefore, fear that ACE2 overexpression could increase SARS-CoV-2 host-cell entry is not substantiated. On the contrary, ACE2 up-regulation may be beneficial rather than harmful in SARS-CoV-2 infected patients due to an increase in the catabolism of 'bad' angiotensin II and the production of 'good' angiotensin 1-7.(20) Even though we lack reports on the effects of PCSK9 inhibitors against SARS-CoV-2, previous evidence suggests that PCSK9 might interfere with the pathogenesis of viral infections, such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV). (23, 24) In-vitro and in-vivo studies have shown that PCSK9 or a more active membrane-bound form of the protein (PCSK9-ACE2) potentially reduce HCV infectivity through the downregulation of putative liver HCV receptors, namely CD81 and low-density lipoprotein receptors (LDL-R). (23) Another study revealed that HCV enhanced LDL-R expression and 6 decreased PCSK9 expression in order to facilitate viral propagation. (25) On the other hand, a human cohort showed that HCV and HIV co-infection was associated with both high PCSK9 levels and increased LDL-R. (26) Consequently, there were concerns as to whether PCSK9 inhibitors actually increase the risk of viral infections and especially hepatitis C. An experimental study showed that PCSK9 inhibition with alirocumab had no effect on CD81 and did not result in increased susceptibility to HCV entry. (27) Likewise, FOURIER and ODYSSEY OUTCOMES, the two major randomized clinical trials (RCTs) evaluating cardiovascular outcomes with the use of PCSK9 inhibitors over a period of 2 to 3 years, showed no differences regarding the rates of incident HCV between evolocumab or alirocumab and placebo (0.02% vs 0.00% and 0.01% vs 0.01%, respectively). (28, 29) Elevated liver enzymes are frequently noticed in COVID-19 patients. In addition to their immunomodulating properties, statins and PCSK9 inhibitors exert direct antioxidative and antithrombotic properties, since their use has been experimentally associated with improved endothelial function, reduced oxidative stress, less platelet adhesion and increased atherosclerotic plaque stability. (50, 66) Available evidence suggests that statins may protect against arrythmias and heart failure ( Figure) . (67, 68) Therefore, both drug classes could ameliorate the endothelial dysfunction, instability of the atherosclerotic plaque and myocardium inflammation or fibrosis induced by COVID-19 and protect against its cardiovascular complications. Finally, patients at high cardiovascular risk, such as elderly people with cardiovascular comorbidities or patients diagnosed with familial hypercholesterolemia are more likely to 13 develop severe COVID-19. (8, 69) Likewise, such patients are likely to be at increased long-term risk of an atherothrombotic event following COVID-19. (8, 69) In this context, lipid-lowering therapy in patients at high cardiovascular risk should not be discontinued during infection and, because of their possible increased ASCVD risk, could even be intensified following recovery from COVID-19. (70, 71) Of note, the potential advantages of intensifying lipid-lowering therapy for such patients after COVID-19 epidemic and the potential disadvantages of a lack of intensification, should be explored in future epidemiological investigations. COVID-19 has been associated with coagulation abnormalities and increased incidence of PCSK9 inhibitors have reportedly low rates of adverse effects and drug interactions, (86) and their use appears safe in the setting of COVID-19. 16 Available evidence seems to support the hypothesis that statins and PSCK9 inhibitors favorably interfere with several pathways in COVID-19. Considering the need for effective therapeutic strategies to address cases of COVID-19 ranging from mild to severe, further research may be warranted to evaluate potential benefits with these agents. Nonetheless, their well-established cardioprotective effects should prompt physicians to maintain lipidlowering therapy when treating patients infected by SARS-CoV-2. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 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