Statins in COVID-19: a new ray of hope

Abstract

To, The Editor Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread around the world like a wildfire in the past six months. With a high infectivity rate, the disease has already accounted for nearly ten million cases worldwide with deaths accounting to more than a half a million 1 . A lack of specific drug therapy has prompted a global race to develop or search for newer therapies as well as repurposing the older drugs such as hydroxychloroquine and azithromycin. As better insight has been gained on the disease pathophysiology, focus has now shifted to the use of anti-virals (Remdesivir), anti-inflammatory and immunosuppressive agents such as tocilizumab. Repurposing of old drugs developed for other diseases has an advantage that a detailed information exists regarding the pharmacological and safety profile in humans thus being cost-effective and a time saving strategy 2 . One such class of repurposed drugs which can be of benefit in COVID-19 infection are the statins. Inflammatory cascade in COVID-19 SARS-CoV-2 binds to the angiotensin-converting enzyme-2 (ACE-2) receptors which are present in the type II pneumocytes in lungs, heart and vascular endothelium. Following this, there occurs a down-regulation of ACE-2 receptors, cellular viral replication followed by exocytosis and release of mature virions 3 . SARS-CoV-2 leads to a multisystem inflammatory state due to cytokine storm via activation of Toll-like receptor (TLR) 3, TLR7, TLR8 and TLR9. There occurs a triggering of downstream inflammatory cascade through the TLR-MYD88-NF-κB pathway leading to an increased production of various pro-inflammatory molecules such as interleukin-1 (IL-1), IL-2, IL-4, IL-6 of which IL-6 is a major cytokine 3 . This causes an increase in vascular permeability, damage to the alveolar epithelial cells and ultimately culminating in acute respiratory distress syndrome. In addition, COVID-19 infection is also associated with coagulopathy and thromboembolic complications including life-threatening pulmonary embolism 3 . Statins - the old workhorse Statins, first discovered in 1976, are potent inhibitors of cholesterol synthesis and have been the mainstay of lipid lowering therapies in patients with cardiovascular diseases 4 . However, statins also have pleotropic effects which accounts for its anti-inflammatory, anti-oxidative, immunomodulatory and anti-thrombotic properties 4 . Statins inhibits the synthesis of isoprenoids, a vital component in prenylation of signaling molecules such as Rho, Ras which regulate various pro-inflammatory pathways. Statins by binding to a novel allosteric site in the β2-integrin selectively inhibits the leucocyte function antigen-1 which plays a vital role in leucocyte adhesion and T-cell activation. In addition, by reducing the expression of MHC-class II receptors on endothelial cells and macrophages, statins lead to a reduction of T-cell activation. Studies have shown that statins also reduce the expression of various pro-inflammatory cytokines such as IL-6, IL-8 and MCP-1 in inflammatory cells. Statins also play an important role in regulating the inflammatory cytokine mediated host cell damage by downregulating the expression of MYD88-NF-κB pathway 4 . Apart from its anti-inflammatory properties, statins also affect the vascular endothelial function by increasing production of nitric oxide which is a potent vasodilator and inhibits platelet aggregation thus accounting for its anti-thrombotic properties 5 . In addition, animal models have suggested that statins reduce the expression of plasminogen activator inhibitor-1 and tissue factor thus having a profibrinolytic and anticoagulant activity too 5 (Figure 1 ). Figure. 1 Pictographic representation showing the potential role of statins in COVID-19 infection. SARS-CoV-2 activates the immune response through interaction with various inflammatory cells followed by release of inflammatory cytokines and host cell damage through the MYD88-NF-κB pathway culminating in ARDS, myocarditis and shock. In addition, SARS-CoV-2 also leads to a pro-coagulant state through activation of tissue-factor pathway and by virtue of a pro-inflammatory state. Statins have a pleotropic response and has anti-inflammatory action through (i) reduced MHC-class II expression on APCs hence decreased T-cell stimulation, (ii) reduced T-cell activation and (iii) downregulation of MYD88-NF-κB pathway. In addition, statins also exert an anti-coagulant and vasodilatory effects thus mitigating the adverse effects of “cytokine storm” in COVID-19. APCs: Antigen presenting cells; ARDS: Acute respiratory distress syndrome; MHC: major histocompatibility complex. Created with BioRender.com. Figure 1 Statins and its role in viral infections Previous studies have suggested that statin use was associated with improved clinical outcomes in patients with viral or bacterial pneumonia along with a decrease in the systemic inflammatory response. However, most of these studies had included patients with influenza virus or were observational in nature and hence prone to bias 6 . Evidence of statin use in COVID-19 Preliminary studies from China had shown that patients with COVID-19 infection had lower cholesterol levels as compared to healthy controls leading to speculations that statins should be stopped in life-threatening COVID-19 infection 7 . However, recent evidence has been contrary to the previous reports suggesting a beneficial effect of statins in COVID-19 infection. Zhang et al. 8 evaluated the role of statins in a large retrospective series involving 13981 COVID-19 patients of whom 1219 had an in-hospital use of statins (statin group). There was a significantly lower crude 28-day mortality in the statin group (mortality rate: 5.5%) as compared to the non-statin group (mortality rate: 6.8%; P = 0.046). In addition, the mixed-effect Cox model after propensity score-matching (for baseline differences between groups) found that the risk for 28-day all-cause mortality was 5.2% in statin group as compared to 9.4% in non-statin groups with an adjusted hazard ratio of 0.58. In addition, the authors also reported that among statin users CRP and IL-6 levels were lower both at admission and prior to discharge with no significant increase during the period of hospitalization. However, a major limitation was the retrospective nature of this study making it difficult to propose a causality assessment between statin use and mortality. Secondly, despite using propensity matching to match the two groups, multiple unknown confounders may affect the final results. Another retrospective multicenter study to determine the association between ACEi/ARB and/or statin use with outcomes in COVID-19 patients showed a significant association between statin use and absence of symptoms (OR 2.91; CI 1.27-6.71) 9 . However, both the studies were retrospective in nature hence, a need for RCTs regarding the role of statins in COVID-19 patients. The role of statins in reducing thromboembolic complications has been highlighted in a recent study which reported a lower incidence of pulmonary embolism among COVID-19 patients on statin therapy prior to admission 10 . In addition, another beneficial effect of statins in COVID-19 infection could be its cardioprotective action. Since patients with COVID-19 has been predisposed to myocardial injury which portrays a bad prognostic, use of statins could be protective in these patients 3 . Issues with use of statins in COVID-19 (i) Side effects of statins: One of the major side-effects of statin use is drug-induced myotoxicity which ranges from mild symptoms of myalgias to myopathies and rhabdomyolysis leading to acute kidney injury. In addition, statins are also known to cause hepatotoxicity and increase in liver enzymes. Critically ill patients with advanced liver and renal involvement are often predisposed to these side-effects of statins. Initiating statins in critically ill COVID-19 patients can lead to an increased risk of myopathy as well as associated renal damage hence, a poor prognosis 4 . (ii) Drug interactions with statins: Another issue with the use of statins lie in the fact that these drugs are metabolized by cytochrome P450 (CYP) enzyme system. A lot of drugs used for COVID-19 treatment including anti-virals are either CYP enzyme inducers or inhibitors hence affecting therapeutic levels of statins. Drugs such as protease inhibitors (lopinavir/ritonavir) are potent inhibitors of the CYP enzymes which increases the serum levels of statins leading to a greater risk of adverse effects 4 . Statins are a low-cost therapy with an excellent safety profile even in elderly patients and hence can be a potent adjuvant therapy in COVID-19 infection owing to this immuno-modulatory, anti-inflammatory and anti-coagulant effects. In addition, a favourable evidence garnered till date allows for continuation of statins in COVID-19 patients who have been on it prior to infection. Phase III clinical trials are the need of the hour to test this potentially exciting adjuvant therapy in COVID-19 patients. Author contributions SK and KG contributed to the conception or design of the work. SK, KG, SG contributed to the literature review. SK and KG drafted the manuscript. SG critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. Declaration of Competing Interest Authors have no conflict of interest to disclose