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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 2  |  Page : 55-59

Considerations for the use of statin therapy in Coronavirus Disease 2019 Era

Date of Submission05-Aug-2020
Date of Decision22-Aug-2020
Date of Acceptance27-Aug-2020
Date of Web Publication07-Oct-2020

Correspondence Address:
Dr. Kunal Mahajan
Department of Cardiology, Indira Gandhi Medical College, Shimla - 171 001, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2666-6979.297513

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  Abstract 


Background: Patients with cardiovascular disease (CVD) are at an increased risk of developing severe disease and mortality associated with coronavirus disease 2019 (COVID-19). Statins form the cornerstone of therapy for primary and secondary prevention of CVD. Objective: This review aims at exploring the possible advantages and the risks associated with the use of statins in patients with COVID-19. Methods: We searched the PubMed and Google Scholar databases until June 5, 2020, and reviewed the available literature on this topic. Results: Statins have been shown to improve outcomes in acute respiratory distress syndrome, which is one of the major causes of death in COVID-19. Statins exert many pleiotropic effects (anti-inflammatory, immunomodulatory effect, nitric oxide release, and effects on coagulation cascade), which would theoretically appear beneficial in COVID-19. Statins also increase angiotensin-converting enzyme 2 levels in animal models and can potentially reduce lung injury related to viral infections. Besides, the cardioprotective effects of statins can be beneficial in cardiovascular complications (e.g., acute myocardial infarction) of COVID-19. Nonetheless, there are concerns regarding the adverse effects associated with the use of statins in the setting of COVID-19, which can be simply avoided by dose modification and clinical monitoring. Conclusions: Statins appear to be beneficial in COVID-19 and may improve the outcome, but future-focused studies are needed before recommending their de novo use in COVID-19.

Keywords: Coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, statin therapy


How to cite this article:
Thakur P, Mahajan K, Negi PC, Ganju N, Asotra S, Kandoria A. Considerations for the use of statin therapy in Coronavirus Disease 2019 Era. Ann Clin Cardiol 2020;2:55-9

How to cite this URL:
Thakur P, Mahajan K, Negi PC, Ganju N, Asotra S, Kandoria A. Considerations for the use of statin therapy in Coronavirus Disease 2019 Era. Ann Clin Cardiol [serial online] 2020 [cited 2020 Dec 5];2:55-9. Available from: http://www.onlineacc.org/text.asp?2020/2/2/55/297513




  Introduction Top


Coronavirus disease 2019 (COVID-19) pandemic seems to be the biggest challenge of this century. It has already affected millions of people worldwide and has already claimed numerous lives.[1] COVID-19 is a pneumonia-like disease presenting primarily with symptoms including fever, shortness of breath, and dry cough. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the human body through varied mechanisms, leading to multisystem disease, which can be fatal in some.[1] Patients with diabetes mellitus (DM) and cardiovascular disease (CVD)[1] are at increased risk of developing severe disease and mortality. Several treatments have been proposed and are under investigation for COVID-19. The effect of statin therapy on the SARS-CoV-2 pathogenesis is quite intriguing. Although there are no clinical data proving the beneficial effects of statins in COVID-19 disease, statins exert many pleiotropic effects (e.g., anti-inflammation and immunomodulation), in addition to lower serum cholesterol levels. Thus, theoretically, statins may prove helpful in patients with COVID-19. India has about 3·8 million cases of ischemic heart disease (IHD) and approximately 65 million people affected by DM.[2],[3] Statins form the cornerstone of therapy for primary and secondary prevention in diabetes and IHD. Since the pandemic is expected to worsen in India in the coming months, it becomes prudent for us to explore the interactions between commonly used drugs and COVID-19 and its outcomes. There are conflicting opinions regarding the effects of statins in COVID-19 patients. This article reviews the potential benefits and concerns and presents recommendations about the use of statins in the COVID-19 setting.


  Methods Top


Electronic databases, namely PubMed and Google Scholar, were searched for manuscripts related to the possible benefits and harms associated with the use of statins in COVID-19. Search items were “statin,” “COVID-19,” and “coronavirus.” A total of 26 articles were found suitable and were analyzed in detail to prepare the present literature review.


  Results Top


Proposed beneficial effects of statins in coronavirus disease 2019 [Figure 1]
Figure 1: The various ways in which statins interact and exert a beneficial effect against the pathogenetic mechanisms involved in coronavirus disease 2019-associated tissue injury Abbreviations: ACE2=Angiotensin-converting enzyme 2; ARDS=Acute respiratory distress syndrome; TLR-MYD88=Toll-like receptor-myeloid differentiation primary response 88

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The benefit of statins in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is an immunopathological manifestation and one of the major causes of death following infection with SARS-CoV-2.[1],[4],[5] The key mechanism of ARDS following COVID-19 infection includes an uncontrolled and intense systemic inflammatory response and cytokine storm characterized by the release of pro-inflammatory cytokines (e.g., interleukins [ILs], interferons [IFNs], and tumor necrosis factor-alpha) and chemokines.[4],[5] The pathogenesis of ARDS involves excessive inflammation resulting in alveolar-capillary damage. Inflammatory damage leads to the exudation of protein-rich fluid, filling the alveoli and causing respiratory failure, which may progress to multiorgan failure, and ultimately death.[4],[5] Therapies suppressing inflammation appear to reduce this damage and can be beneficial. Statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown anti-inflammatory properties in the setting of atherosclerosis.[6],[7] There are also clinical data suggesting that statins exert pleiotropic effects on vascular endothelium, nitric oxide release, and the coagulation cascade, which are also implicated in the ARDS pathogenesis.[4],[5],[7],[8] All these pleiotropic effects, along with anti-inflammatory and immunomodulatory properties of statins, have prompted many researchers to assess the role of statins in lung injury. Fessler et al. showed that pretreatment with lovastatin in murine models of lung injury resulted in lesser lipopolysaccharide (LPS)-induced pulmonary inflammation.[9] In another study, healthy adults were pretreated with 4 days of either simvastatin or placebo, followed by inhalation of LPS. The individuals with simvastatin pretreatment showed significantly lower markers of systemic and pulmonary inflammation.[10] Nonetheless, a study of 404 patients with sepsis-associated ARDS showed improvement in the outcome using continuous statin therapy in patients having a history of prior statin therapy.[11] Therapy revealed 28-day survival improvements, specifically in severe ARDS cases, compared to that without statin therapy (88.5% and 62.5%, respectively; P = 0.0193).[11] Furthermore, a multicentric prospective study involving patients with severe sepsis suggested that the continuation of atorvastatin (in patients already on statin treatment) resulted in improved survival.[12] On the contrary, a systematic review and meta-analysis of 5 trials, including 3 randomized controlled trials (RCT), showed that in patients with acute lung injury (ALI)/ARDS, de novo use of statin therapy did not lead to a significant decrease in mortality, intensive care unit (ICU)-free days, ventilator-free days, and length of ICU stay.[13] HMG-CoA reductase inhibition in ALI to Reduce Pulmonary dysfunction trial (a multicenter RCT) also failed to show the benefit of de novo simvastatin therapy in patients with ARDS in terms of mortality and ventilator-free days.[14] Simvastatin therapy, however, was safe and did not cause significant adverse effects in ARDS patients.[14]

Thus, conflicting data exist regarding the beneficial effects of statin in patients with ARDS. The studies mentioned above-demonstrated statins to be useful in preventing the occurrence of ARDS, but their benefit on already established ALI needs further research. ARDS is one of the major causes of mortality in patients with COVID-19; therefore, during this pandemic, it would be prudent to continue using statin therapy in patients already receiving this drug and initiate it among those who have the indications for its use. Importantly, no clinical evidence in COVID-19 supports the de novo use of statin therapy because of beneficial potential in ARDS.

Effect of statins in coronavirus disease 2019 pathogenesis

Statins possess an immunomodulatory effect and can affect the immune response of the human body against various endogenous and exogenous pathogens. One of the mechanisms is via Toll-like receptors (TLRs), which seem to be important in the pathogenesis of SARS-CoV-2 and other coronaviruses.[15],[16],[17] TLRs are a family of transmembrane receptors. These are important for the identification of pathogens and innate immune response, especially to viruses. TLRs lead to the activation of the transcription factors nuclear factor-kappa B (NF-kB) and IFN regulatory transcription factors and help in regulation of innate immune responses.[16] TLRs works via myeloid differentiation primary response 88 (MYD88) dependent or MYD88-independent pathway. In the pathogenesis of infection with coronaviruses, TLR/MYD88 pathway plays a significant role.[17]

SARS-CoV infection was demonstrated to cause the MYD88 gene's excessive induction, which further activated NF-kB (downstream of the TLR-MYD88 pathway) and led to marked inflammation.[16] Excessive activation of the MYD88 gene facilitated the survival of the virus into the cells. Both excessive and deficient expressions of MYD88 have been demonstrated to be associated with high mortality in SARS-CoV and the Middle East respiratory system coronavirus infections.[16],[17] A balanced response of this pathway is essential for better outcomes in such respiratory viral infections. Statins are known to antagonize the TLR-MYD88 pathway.[17] Statins do not change the MYD88 levels under normal conditions but have been shown to maintain the normal levels of MYD88 during hypoxia or after hydrogen peroxide treatments.[17] On this basis, early and a high dose of a statin has been proposed to mitigate coronavirus infection potentially.[17] Since similar pathogenic mechanisms and results are expected with SARS-CoV-2 as well, statins may prove theoretically beneficial in mitigating the severity of organ damage associated with SARS-CoV-2 infection.

Effect of statins on angiotensin-converting enzyme 2 levels

In the classical pathway of the renin–angiotensin system, angiotensinogen is converted to angiotensin I by renin, a protease protein secreted solely by the juxtaglomerular cells in the kidneys. Angiotensin-converting enzyme (ACE) further converts angiotensin I to angiotensin II, and the latter then binds to its Ang-II type 1 (AT1) receptor to activate numerous cellular processes including aldosterone production, vasoconstriction, vascular inflammation, sympathetic activation, endothelial dysfunction, and increased oxidative stress.[1] These destructive cellular processes result in the development of ARDS. On the contrary, ACE2 is a cell membrane-associated enzyme present in lung endothelium, kidney, and heart, which counter-regulates the harmful effects of angiotensin II by degrading it to angiotensin (1–7).[1] Angiotensin (1–7) further interacts with the Mas receptor (MAS-R) and exerts its protective effects against the development of ARDS in vasodilation, tissue regeneration, and reduction in oxidative and inflammatory stress.[1],[18],[19] Thus, the “ACE2-angiotensin (1–7)-MAS axis” counteracts the effects of the ACE-Ang-II-AT1 axis. Therefore, any agent that augments the level/activity of ACE2 is likely to have protective effects by decreasing Ang-II and increasing angiotensin (1–7).[18],[19] Importantly, SARS-CoV-2 is believed to enter cells by attaching to ACE2.[12] However, no evidence exists suggesting the increased risk of infection with SARS-CoV-2 with the agents that increase ACE2 levels.[1],[18],[19] Furthermore, after entering the cells, the virus causes the downregulation of ACE2 levels resulting in excessive angiotensin II and leading to organ injury.[1] Thus agents that upregulate ACE2 are likely to benefit against this organ injury. In experimental animal models, statins have caused the upregulation of ACE2 levels by epigenetic modifications.[20],[21] Hence, statins by increasing ACE2 levels appear to be beneficial in COVID-19.

Cardioprotective actions of statins

Patients with CVD are at increased risk of SARS-CoV-2 infection, development of complications, and fatal disease outcomes.[1],[22] Besides, there is evidence of increased cardiovascular complications (e.g., increased risk of plaque rupture leading to acute myocardial infarction, exacerbation of heart failure, and increased risk of the thromboembolic phenomenon) associated with COVID-19.[1],[22] Statins form the cornerstone of therapy for primary and secondary prevention of CVDs.[23] However, it is not clear whether the prior use of statins mitigates the effects of cardiovascular complications in patients with COVID-19. However, their use should be continued in COVID-19-positive CVD patients already taking them. The hypothesized protective role of de novo use of statins against cardiovascular complications in COVID-19 patients is a matter of curiosity and needs further investigation.

Concerns regarding the use of statins in coronavirus disease 2019

Statin is a well-tested class of drugs, but statins are also associated with few adverse effects like all other medications. Some of these adverse effects may be increased or may overlap with the complications of COVID-19. Myotoxicity is a well-known side effect of statins, which may range from myalgia to myopathies, and rarely, rhabdomyolysis can be seen.[24] Rhabdomyolysis can lead to acute kidney injury. Importantly, increased creatine phosphokinase and acute kidney injury can be a feature of COVID-19 also.[25] Similarly, statin therapy and COVID-19 can both cause liver injury which makes it difficult to differentiate whether statin therapy or COVID-19 is the primary cause of deranged liver function tests.[25]

Statins are usually metabolized by P-glycoproteins and cytochrome P450-3A. Some antiviral drugs like protease inhibitors (ritonavir/lopinavir) are known to inhibit these enzymes, which may lead to decreased metabolism of statins. During co-administration of statins with these antiviral drugs, increased adverse effects of statins can occur, necessitating a reduction in the statin dose.[25]

Interestingly, some authors have hypothesized that statins may also increase the progression to ARDS by inflammasome-mediated increased levels of IL-18.[26],[27] The inflammasomes are intracellular macromolecule complexes, which appear to be crucial in lung injury by activating the pro-inflammatory cytokines that propagate the acute inflammatory process.[28] At least four inflammasome complexes (designated NLRP1, NLRP3, IPAF, and AIM2) have been recognized. Past studies in avian influenza have demonstrated that viral proteins lead to prolonged and excessive stimulation of these inflammasome complexes, which results in excessive IL-18 production, thereby inducing the IFN-γ-mediated cytokine storm. This cytokine storm is detrimental and has been shown to cause ALI and ARDS.[28],[29] COVID-19-associated lung injury also appears to involve a similar pathogenic mechanism.[1],[30] Furthermore, studies in patients with COVID-19 have been shown an association between the high serum levels of ILs and more severe ARDS and increased mortality.[30] In experimental studies, statins have been shown to enhance NLRP3-inflammasome activation by increasing the mitochondrial reactive oxygen species generation in macrophages.[27] Thus, it is hypothesized that through the activation of the inflammasome/IL-18 pathway, statins may lead to lung injury and ARDS progression. However, the hypothesis is based on anecdotes, and further research is needed for its validation.


  Conclusions Top


On the whole, statins appear to be beneficial in COVID-19 through various mechanisms and may improve the outcome, but further clinical evidence generated through focused research is needed. Meticulous and detailed reporting of statin use among COVID-19-affected patients is crucial to understand the multifaceted interaction between the virus, statin therapy, and clinical outcome. Nevertheless, based on current evidence, we recommend continuing the guideline-based use of statins for primary and secondary prevention of CVD irrespective of the COVID-19 status. Data regarding the de novo use of statins to treat COVID-19-associated ARDS are insufficient to make any recommendations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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