Secondary Logo

Journal Logo

Perspectives

Statins as candidate therapeutic agents for coronavirus disease 2019 (COVID-19)

Li, Sheng-De1; Zhang, Shu-Yang2; Peng, Bin1

Editor(s): Wei, Pei-Fang

Author Information
doi: 10.1097/CM9.0000000000001205
  • Open

Statins are 3-hydroxy-3-methyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, acting on the rate-limiting enzyme for the conversion of HMG-CoA to L-mevalonate to reduce cholesterol biosynthesis. Apart from reducing cardiovascular events by lowering low-density lipoprotein cholesterol concentrations, pleiotropic cholesterol-independent functions of statins, including immunomodulatory and anti-inflammatory effects, are increasingly recognized. The current coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),[1] has caused >500,000 deaths worldwide as of July 2, and it continues to spread without specific antiviral therapies. Statins, with potential antiviral functions as a host-directed therapy (HDT), could be a safe means of improving outcomes for patients with COVID-19.[2,3]

Clinical Evidence

Statin use reduces viral infection and improves clinical outcomes in patients with influenza,[4] human immunodeficiency virus (HIV), and other viruses.[3] It markedly and dose-dependently reduces mortality from influenza.[4] Studies on patients with HIV found that statins reduce viral copies and lower markers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α).[5]

Among all COVID-19 patients, 60.7% show CRP ≥10 mg/L, rising to 81.5% in those with severe disease.[6] RNAemia, immune dysregulation, and elevated serum cytokines, such as interleukin (IL)-6, IL-10, and TNF-α, have been observed and might indicate disease severity.[7] Another finding was that coexisting cardiovascular diseases are more frequent in patients with severe disease and are associated with poor prognosis for COVID-19.[6] Since statins show antiviral, anti-inflammatory, and immunomodulatory effects, they might be effective for COVID-19 treatment and reducing cardiovascular events in those with underlying cardiovascular diseases.[3] However, more clinical studies are needed to decide whether statin treatment should be started for patients without underlying cardiovascular diseases.

Although statins have a well-established, safe therapeutic profile, their use is not risk-free. Side effects include rhabdomyolysis, statin-induced necrotizing autoimmune myopathy, new onset diabetes mellitus, and potential hemorrhagic stroke, which appear to be dose-dependent for common types of statins.[8] Meanwhile, patients with COVID-19 might show serum creatine kinase ≥ 200 U/L (13.7% of patients) and rhabdomyolysis (0.2%),[6] suggesting that statin use could increase myopathy frequency. In addition, studies on influenza have found that statin use reduces the effectiveness of vaccines against medically attended acute respiratory illness.[9] As such, the potential side effects of statins during future COVID-19 vaccination should be considered. Another concern is that statin-induced IL-18 production might increase COVID-19 severity via cytokine storms,[10,11] but this is unconfirmed.

Pre-clinical evidence

Antiviral function

SARS-CoV-2 is a member of the betacoronavirus (β-CoVs), similar to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).[1] Ongoing virological studies on SARS-CoV-2 have shown that angiotensin converting enzyme 2 (ACE2) is a receptor bound by SARS-CoV-2 for cell entry,[12] similar to that with SARS-CoV, which uses spike glycoproteins (S protein) on the viral envelope for binding. Depleting cholesterol in ACE2-expressing cells decreases ACE-S protein binding by 50%,[13] indicating that decreased cholesterol levels in host cells might inhibit SARS-CoV-2 replication, as lipid rafts and cholesterol are required for SARS-CoV entry into host cells. Such inhibitory effects on CoV entry could be restored by the addition of exogenous cholesterol. In addition, statins inhibit HMG-CoA reductase, resulting in reduced mevalonate synthesis and suppressed cholesterol production,[3] and cholesterol is required by viruses for replication.[2] For example, influenza virus causes infected cells to produce lipid droplets, potentially as materials for their lipid components, but this can be effectively inhibited by atorvastatin, resulting in reduced viral replication.[14] Third, statins also inhibit the downstream production of lipid isoprenoid intermediates such as farnesyl pyrophosphate and geranyl-geranyl pyrophosphate, which are crucial for host-cell protein prenylation functions.[3,15] During prenylation, isoprenoids are required for G protein subunits such as Ras, Rab, Rho, Rac, and Rap, as their activation induces host cell proliferation or inflammatory factor production.[3] For example, statins directly inhibit HIV via Rho pathway downregulation.[16] Defined as detectable serum SARS-CoV-2 viral loads, RNAemia was observed in patients with COVID-19 and can trigger cytokine storms, which was associated with increased IL-6 levels and poor prognosis.[7] Statins might decrease the risk of RNAemia and reduce respiratory viral loads, which might help suppress transmission.[17]

Anti-inflammatory function

In clinical practice, the uncontrolled hyperproduction of cytokines and chemokines such as IL-6, IL-8, TNF-α, interferon (IFN), C-C motif chemokine 8, and C-X-C motif chemokine ligand 10 (CXCL10) can have disastrous consequences. In an in vitro study, imbalanced host responses to SARS-CoV-2 have been reported, as inhibited innate antiviral defense coexists with the excess release of inflammatory cytokines, especially IL-6, which is in line with highly elevated IL-6 in COVID-19 patients.[7,18] Statins can markedly reduce pro-inflammatory cytokines and chemokines by targeting multiple functions of virus-infected host cells.[19] For example, Rho proteins can increase levels of pro-inflammatory cytokines such as TNF-α and IL-6 via nuclear factor-κB (NF-κB) signaling.[3,19] Statins can reduce IL-6 synthesis by inhibiting NF-κB and Rho pathways.[20] To inhibit virus-induced cytokine storms, immunosuppressive therapy has been proposed, with tocilizumab (blocking IL-6 receptors) suggested to treat severe cases. Despite their anti-inflammatory effects, statins have not been investigated for applications to COVID-19.

Immunomodulatory function

Statins could inhibit major histocompatibility complex (MHC)-II-mediated T-cell activation, affect the ability of phagocytes and lymphocytes, and influence lymphocyte proliferation. Since an increase in this ratio indicates poor prognosis for patients with COVID-19, statins might be helpful as simvastatin decreased CD4+/CD8+ ratio.[21] In addition, lovastatin can attenuate ambient particulate matter-induced recruitment and activation of alveolar polymorphonuclear leukocytes and macrophages, reduce local inflammatory responses, and facilitate foreign particle clearance from lung tissues.[22] However, decreased T-cell numbers might reduce earlier viral clearance and could be associated with severe cases, thus possibly worsening COVID-19 disease.[23] Third, elevated levels of ACE2 are associated with reduced disease severity in patients and animal models with ARDS,[24,25] whereas atorvastatin could upregulate ACE2 activity in rat models.

Although the effects of statins, as an HDT, are antiviral, anti-inflammatory, and immunomodulatory, which will help clinicians design serum or viral biomarkers for statin therapy in COVID-19 patients, these effects are always seen together. We noticed that although high-dose statins might be more effective against viral infections,[4,26] the effects might vary depending on the type of statin, dose, treatment duration, and disease severity; this will need to be carefully assessed to avoid exacerbating COVID-19 or producing deleterious side effects. Unfortunately, no large-scale clinical trial has provided direct evidence regarding the use of statins for COVID-19 patients, indicating the necessities of further in-depth analysis on COVID-19, including pre-clinical and clinical studies.

In summary, statins might be useful in inhibiting SARS-CoV-2 replication, suppressing the release of inflammatory factors, and reducing local pulmonary immune responses, thus attenuating cytokine storms and reducing damage to lung tissue, but this warrants further clinical studies.

Conflicts of interest

None.

References

1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382:727–733. doi: 10.1056/NEJMoa2001017.
2. Kaufmann S, Dorhoi A, Hotchkiss RS, Bartenschlager R. Host-directed therapies for bacterial and viral infections. Nat Rev Drug Discov 2018; 17:35–56. doi: 10.1038/nrd.2017.162.
3. Parihar SP, Guler R, Brombacher F. Statins: a viable candidate for host-directed therapy against infectious diseases. Nat Rev Immunol 2019; 19:104–117. doi: 10.1038/s41577-018-0094-3.
4. Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest 2007; 131:1006–1012. doi: 10.1378/chest.06-1997.
5. Calza L, Trapani F, Bartoletti M, Manfredi R, Colangeli V, Borderi M, et al. Statin therapy decreases serum levels of high-sensitivity C-reactive protein and tumor necrosis factor-α in HIV-infected patients treated with ritonavir-boosted protease inhibitors. HIV Clin Trials 2012; 13:153–161. doi: 10.1310/hct1303-153.
6. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382:1708–1720. doi: 10.1056/NEJMoa2002032.
7. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506. doi: 10.1016/s0140-6736(20)30183-5.
8. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388:2532–2561. doi: 10.1016/S0140-6736(16)31357-5.
9. Chiu HT, Shen LJ, Chen YC, Lin JH, Wang CC. Effect of statin use on the risk of medically attended acute respiratory illness among influenza vaccinated elderly. Vaccine 2018; 36:6133–6137. doi: 10.1016/j.vaccine.2018.08.067.
10. Takahashi HK, Mori S, Iwagaki H, Yoshino T, Tanaka N, Nishibori M. Simvastatin induces interleukin-18 production in human peripheral blood mononuclear cells. Clin Immunol 2005; 116:211–216. doi: 10.1016/j.clim.2005.04.007.
11. Wawrocki S, Druszczynska M, Kowalewicz-Kulbat M, Rudnicka W. Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol 2016; 63:59–63. doi: 10.18388/abp.2015_1153.
12. Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11:1620doi: 10.1038/s41467-020-15562-9.
13. Glende J, Schwegmann-Wessels C, Al-Falah M, Pfefferle S, Qu X, Deng H, et al. Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2. Virology 2008; 381:215–221. doi: 10.1016/j.virol.2008.08.026.
14. Episcopio D, Aminov S, Benjamin S, Germain G, Datan E, Landazuri J, et al. Atorvastatin restricts the ability of influenza virus to generate lipid droplets and severely suppresses the replication of the virus. FASEB J 2019; 33:9516–9525. doi: 10.1096/fj.201900428RR.
15. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006; 6:358–370. doi: 10.1038/nri1839.
16. del Real G, Jiménez-Baranda S, Mira E, Lacalle RA, Lucas P, Gómez-Moutón C, et al. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 2004; 200:541–547. doi: 10.1084/jem.20040061.
17. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020; 382:1177–1179. doi: 10.1056/NEJMc2001737.
18. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181:1036–1045. e9. doi: 10.1016/j.cell.2020.04.026.
19. Mehrbod P, Omar AR, Hair-Bejo M, Haghani A, Ideris A. Mechanisms of action and efficacy of statins against influenza. Biomed Res Int 2014; 2014:872370doi: 10.1155/2014/872370.
20. Wang J, Kitajima I. Pitavastatin inactivates NF-kappaB and decreases IL-6 production through Rho kinase pathway in MCF-7 cells. Oncol Rep 2007; 17:1149–1154.
21. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis 2020; 221:1762–1769. doi: 10.1093/infdis/jiaa150.
22. Miyata R, Bai N, Vincent R, Sin DD, Van Eeden SF. Statins reduce ambient particulate matter-induced lung inflammation by promoting the clearance of particulate matter < 10 μm from lung tissues. Chest 2013; 143:452–460. doi: 10.1378/chest.12-1237.
23. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020; 71:762–768. doi: 10.1093/cid/ciaa248.
24. Wösten-van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol 2011; 225:618–627. doi: 10.1002/path.2987.
25. Wösten-van Asperen RM, Bos AP, Bem RA, Dierdorp BS, Dekker T, van Goor H, et al. Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome. Pediatr Crit Care Med 2013; 14:e438–441. doi: 10.1097/PCC.0b013e3182a55735.
26. Chansrichavala P, Chantharaksri U, Sritara P, Chaiyaroj SC. Atorvastatin attenuates TLR4-mediated NF-kappaB activation in a MyD88-dependent pathway. Asian Pac J Allergy Immunol 2009; 27:49–57.
Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.