Statins as Candidate Therapeutic Agents for Coronavirus Disease 2019 (COVID-19)
The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant global morbidity and mortality. As of July 2, 2020, the virus had caused over 500,000 deaths worldwide, with no specific antiviral therapies available. Statins, a class of drugs traditionally used to lower cholesterol, have emerged as potential candidate therapeutic agents for COVID-19 due to their pleiotropic effects, including immunomodulatory and anti-inflammatory properties. This article explores the clinical and preclinical evidence supporting the use of statins in the treatment of COVID-19, their mechanisms of action, and the potential risks associated with their use.
Clinical Evidence
Statins are 3-hydroxy-3-methyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, which reduce cholesterol biosynthesis by acting on the rate-limiting enzyme for the conversion of HMG-CoA to L-mevalonate. Beyond their cholesterol-lowering effects, statins have been shown to exhibit antiviral, anti-inflammatory, and immunomodulatory properties. These pleiotropic effects make statins a promising host-directed therapy (HDT) for COVID-19.
Clinical evidence suggests that statins can reduce viral infection and improve outcomes in patients with influenza, human immunodeficiency virus (HIV), and other viral infections. For example, statin use has been associated with a dose-dependent reduction in mortality from influenza. In patients with HIV, statins have been shown to reduce viral copies and lower markers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-alpha (TNF-α).
In the context of COVID-19, studies have shown that 60.7% of patients exhibit elevated CRP levels (≥10 mg/L), with this proportion rising to 81.5% in severe cases. RNAemia, immune dysregulation, and elevated serum cytokines, such as interleukin (IL)-6, IL-10, and TNF-α, have been observed in COVID-19 patients and are associated with disease severity. Additionally, coexisting cardiovascular diseases are more frequent in patients with severe COVID-19 and are linked to poor prognosis. Given their antiviral, anti-inflammatory, and immunomodulatory effects, statins may be beneficial in treating COVID-19 and reducing cardiovascular events in patients with underlying cardiovascular conditions. However, more clinical studies are needed to determine whether statin treatment should be initiated in patients without pre-existing cardiovascular diseases.
Despite their well-established safety profile, statins are not without risks. Potential side effects include rhabdomyolysis, statin-induced necrotizing autoimmune myopathy, new-onset diabetes mellitus, and hemorrhagic stroke, which appear to be dose-dependent. In COVID-19 patients, elevated serum creatine kinase levels (≥200 U/L) have been observed in 13.7% of cases, with rhabdomyolysis occurring in 0.2%. These findings suggest that statin use could increase the frequency of myopathy in COVID-19 patients. Additionally, statins have been shown to reduce the effectiveness of influenza vaccines, raising concerns about their potential impact on future COVID-19 vaccinations. Another concern is that statin-induced IL-18 production might exacerbate COVID-19 severity by contributing to cytokine storms, although this remains unconfirmed.
Preclinical Evidence
SARS-CoV-2 is a member of the betacoronavirus family, which includes severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Angiotensin-converting enzyme 2 (ACE2) has been identified as the receptor that SARS-CoV-2 uses for cell entry, similar to SARS-CoV, which uses spike glycoproteins (S protein) on the viral envelope for binding. Preclinical studies have shown that depleting cholesterol in ACE2-expressing cells reduces ACE-S protein binding by 50%, indicating that decreased cholesterol levels in host cells might inhibit SARS-CoV-2 replication. This is because lipid rafts and cholesterol are required for SARS-CoV entry into host cells. The inhibitory effects on coronavirus entry can be restored by the addition of exogenous cholesterol.
Statins inhibit HMG-CoA reductase, leading to reduced mevalonate synthesis and suppressed cholesterol production. Cholesterol is essential for viral replication, and statins have been shown to inhibit the replication of various viruses. For example, influenza virus causes infected cells to produce lipid droplets, which can be inhibited by atorvastatin, resulting in reduced viral replication. 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. During prenylation, isoprenoids are required for G protein subunits such as Ras, Rab, Rho, Rac, and Rap, which are involved in host cell proliferation and inflammatory factor production. Statins have been shown to directly inhibit HIV via Rho pathway downregulation.
RNAemia, defined as detectable serum SARS-CoV-2 viral loads, has been observed in COVID-19 patients and is associated with cytokine storms and poor prognosis. Statins may decrease the risk of RNAemia and reduce respiratory viral loads, potentially helping to suppress viral transmission.
Anti-Inflammatory Function
In COVID-19, 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 lead to severe complications. In vitro studies have reported imbalanced host responses to SARS-CoV-2, with inhibited innate antiviral defense coexisting with the excess release of inflammatory cytokines, particularly IL-6. Statins have been shown to reduce pro-inflammatory cytokines and chemokines by targeting multiple functions of virus-infected host cells. For example, Rho proteins can increase levels of pro-inflammatory cytokines such as TNF-α and IL-6 via nuclear factor-kB (NF-kB) signaling. Statins can reduce IL-6 synthesis by inhibiting NF-kB and Rho pathways.
To counteract virus-induced cytokine storms, immunosuppressive therapy has been proposed, with tocilizumab (an IL-6 receptor blocker) suggested for the treatment of severe COVID-19 cases. Despite their anti-inflammatory effects, statins have not been extensively investigated for their potential application in COVID-19 treatment.
Immunomodulatory Function
Statins have immunomodulatory effects, including the inhibition of major histocompatibility complex (MHC)-II-mediated T-cell activation, modulation of phagocyte and lymphocyte function, and influence on lymphocyte proliferation. In COVID-19 patients, an increased CD4+/CD8+ ratio is associated with poor prognosis. Simvastatin has been shown to decrease the CD4+/CD8+ ratio, suggesting a potential benefit in COVID-19. Additionally, 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. However, decreased T-cell numbers might reduce earlier viral clearance and could be associated with severe COVID-19 cases, potentially worsening the disease.
Elevated levels of ACE2 are associated with reduced disease severity in patients and animal models with acute respiratory distress syndrome (ARDS). Atorvastatin has been shown to upregulate ACE2 activity in rat models, suggesting a potential protective effect in COVID-19.
Conclusion
Statins exhibit antiviral, anti-inflammatory, and immunomodulatory effects, making them a promising candidate for the treatment of COVID-19. They may inhibit SARS-CoV-2 replication, suppress the release of inflammatory factors, and reduce local pulmonary immune responses, thereby attenuating cytokine storms and reducing lung tissue damage. However, the potential risks associated with statin use, including myopathy and reduced vaccine effectiveness, must be carefully considered. Further clinical studies are needed to determine the optimal use of statins in COVID-19 patients, including the type of statin, dose, treatment duration, and disease severity. Large-scale clinical trials are necessary to provide direct evidence regarding the efficacy and safety of statins in COVID-19 treatment.
doi.org/10.1097/CM9.0000000000001205
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