Cholesterol-lowering statins show promise for the treatment of severe COVID-19 infections

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The use of cholesterol-lowering drugs called statins is associated with a lower death rate and a lower incidence of mechanical ventilation in patients hospitalized with Coronavirus disease 2019 (COVID-19), researchers report June 24 in Cell Metabolism.

The large-scale retrospective study also showed that mortality risk and other negative outcomes were not increased by combination therapy consisting of statins and blood pressure-lowering drugs called angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).

“These results support the safety and potential benefits of statin therapy in hospitalized patients with COVID-19 and provide a rationale for prospective studies to determine whether statins confer protection against COVID-19-associated mortality,” says senior study author Hongliang Li of Wuhan University.

“Moreover, our findings represent an important contribution to the accumulating clinical evidence regarding the beneficial or detrimental effects of prescribing ACE inhibitors or ARBs to patients with COVID-19.”

Currently, there is no vaccine or specific antiviral drug approved to prevent or treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes COVID-19. Because a vaccine or drugs for COVID-19 will likely not be available for months or even years, repurposing clinically approved therapies might be a more attractive option.

Statins may serve such a purpose because these drugs slow the progression of lung injury in animals, improve immune cell responses, and strongly reduce inflammation, which is likely responsible for severe COVID-19 complications such as organ damage.

Although statins generally have an excellent safety profile in humans, animal studies have shown that they increase the expression of angiotensin-converting enzyme II (ACE2)–the receptor that SARS-CoV-2 binds to and uses to enter host cells.

On the other hand, animal studies have also shown that ACE2 protects organs such as the lungs against virus-induced injury. As a result, it has not been clear how clinical outcomes in patients with COVID-19 are affected by the use of statins, either alone or in combination with ACE inhibitors and ARBs, which are commonly prescribed with statins and also increase ACE2 expression in animals.

To address this gap in knowledge, Li and his collaborators carried out a retrospective study of 13,981 COVID-19 patients admitted to 21 hospitals in Hubei Province, China. Among these patients, 1,219 used statins, primarily atorvastatin at an average dose of 20 mg/day.

Among patients with hypertension (i.e., high blood pressure), 319 used statins combined with ACE inhibitors or ARBs, and 603 used statins combined with other antihypertensive drugs.

The researchers analyzed mortality rates and secondary outcomes, including the incidence of invasive mechanical ventilation, admission to intensive care units, acute respiratory distress syndrome, and liver, kidney, or heart injury.

Because patients on statins were older and had a higher incidence of lung lesions and chronic diseases, the researchers also performed analyses on subsets of patients that were matched for baseline characteristics such as age, disease severity, and pre-existing conditions.

Over a 28-day follow-up period, statin use was associated with a lower death rate and a lower incidence of mechanical ventilation. Statin use was associated with 5.5% mortality rate, compared to 6.8% without statin use, representing a 19% decrease.

When the researchers examined the matched cohort of 861 patients in the statin group and 3,444 patients in the non-statin group, statin use was associated with a 45% decrease in the mortality rate, from 9.4% to 5.2%.

In the matched cases, statin use was also associated with lower levels of three inflammation biomarkers, and a lower incidence of acute respiratory distress syndrome and admission to intensive care units.

In the unmatched sample, mortality and secondary outcomes over 28 days were not affected by the use of statins combined with ACE inhibitors or ARBs, compared to combination therapy consisting of statins and other antihypertensive drugs.

But in the matched cohort with 204 patients in each group, the use of statins combined with ACE inhibitors or ARBs versus other antihypertensive drugs was associated with a 65% drop in the death rate (3.4% versus 9.8%) and a lower incidence of heart injury and acute respiratory distress syndrome.

“Although the use of an ACE inhibitor or ARB was once speculated to be potentially harmful in patients with COVID-19, several professional societies have recommended the continued use of these drugs in patients with COVID-19 and pre-existing hypertension,” Li says.

“To our knowledge, the results from this study are the first clinical evidence supporting the notion that the risk of COVID-19 mortality is not increased by using ACE inhibitors or ARBs in combination with statin treatment.”

However, the study does not prove that the lower death rate of patients with COVID-19 is directly caused by the use of statins, either alone or in combination with ACE inhibitors or ARBs. For now, it is also unclear whether the findings apply to non-hospitalized patients with COVID-19.

Moreover, the results of retrospective studies should be interpreted with caution, Li says. “Although these data do provide supportive evidence for the safety of statins or the combination of statins with ACE inhibitors or ARBs for treatment in patients with COVID-19, further randomized controlled trials to prospectively explore the efficacy of statins on COVID-19 outcomes appear justified.”

Funding: This work was supported by grants from the National Key R&D Program of China, the Science and Technology Projects of Guangdong Province, the National Science Foundation of China, the Major Research Plan of the National Natural Science Foundation of China, the Hubei Science and Technology Support Project, and the Medical flight plan of Wuhan University. The authors declare no competing interests.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of the current pandemic of coronavirus disease 2019 (COVID-19). SARS-CoV-2 is a positive-sense single-stranded RNA betacoronavirus sharing genetic similarities with the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East respiratory syndrome-related coronavirus (MERS-CoV).1 SARS-CoV-2 enters the cells mainly through angiotensin-converting enzyme 2 (ACE2), and triggers an intense inflammatory host response, sometimes leading to a life-threatening acute respiratory distress syndrome (ARDS).1 Several randomized controlled trials (RCTs) are investigating the safety and efficacy of various antiviral and immunosuppressive agents. Still, many of these drugs have serious adverse effects, and may not be readily available in some healthcare settings, such as in low-income countries.

In this paper we support the rationale for the use of statins, a class of drugs with widespread availability and an optimal tolerability profile, as an add-on treatment for COVID-19 patients, on the basis of their known immunomodulatory properties.

Besides their lipid-lowering activity, statins exert pleiotropic effects on inflammation and oxidative stress, contributing to their beneficial impact on cardiovascular diseases. Statins modulate the immune response at different levels, including immune cell adhesion and migration, antigen presentation, and cytokine production. Moreover, they restore the vascular redox balance by reducing reactive oxygen species and increasing antioxidants, and ameliorate nitric oxide bioavailability, endothelial function, and integrity. Most of these effects depend on statin-mediated inhibition of the production of isoprenoids, which are fundamental constituents of small GTPases (such as Ras, Rho, and Rac), and on consequential down-regulation of redox-sensitive proinflammatory transcriptional factors such as NF-κB.2

Statins have proven to be beneficial as an add-on therapy in patients with different autoimmune inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and graft-versus-host disease).2 Statins have also been evaluated as an immunomodulatory treatment in various infectious diseases. Although observational studies have reported improved outcomes in patients with community-acquired pneumonia or sepsis receiving statins,3,4 most RCTs on inpatient statin treatment in sepsis or ventilator-associated pneumonia failed to demonstrate a beneficial effect.4 On the other hand, statin therapy appears promising in the context of viral infections. Avian influenza viruses induce an intense host response characterized by a cytokine storm, which can sometimes lead to ARDS.3 Few large observational studies have reported the effectiveness of statin treatment in reducing influenza-related hospitalizations and deaths.3 Further, a recently completed RCT (ClinicalTrials.gov number, NCT02056340) showed a significant improvement of symptoms in statin-naïve patients hospitalized for seasonal influenza receiving atorvastatin 40 mg compared with placebo. An association between outpatient statin use and reduction in disease severity among patients hospitalized during the 2009 H1N1 pandemic has also been demonstrated.3 Some authors have therefore advocated statin use as an immunomodulatory therapy for viral infections with potential for epidemics and pandemics.3 Although no RCT has yet investigated this hypothesis, statins [together with angiotensin receptor blockers (ARBs)] were effective in targeting the host response and preventing endothelial barrier damage in patients infected with Ebola virus during the recent Ebola outbreak in West Africa.5

Similar to avian influenza viruses, betacoronaviruses cause severe respiratory illnesses by triggering an intense proinflammatory host response. Some immunomodulatory therapies have indeed proven beneficial in patients with SARS, MERS, and COVID-19; for example, tocilizumab, a humanized monoclonal antibody against the interleukin-6 receptor, was effective as a supportive therapy in selected COVID-19 patients.1 SARS-CoV-1 interaction with Toll-like receptors on the host cell membrane significantly increases the expression of the MYD88 gene, whose product activates NF-κB, thereby triggering inflammatory pathways.6 Notably, inhibition of NF-κB resulted in reduced lung infection and increased survival in a murine model of SARS-CoV-1 infection.7 Experimental models have demonstrated that statins stabilize MYD88 levels after a proinflammatory trigger such as hypoxia.8 Moreover, in murine cells, atorvastatin 0.1 μM (corresponding to the plasma concentration obtained with a daily dose of ∼40 mg in humans) significantly attenuated NF-κB activation within 48 h.9 (Figure 1). Based on this evidence, the use of a statin as an immunomodulatory treatment for COVID-19 patients may deserve consideration.

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Figure 1
Molecular mechanism of actions and proposed advantages of statins in COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), enters the cell through angiotensin-converting enzyme 2 (ACE2). Once in the cell, SARS-CoV-2 causes ACE2 down-regulation, thus reducing its protective effects on various tissues. Coronaviruses are known to induce a proinflammatory host response via the activation of the Toll-like receptor (TLR)–MYD88–NF-κB pathway. Statins are available worldwide, and are low-cost, safe drugs with lipid-lowering and immunomodulatory effects. In experimental models, statins inhibit the MYD88–NF-κB proinflammatory pathway and promote ACE2 up-regulation. Through these mechanisms, statins may prove beneficial in COVID-19 patients. Statins may also counteract hyperlipidaemia caused by some antiviral and immunosuppressive treatments currently used for COVID-19.

Statins also interfere with ACE2 signalling. After initial entry through ACE2, SARS-CoV-2 down-regulates ACE2 expression, possibly facilitating the initial infiltration by innate immunity cells and causing an unopposed angiotensin II accumulation, leading to organ injury.1 Statins, as well as ARBs, are known to experimentally up-regulate ACE2 via epigenetic modifications.5 (Figure 1). Since an increase in ACE2 might prove beneficial for COVID-19 patients, RCTs with recombinant human ACE2 or ARBs are currently underway,1 and there is biological plausibility to investigate statins too.5

Cardioprotective actions of statins should also be taken into consideration in the setting of SARS-CoV-2 infection. Observational studies have found that elderly people with cardiovascular comorbidities are more likely to be infected with SARS-CoV-2 and to develop severe symptoms.1 In addition, there is evidence of direct cardiovascular involvement in some cases of COVID-19.1 Furthermore, the lipid-lowering action of statins could treat the hyperlipidaemia associated with the use of protease inhibitor-based antiretroviral and immunosuppressive drugs in COVID-19 infection. Statin therapy has proven effective in improving hyperlipidaemia in patients with human immunodeficiency virus receiving protease inhibitor treatment10 and in patients with rheumatoid arthritis receiving tocilizumab (Figure 1).2 Most statins undergo hepatic metabolism through CYP3A4, and concomitant administration of CYP3A4 inhibitors currently used in COVID-19, such as ritonavir and cobicistat, could increase the risk of muscle and liver toxicity; therefore, starting with a lower dose of statin and monitoring creatine kinase and transaminases would be advisable in these cases.

In conclusion, statins are low-cost, extensively tested, well-tolerated drugs that are less likely to be affected by a shortage in a health crisis such as the current COVID-19 pandemic, even in low-income countries, where treatment with more expensive drugs may not be implemented. Adjuvant treatment and continuation of pre-existing statin therapy could improve the clinical course of patients with COVID-19, either by their immunomodulatory action or by preventing cardiovascular damage. This hypothesis should warrant consideration for phase III clinical trials.

References

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Source:
Cell Press

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