Biological Actions, Implications, and Cautions of Statins Therapy in COVID-19

The Coronavirus Disease 2019 (COVID-19) showed worse prognosis and higher mortality in individuals with obesity. Dyslipidemia is a major link between obesity and COVID-19 severity. Statins as the most common lipid regulating drugs have shown favorable effects in various pathophysiological states. Importantly, accumulating observational studies have suggested that statin use is associated with reduced risk of progressing to severe illness and in-hospital death in COVID-19 patients. Possible explanations underlie these protective impacts include their abilities of reducing cholesterol, suppressing viral entry and replication, anti-inflammation and immunomodulatory effects, as well as anti-thrombosis and anti-oxidative properties. Despite these benefits, statin therapies have side effects that should be considered, such as elevated creatinine kinase, liver enzyme and serum glucose levels, which are already elevated in severe COVID-19. Concerns are also raised whether statins interfere with the efficacy of COVID-19 vaccines. Randomized controlled trials are being conducted worldwide to confirm the values of statin use for COVID-19 treatment. Generally, the results suggest no necessity to discontinue statin use, and no evidence suggesting interference between statins and COVID-19 vaccines. However, concomitant administration of statins and COVID-19 antiviral drug Paxlovid may increase statin exposure and the risk of adverse effects, because most statins are metabolized mainly through CYP3A4 which is potently inhibited by ritonavir, a major component of Paxlovid. Therefore, more clinical/preclinical studies are still warranted to understand the benefits, harms and mechanisms of statin use in the context of COVID-19.

Prevalence of dyslipidemia was 18-39.7% as a comorbid condition in hospitalized COVID-19 patients (13)(14)(15). A population-based analysis on 61.4 million adult patients suggested that patients with hyperlipidemic state had 70% increased odds for catching COVID-19 (16). Moreover, COVID-19 patients may develop dyslipidemia that leads to lifethreatening metabolic diseases and thrombotic complications (17)(18)(19), lipid-regulating agents are thus considered for possible therapeutic effects against  Statins are the most commonly used lipid-regulating drugs, 145.8 million people used statins in 2018 (20). Statins are HMG-CoA reductase inhibitors that can reduce serum total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and have other pleiotropic effects such as modulating immune response and alleviating inflammation (21)(22)(23). Structurally, statins are classified as lipophilic (atorvastatin, lovastatin, simvastatin, and fluvastatin) and hydrophilic (pravastatin and pitavastatin), while rosuvastatin has an intermediate behavior (24). Statin prescription is majorly under consideration for primary preventions of cardiovascular disease, and other pathologies such as thrombosis (25,26). Rational use of different types of statins are recommended according to LDL-C lowering need, pre-existing cardiovascular events or related risk factors including dyslipidemia, diabetes, hypertension, and age (25,26).
Different SARS-CoV-2 variants cause resurges of infections (57)(58)(59)(60). Vaccines and antiviral therapies are powerful tools against COVID-19 (61,62), yet data regarding the responses of obese individuals or statin users to these agents remain limited. It has been hypothesized that vaccines would offer reduced protection in obese individuals, based on evidence of immune cell dysregulation and alterations in inflammatory signaling pathways (4,63). Given the immunomodulatory effects of statins, concerns have also been raised regarding possible interferences with COVID-19 vaccines. Moreover, cautions should be take that drug interactions between statins and some agents used in COVID-19 treatment, may lead to adverse effects (64)(65)(66).
Here, we provide a comprehensive update of the values, possible mechanisms, and noteworthy cautions regarding statin use in COVID-19. This review was conducted by consulting resources from peer-reviewed articles and/or official websites like WHO. Common search terms included "COVID-19 OR SARS-CoV-2" AND "statin OR lipid lowering", etc.

VALUES AND MECHANISMS OF STATINS IN COVID-19
As effective drugs for reducing cholesterol, statins can prevent cardiovascular events which are key risk factors for COVID-19 infection and poor prognosis (9,(67)(68)(69). Cholesterol reduction allows statins to affect cell membrane structure and function, particularly lipid rafts that play important roles in viral entry and cellular processes like signal transduction (70)(71)(72). Moreover, by The study assesses the effectiveness and safety of rosuvastatin plus colchicine, emtricitabine/tenofovir, and their combined use in these patients. Six hundred and forty-nine patients agreed to participate and were enrolled in this study; among them, 633 (97.5%) were included in the analysis. The primary endpoint was 28-day all-cause mortality.
The combined use of emtricitabine with tenofovir disoproxil plus colchicine and rosuvastatin reduces the risk of 28-day mortality and the need for IMV in hospitalized patients with COVID-19 (47).  This study proposes to study whether the combination of two drugs (These drugs include the LPV/r already in use in Côte d'Ivoire as well as an antihypertensive drug-telmisartan, and atorvastatin) is more effective than taking a single drug on reducing the viral load in the respiratory tract but also on reducing inflammation.  (73). Hyperactivation of immune responses, elevated systematic inflammation, increased oxidative stress, and thrombosis events have been observed in severe COVID-19, especially among those with obesity or cardiovascular diseases, while statins have shown suppressive effects against these processes (Figure 1).

Antiviral Effects
SARS-CoV-2 infection initiates from cell entry by attaching to its receptor ACE2 (70,71). The cholesterol-rich membrane lipid rafts is crucial for this process. By reducing cholesterol, disrupting lipid raft composition, altering membrane receptor assembly and localization, statins interfere with virus fusion and entry in HIV models (51,74). Potential mechanism is that statins-mediated blockade of HMG-CoA reductase leads to inhibition of Rho guanosine triphosphatase, a key contributor to clustering of lipid raft-associated receptors (74,75). Statins may increase ACE2 levels under disease situations with unknown clinical relevance (76), and simvastatin significantly affected SARS-CoV-2 cell entry through displacing ACE2 on lipid rafts (77) (Figure 2). Simvastatin can also reduce SARS-CoV-2 replication (77). Viral infection increases HMG-CoA reductase activity and cholesterol synthesis to assist viral replication, which explains the negative impact of statins on viral replication (78, 79) (Figure 2). Viral assembly and release following replication can be suppressed by statins through inhibiting mevalonate synthesis and intracellular cholesterol levels (80,81). Whether statins similarly affect the assembly and release of SARS-CoV-2 remain unknown. Although multiple statins have showed antiviral effects against different viruses, a study suggested higher efficacy for lipophilic statins against Zika viral replication, possibly because they can enter cells via passive transport to reach higher intracellular concentrations (82). Moreover, comparison between the survival curves of patients with a pre-existing chronic cardiovascular disease indicated a significant reduction in mortality in lipophilic statin users vs. hydrophilic group and non-users group (35). Therefore, it will be critical to understand whether and how the type, dose and duration of statin therapy affect antiviral effects and subsequently the outcome of SARS-CoV-2 infection.

Anti-inflammatory and Immunomodulatory Effects
Exacerbated inflammation is a pathological hallmark of COVID-19 (83). During severe COVID-19, a generalized inflammatory state is caused by cytokine storm due to hyperactivation of host immune system, leading to lesions in multiple organs and even death (84). Upon SARS-CoV-2 invasion, antigenpresenting cells recognize the pathogen via Toll-like receptors (TLRs) and activates two main downstream pathways, MyD88and TRIF-dependent pathways, both leading to NF-κB activation (85)(86)(87)(88). NF-κB initiates the first stage of inflammasome activation and induces the production of pro-inflammatory factors, including interleukin-6 (IL-6), a key cytokine associated with COVID-19 severity and mortality (89)(90)(91). Activation of NLRP3 inflammasome involves in response to infection of RNA viruses including SARS-CoV-2 (92-95). Patients with a reduced immune fitness and pre-existing systemic inflammatory state, such as obesity or cardiovascular diseases, are prone to demonstrate dysregulated NLRP3 inflammasome activity and pro-inflammatory cytokines expression, resulting in severe 96,97).
Clinical studies indicate that statins decrease serum CRP levels (110), an inflammatory biomarker and risk factor for adverse COVID-19 outcomes (111). Importantly, in-hospital statin use is significantly associated with ameliorated inflammatory responses, as reflected by lower levels of circulating CRP, IL-6 and neutrophil counts in statin users (29). Correspondingly, simvastatin downregulated SARS-CoV-2-infection-triggered inflammation in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells, showing its anti-inflammatory effect both at the site of viral infection and systemically (77). Statin-mediated CRP reduction can be achieved by lowering LDL-C, suppressing Rac-1 activation and increasing apolipoprotein A-I, all of which alleviate inflammation and subsequent CRP generation (112). Notably, for PCSK9 inhibitors, another class of lipid-lowering drugs that significantly decreases LDL-C but not inflammatory markers like CRP (113,114), evidence is lacked so far regarding their possible benefits on COVID-19 outcomes, while deeper investigation is needed. Since COVID-19 patients with obesity are prone to immune cell dysregulation and elevated inflammations, further studies are warranted to explore whether and how statins may protect them from COVID-19.

Anti-thrombosis Effects
Thrombosis are among the most frequent complications in COVID-19 patients, especially in critically ill cases (115)(116)(117), and elevated D-dimer levels show prognostic significance for poor outcomes (7,116,118). Therefore, prevention/alleviation of thrombosis is a key to COVID-19 treatment, especially for obese patients who are prone to ICU admission and thromboembolic events.
The anti-thrombosis effect of statins has been widely investigated in patients at risk for cardiovascular disease or those with established atherosclerosis, and varies from different statins (145,146), but their impacts on COVID-19-related thrombosis remain largely unknown. A clinical trial in ICU admitted COVID-19 patients observed lower rate of thrombosis event in atorvastatin group, although without significant association, suggesting possible anti-thrombosis role of atorvastatin in COVID-19 cases; assessment of outcomes after long-time followup is ongoing (46).

CLINICAL TRIALS REGARDING STATIN USE AND COVID-19
Currently, among clinical trials regarding statin use and COVID-19, two have published results, while the others remain uncompleted or have not posted results ( Table 1). In INSPIRATION/INSPIRATION-S study (NCT04486508) conducted in Iran ICU admitted COVID-19 patients, atorvastatin (20 mg/day) was not associated with a significant reduction in the composite of thrombosis, ECMO treatment, or all-cause mortality; however, atorvastatin treatment was safe, and may have clinical importance with lower overall event rates (46). Another study (NCT04359095) was conducted in Colombia (47), emtricitabine with tenofovir disoproxil (200/300 mg/day for 10 days) plus colchicine and rosuvastatin (0.5 mg and 40 mg/day for 14 days) combination reduced the risk of 28-day all-cause mortality by 22%, and lowered the need for IMV (47). These findings indicated safety and potential benefits of statins for COVID-19 treatment, yet the therapeutic effect varies from cohort and medications. More randomized controlled trials are therefore warranted to assess the effect of statin administration alone or in combination with regards of medication dose and duration, and to evaluate the influence of chronic statin use on COVID-19-related in-hospital events or long-term complications.

CAUTIONS ABOUT STATINS USE IN COVID-19
Although statins are generally well-tolerated, for COVID-19 patients especially those with obese or chronic statin use, cautions are required for potential risks of statins-associated muscle symptoms, liver injury, new-onset diabetes, renal injury, and neurological and neurocognitive disorders, which may also result from severe COVID-19 (68,84,126,155,156) (Figure 3).
Statin-associated muscular symptoms (SAMS) are principal cause of poor patient compliance that contribute to adverse outcomes (157,158). SAMS include fatigue, weakness and pain, possibly accompanied by elevated serum CK levels and activity (54), while similar symptoms also present at early onset of COVID-19 (159). Therefore, for COVID-19 patients who use statins, careful monitoring muscle symptoms and CK levels are necessary; when muscle symptoms occur, assessment and approaches for statin intolerance may be considered (68,160).
Statins-associated hepatotoxicity may add to COVID-19 related liver injury that potentially caused by psychological stress, systemic inflammation, etc., especially among obese individuals at higher risk of liver dysfunction (161)(162)(163). It has been suggested to avoid statin use in the case of severe liver damages, liver failure, and decompensated cirrhosis (24).
COVID-19 may induce or accelerate type 2 diabetes mellitus (T2DM) development as one of its acute and suspected longterm complications (19,56), while statin may increase incidence of new-onset T2DM, which appears to be more common in obese patients (55,164,165). Despite the risk of T2DM, the cardiovascular benefits of statins should not be masked (166). Therefore, statin therapy can be continued in such patients with glucose monitoring, to achieve better glycemic control and avoid developing metabolic disorders after SARS-CoV-2 infection.
Clinicians should also be cautious when treating statin users with COVID-19 who show renal or neurological symptoms and relevant laboratory abnormalities. Renal dysfunction can be caused by SARS-CoV-2 infection and is associated with COVID-19 poor prognosis (167)(168)(169); whether statin-associated renal toxicity (170,171) exacerbates COVID-19-related renal dysfunction remains unclear. There are also concerns regarding whether use of statin (especially lipophilic ones that can cross the blood-brain barrier) may worsen clinical manifestations of nervous system in COVID-19 patients, given their side effects of causing neurological disorders (171,172).
Caution is also necessary for drug interaction during COVID-19 management. Most statins are predominantly metabolized by CYP450 enzymes, mainly through CYP3A4 (64). Therefore, concomitant administration of CYP3A4 inhibitors, such as some macrolides (clarithromycin/telithromycin/erythromycin) and antiretroviral drugs (lopinavir/ritonavir), with statins can increase the risk of adverse events (68,173). For severe COVID-19 patients treated with IL-6 receptor blocker tocilizumab, rosuvastatin is recommended (68). Additionally, decreased LDL-C was observed in some severe COVID-19 cases (174,175). Such finding may due to a more intensive lipid-lowering treatment in patients with high cardiovascular risk who are more vulnerable to COVID-19 (176), and deeper analysis is warranted to better prescribe appropriate intensity statin therapy.

STATINS AND COVID-19 VACCINES
The impact of statins on vaccine efficacy remain controversy. Take influenza vaccine for example, a clinical trial suggested immunosuppressive effect of chronic statin medication may weaken the immune response to vaccine (177), whereas another study indicated that statin did not modify influenza vaccine effectiveness (178). Presently, multiple COVID-19 vaccines have been approved, notably, vaccination participants with BMI ≥ 30 had a smaller infection risk reduction than those with BMI < 30 (179), and central obesity (higher waist circumference) is associated with lower neutralizing antibody titers following vaccination (180). Presently, no evidence suggests statin may affect COVID-19 vaccine effectiveness.

STATINS AND COVID-19 ANTIVIRALS
SARS-CoV-2 variants may have substantial immune evasiveness that weakens vaccine protection due to spike protein mutations (57)(58)(59)(60). Small molecular antivirals have reduced hospitalization rate and mortality in patients with promising safety (181,182), among which Paxlovid stands out by reducing the risk of COVID-19-related hospital admission or death by 89% (183,184). Paxlovid consists of a SARS-CoV-2 main protease inhibitor PF-07321332, and an anti-HIV drug ritonavir that boosts the effectiveness of protease inhibitors (184). However, co-administration of statins and Paxlovid may increase statin exposure and the risk of adverse effects including muscle symptoms and liver toxicity, because ritonavir potently inhibits CYP3A4 through which lipophilic statins are predominantly metabolized (64)(65)(66). Therefore, when such concomitant use is needed, it is possible to continue rosuvastatin therapy starting a low dose and titrating up (68,156). More studies are needed to clarify the possible risks regarding co-administration of statins and antivirals, to find a proper regimen, and to explore whether obesity and dyslipidemia may interfere the efficacy of antivirals.

CONCLUSION AND FUTURE PERSPECTIVES
Current data suggest that statins are safe for COVID-19 patients and may exert therapeutical benefits. Generally, there is no necessity to discontinue statin use, and no evidence suggesting interference between statins and COVID-19 vaccines. However, cautions should be taken to achieve proper medication for statin users with COVID-19, considering possible side effects and drug interaction (Figure 3). Two major cautions are: Proper type of statin. Compared to hydrophilic statins, lipophilic statins enter cells via passive transport to reach higher intracellular concentrations, and have a larger distribution volume, thus may be more protective in respect of anti-viral ability. Intensity of statin therapy. Hypolipidemia is harmful. Decreased LDL-C is observed in some COVID-19 patients and associated with COVID-19 severity (174,175), yet such findings may due to a more intensive lipid-lowering treatment in patients with high cardiovascular risk who are more vulnerable to COVID-19 (176). Low-, moderate-, high-intensity statin therapy should be applied according to specific LDL-C lowering needs. Importantly, careful monitoring of LDL-C, CK, blood glucose and liver function is recommended in context of COVID-19.
Currently known impacts of statins in COVID-19 are mostly based on observational studies and may vary due to heterogenicity in different trials/cohorts. To address the effect of statins in COVID-19 patients, especially in those with obesity or dyslipidemia-related diseases, randomized controlled trials with proper patient stratification are warranted. Moreover, experimental evidence of how different statins act in COVID-19 models are rare, highlighting the importance of related studies.

ACKNOWLEDGMENTS
We sincerely appreciate the investigators and authors who have contributed to this field and apologize that we could not discuss and cite all of them in this review due to space limitations.