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Statin Therapy to Improve Outcome of COVID-19 Patients: Useful or Not Useful?

About one year ago, the journal published a large population-based cohort study from South Korea investigating the potential benefits associated with statins at preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection or improving the outcome of hospitalized coronavirus disease-2019 (COVID-19) patients [...].

For one-year, numerous other clinical studies were published, and many hypotheses were suggested to explain possible interactions between statins and SARS-CoV-2 and to investigate possible clinical benefits to administer statins in COVID-19 patients. The objectives of this commentary article were to report newly published findings updating statin-attributed effects in COVID-19 patients and their underlying mechanisms.

The Relationships between Serum Lipids and SARS-CoV-2 Infection
In most studies, histories of hyperlipidemia and hypercholesterolemia were not associated with increased risk of SARS-CoV-2 infection [2,3] or with worsened outcome [4], despite contradictory findings [5]. Curiously, whether past hypertriglyceridemia might be associated with deleterious consequences on the risk or severity of SARS-CoV-2 infection remained unknown.
However, like most viral infections, marked changes in lipid metabolism and subsequently in serum lipid profile were observed in COVID-19 patients, including decreases in serum total cholesterol, HDL-cholesterol, and ApoA1 levels and elevation in serum triglycerides as compared to normal subjects [6,7]. Since lipids such as arachidonic acid and omega-3 derivatives are modulators of the inflammatory response, changes in lipid profiles result from hyperinflammatory states and are more marked in critically than mildly-tomoderately ill COVID-19 patients [8]. Of note, a decrease in HDL-cholesterol was only observed in critically ill COVID-19 patients; however, despite adjustments for age, gender, and comorbidities, conflicting relationships persisted between HDL-cholesterol levels and the risk of severe complications. In one study, mean HDL-cholesterol was reported at 1.2 mmol/L (1.0-1.5) in discharged versus 1.4 mmol/L (1.0-1.7) in hospitalized patients (p = 0.88) [9], but in another study, the risk of developing severe presentations was significantly associated to HDL-cholesterol (adjusted hazard ratio (HR) 2.83; 95% CI 1.19-6.71, p = 0.02) [10]. While total and LDL-cholesterol decreased over time and were restored on discharge, HDL-cholesterol decreased over time but was not normalized on intensive care unit (ICU) discharge [11].

The Mechanisms by Which Statins May Interact with SARS-CoV-2 Infection
Given the relationships between SARS-CoV-2 and serum lipids, the role of statins (i.e., 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors) to modulate the risk and severity of COVID-19 was questioned. Experimental studies were conducted to investigate pathways allowing statins to attenuate SARS-CoV-2 replication and the resulting cytokine storm, as well as pulmonary injuries. Multiple pathophysiological mechanisms to support such benefits were described [12].
First, direct inhibitory effects on SARS-CoV-2 cell entry and replication involving the inhibition of the viral RNA-dependent RNA polymerase and the main protease were demonstrated. Using computational blind docking analyses, statins exhibited strong although molecule-dependent affinities to critical SARS-CoV-2 structural and functional proteins, including the mutant spike proteins [13]. Stable drug-protein complexes were observed using molecular dynamics simulation, suggesting potent antiviral activities attributed to statins.
Recently, lipid rafts were identified as functional plasma membrane microdomains with tightly packed lipids enriched in sphingolipids and cholesterol and concentrating various receptors and molecules involved in pathogen recognition [14]. Lipid rafts were shown to be effective platforms for SARS-CoV-2 entry [15], due to elevated contents in signaling molecules involved in SARS-CoV-2-cell interaction such as angiotensin-converting enzyme-2 (ACE2), transmembrane serine proteases (TMPRSS), heparan sulfate proteoglycans (HSPGs), Toll-like receptors (TLRs), CD-147, and HDL-scavenger receptor B type 1 (SR-B1). Lipid rafts were shown to facilitate the attachment of the viral spike protein to the ACE-2 receptor and to allow SARS-CoV-2 to recruit key regulator proteins of the lipid metabolism [16]. Hypercholesterolemia involved in enhanced formation of lipid rafts was suggested to facilitate SARS-CoV-2's entry into the target cells, and by contrast, drugs depleting cholesterol or altering intracellular cholesterol homeostasis such as statins were suggested to impair cell infection [15,17].
Secondly, indirect benefits of statins were attributed to their pleiotropic immunomodulatory and anti-inflammatory effects. Statins were reported to lower serum C-reactive protein (CRP) level and to moderately reduce the risk of pneumonia in healthy adults [18]. Excessive LDL-cholesterol was shown to activate the inflammasome and the release of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18 [19], explaining why dyslipidemia should be considered as a pro-inflammatory trigger. Interestingly, statins were shown to reduce serum IL-6 levels achieved by TLR4 inhibition and macrophage activity modulation. Additionally, anti-thrombosis and anti-oxidative properties consisting of the reduction in various mediators in lung tissue, such as plasminogen activator inhibitor type-1 (PAI-1), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF), were suggested to limit COVID-19-related thrombosis and resulting pulmonary fibrosis.
Using K18-hACE2-transgenic mice, statin-attributed beneficial properties were assessed in vivo [20]. Simvastatin was shown to significantly reduce SARS-CoV-2 replication, downregulate the triggered systemic inflammation, limit lung damage, and delay mortality. Simvastatin displaced ACE2 on cell membrane lipid rafts, thus affecting the course of SARS-CoV-2 infection and limiting inflammation at the infection site.

Clinical Studies Investigating the Benefits of Statins in COVID-19 Patients
Multiple clinical studies with various methodologies and flaws were conducted. Important biases were expected from simple observations since in comparison to non-statin users, statin users were supposed to be older, with more hypertension, heart failure, chronic obstructive pulmonary disease, and severe diabetes of longer duration and with more macrovascular and microvascular complications. Therefore, more accurate studies were rapidly requested.

Interventional Studies
Based on observations, pharmacological manipulation of intracellular cholesterol using statins was rapidly considered as promising to mitigate SARS-CoV-2 infection. Randomized placebo-controlled trials (RCTs) testing the benefits of statin administration in hospitalized COVID-19 patients were conducted. A first RCT conducted in mild-to-moderate COVID-19 patients showed that 40 mg atorvastatin once daily for two weeks significantly reduced serum CRP level, supplemental oxygen need, and hospitalization length [43]. By contrast, in the RESIST RCT, including mild-to-moderate COVID-19 patients, aspirin, atorvastatin, or their combination did not prevent clinical deterioration (atorvastatin: HR, 1.0; 95% CI, 0.41-2.46; p = 0.99 and aspirin: HR, 0.7; 95% CI, 0.27-1.81; p = 0.46) [44]. Another RCT conducted in ICU COVID-19 patients showed that atorvastatin did not significantly improve outcome defined as the composite of venous or arterial thrombosis, need for extracorporeal membrane oxygenation, or all-cause mortality [45]. Inconsistent with these results, an RCT showed deleterious effects of statins in hospitalized COVID-19 patients. Atorvastatin in addition to standard care delayed symptom improvement and subsequently increased hospitalization length (1.71-fold delayed remission; HR, 1.70; 95% CI, 1.22-2.38; p = 0.002) [46].
Like isolated observational studies and RCTs, metanalyses were unable to solve discrepancies. However, decrease in all-cause in-hospital mortality in COVID-19 patients as observed in most studies supported statin use, if previously used or indicated otherwise [52].

The Issue of Statin-Attributed Adverse Effects in COVID-19 Patients
In addition to their debated effectiveness, the safety of statins might represent an issue, especially in frail and critically ill COVID-19 patients. To the best of our knowledge, no study except one [35] reported increased adverse effects such as liver cytolysis, rhabdomyolysis, and/or serum glucose dysregulation for which COVID-19 patients are considered at highrisk [31,45]. No safety issue was found in a large study in ICU COVID-19 patients [31]. However, patient monitoring should be careful. Drug-drug interactions involving cytochromes P450 3A, which metabolize statins, are highly possible [53]. In case of ritonavir-boosted nirmatrelvir prescription, substitution of simvastatin and lovastatin by pravastatin or fluvastatin and a dose reduction for atorvastatin and rosuvastatin were recommended.

Conclusions
Although this review is narrative and not systematic, our findings underline that, despite well-conducted large cohort studies, unsolved issues persist with statin prescription in the COVID-19 patient. However, considering their safety and debated benefits on outcome as suggested by robust pathophysiological evidence and multiple clinical studies, in-hospital statin administration could be considered in hospitalized COVID-19 patients and at least not stopped on admission in those previously treated, even if critically ill, given their proven benefits in cardiovascular diseases as lipid-lowering therapy.