A Review of Statins and COVID-19

Abstract

Statins are a well-established class of β-Hydroxy β-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors that have recently been discussed as a possible therapeutic in COVID-19. The breadth of this chapter reviews the evidence for use of statins alone or in combination with other drugs as treatment for patients hospitalized with moderate to severe COVID-19. Discussion will include a (1) biochemical argument for the role of statins in COVID-19, (2) a systematic literature review of relevant studies to date, and (3) an investigation into early-phase interventional studies. Outcome measures based on all aforementioned relevant studies will be clearly defined and compared.

1. Introduction

The COVID-19 pandemic that emerged from the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) will be remembered as one of the worst outbreaks in modern history. To date, over 651 million individuals worldwide have tested positive for the disease with over 6 million confirmed deaths [1]. Research from the scientific and medical communities has primarily focused on disease management, specifically in hospitalized patients who have a considerable risk of progression to multi organ failure, acute respiratory distress syndrome, and death. These efforts have included evaluating the effectiveness of various antiviral and anti-inflammatory drugs. Antiviral therapies, such as remdesivir, molnupiravir, and nirmatrelvir with ritonavir; immunomodulators, such as corticosteroids, baricitinib, and tocilizumab; and monoclonal antibodies, such as casirivimab with imdevimab, sotrovimab, and bamlanivimab with etevimab are all authorized therapeutics by the World Health Organization (WHO), National Institutes of Health (NIH), and the U.S. Food and Drug Administration (FDA) for the treatment of COVID-19 [2, 3, 4]. While these interventions have proven successful in treating the disease, the systemic adverse effects from a variety of these immunosuppressive agents leaves much to be desired [5]. A number of observational studies and clinical trials have been conducted worldwide to assess the role of repurposing existing medications to increase survival rates and lower morbidity in COVID-related hospitalizations [6, 7, 8, 9, 10].

Statins are a class of oral β-Hydroxy β-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors that was first approved for commercial use in the United States in 1987 for the primary and secondary prevention of atherosclerotic cardiovascular disease [11]. HMG-CoA reductase is a rate-controlling enzyme that catalyzes the conversion of HMG-CoA to mevalonate in the biochemical pathway of cholesterol metabolism [12, 13, 14, 15, 16]. Inhibition of this reductase has been well-associated with the reduction of overall serum cholesterol and improvement of lipid profile in humans [17]. In recent years, other studies have noted a variety of beneficial, “pleiotropic” immunomodulatory effects that reduce inflammation by downregulating expression of inflammatory cytokines, inhibiting thrombogenic response, and reducing oxidative stress [18, 19, 20, 21, 22].

The role of statins has been previously studied in other viral respiratory infections. Similar to COVID-19, influenza viruses have been known to induce a cytokine storm, leading to ARDS [23]. A recently completed clinical trial by [24] in 2019 demonstrated that patients who were administered atorvastatin 40 mg orally daily for 5–7 days showed a significant improvement in influenza-related outcomes when compared to the placebo group. This conclusion was also supported by multiple large observational studies done by Vandermeer et al. [25] and Mortensen et al. [26]. In the setting of respiratory syncytial virus (RSV) infection, a study by Malhi et al. [27] to assess a novel approach to screening for RSV inhibitors provides strong evidence that modulation of lipid metabolites by statins decreases production of viral particles in-vitro. Notably, RSV and many other viruses including influenza A, rhinoviruses, and adenoviruses have all been observed to favor lipid-rich environments for infection and upregulate lipid metabolic enzymes such as HMG-CoA reductase [28, 29, 30, 31, 32].

Statin therapy mediates proinflammatory pathways by inhibiting SARS-CoV-2 replication, suppressing the release of inflammatory factors, and attenuating cytokine storms [33, 34, 35]. Upon initial exposure to lung tissue, SARS-CoV-2 binds to angiotensin-converting-enzyme 2 (ACE2) receptors to replicate and infect other ACE2 tissue cells [36]. The suppression of cholesterol production by HMG-CoA reductase inhibitors causes the disruption of lipid raft formation, negatively affecting the viral replication process [37, 38]. Secondly, SARS-CoV-2 tends to bind to toll-like-receptors (TLR) leading to the overexpression of the MYD88 gene, which induces activation of nuclear factor kappa B (NF-kB), a master regulator of proinflammatory gene expression [39, 40]. In rat models, statins are reportedly able to inhibit NF-kB and preserve MYD88 levels after a proinflammatory trigger [34]. Thirdly, SARS-CoV-2 is noted to uncontrollably increase production of inflammatory cytokines including Interleukin (IL) 6, IL-2, IL-7, IL-10, etc. leading to a higher risk of development of a cytokine storm [41, 42]. In experimental studies, statins were shown to attenuate pulmonary inflammation by suppressing the production of such cytokines [35]. The combined pleiotropic effects of statin therapy makes it a promising candidate to mitigate respiratory injury from the SARS-CoV-2 virus.

The breadth of this chapter reviews existing and prospective observational and interventional studies repurposing statins for treatment of COVID-19.

2. Search methodology

This literature search identified studies that evaluate antecedent and/or subsequent statin therapy during COVID-related hospitalization. The search included observational studies, randomized control trials, and prospective/existing clinical trials that assess the efficacy of statin therapy on COVID-19 outcomes. Excluded were meta-analyses, review articles, case reports, case series, book chapters, author responses, and news articles.

The WHO COVID-19 Database, which contains global literature on COVID-19 from several major online databases, was utilized in conjunction with PubMed, ClinicalTrials.gov, and NIH Clinical Center. Keywords searched for within the Title and Abstract consisted of SARS-CoV-2, COVID-19, coronavirus disease, statins, statin therapy, atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, simvastatin. Additional manual searches were performed within the bibliography of chosen articles to include other relevant titles.

Quality assessment of observational studies was performed using the Newcastle-Ottawa Scale (NOS), while the risk of bias of randomized controlled trials was determined using the Cochrane tool for randomized trials (RoB 2.0) [43, 44]. In the former, articles were independently screened and rated by two authors based on NOS criteria. Scores were subsequently compared and any discrepancies were discussed and resolved. Studies with a low risk of bias using RoB 2.0 and a “High” NOS rating were given priority.

3. Evidence

Herein, we describe 26 appropriately screened studies that provide evidence regarding the role of statins in the treatment of COVID-19. Of the aforementioned total, 16 constitute observational studies (see Table 1). Four are completed interventional clinical trials (see Table 2). Six account for active, ongoing clinical trials (see Table 3).

Observational studies
#	Authors	Title	Location	Study Design	NOS Assessment
1	Umakanthan, et al.	The effect of statins on clinical outcome among hospitalized patients with COVID-19: A multi-centric cohort study	India	retrospective cohort	High
2	Zhang et al.	In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19	Hubei Province, China	retrospective cohort	High
3	Tan et al.	Statin use is associated with lower disease severity in COVID-19 infection	Singapore	retrospective cohort	Fair
4	Vahedian-Azimi et al.	Association of in-hospital use of statins, aspirin, and renin-angiotensin-aldosterone inhibitors with mortality and ICU admission due to COVID-19	Iran	retrospective cohort	Fair
5	Rodriguez-Nava et al.	Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study	Illinois, United States	retrospective cohort	Fair
6	Spiegeleer et al.	The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents	Belgium	retrospective cohort	High
7	Oh et al.	Statin therapy and the risk of COVID-19: A cohort study of the National Health Insurance service in South Korea	South Korea	retrospective cohort	High
8	Cariou et al.	Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: Results from the CORONADO study	France	retrospective cohort	High
9	Fan et al.	Association of statin use with the in-hospital outcomes of 2019-coronavirus disease patients: A retrospective study	Wuhan, China	retrospective cohort	High
10	Peymani et al.	Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients	Shiraz Province, Iran	retrospective cohort	High
11	Israel et al.	Identification of drugs associated with reduced severity of COVID-19 – a case–control study in a large population	Israel	case control	High
12	Ayeh et al.	Statins use and COVID-19 outcomes in hospitalized patients	Maryland, United States	retrospective cohort	High
13	Bifulco et al.	The benefit of statins in SARS-CoV-2 patients: further metabolic and prospective clinical studies are needed	Mlan, Italy	retrospective cohort	Fair
14	Maric et al.	Decreased mortality rate among COVID-19 patients prescribed statins: Data from electronic health records in the US	United States	retrospective cohort	High
15	Saeed et al.	Statin Use and in-hospital mortality in patients with diabetes mellitus and COVID-19	Bronx, New York, United States	retrospective cohort	High
16	Karampoo et al.	The role of lovastatin in the attenuation of COVID-19	Iran	case–control	Fair

Table 1.

Observational studies.

Interventional studies
#	Authors	Title	Location	Study Design	RoB 2.0 Score
1	Ghati et al.	Statin and aspirin as adjuvant therapy in hospitalized patients with SARS-CoV-2 infection: a randomized clinical trial (RESIST trial)	India	open label, randomized control trial	Low Risk
2	INSPIRATION-S Investigators	Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial	Iran	double-blind, randomized control trial	Low Risk
3	Ghafoori et al.	Survival of the hospitalized patients with COVID-19 receiving atorvastatin: A randomized clinical trial	Bojnurd, Iran	single-blind, randomized control trial	Low Risk
4	Matli et al.	Managing endothelial dysfunction in COVID-19 with statins, beta blockers, nicorandil, and oral supplements: A pilot, double-blind, placebo-controlled, randomized clinical trial	Lebanon	double-blind, randomized control trial	Low risk

Table 2.

Completed interventional studies.

#	Trial Identifier	Trial Phase	Study Design	Title	Sponsor/Institution	Location
1	NCT04952350	III	Quadruple blinded placebo-controlled randomized trial	COVID-STAT	Mansoura University	Egypt
2	CTRI/2021/04/032648	III	Randomized, Parallel Group Trial	NAAC	Dr. Ambudhar Sharma	India
3	NCT04472611	III	Open-label, parallel assignment randomized trial	COLSTAT	Yale University	United States
4	NCT04466241	IIb	Open-label, parallel assignment randomized trial	INTENSE-COV	ANRS, Emerging Infectious Diseases	Côte D’Ivoire
5	NCT04380402	II	Open-label, parallel assignment randomized trial	STATCO19	Mount Auburn Hospital	United States
6	NCT04348695	II	Open-label, parallel assignment randomized trial	Ruxo-Sim-20	Fundación de investigación HM	Spain

Table 3.

Ongoing clinical trials.

3.1 Observational studies

In a retrospective cohort study conducted in India, Umakanthan et al. [45] compared the clinical outcome and laboratory results of prior statin use (n = 524) to non-statin use (n = 1102) of patients hospitalized with COVID-19. A 1:1 propensity-score matching (PSM) was also performed with 384 statin users and 384 non-statin users. Laboratory results revealed that statin users had a lower mean white blood cell count (P < 0.01), C-reactive protein (CRP) (P < 0.001), and more favorable total lipid profiles when compared to non-statin COVID-19 patients. Additionally, they found statin use was associated with lower odds of mortality (P < 0.001). There were no significant differences in mechanical ventilation (P = 0.07) and hemodialysis (P = 0.41) between antecedent statin users and non-statin users.

Zhang et al. compared the in-hospital use of statin (n = 1219) and non-statin treatment (n = 12,762) in a retrospective cohort study on 13,981 COVID-19 patients over 21 hospitals in Hubei Province, China [46]. A mixed-effect Cox model after PSM revealed the risk for 28-day all-cause mortality in the statin group versus non-statin group to be 5.2% and 9.4%, respectively, with an adjusted hazard ratio (HR) of 0.58 (P = 0.001). Statin use was also associated with lower risk of mortality based on the mixed-effect Cox model (P = 0.001) and marginal structural model analysis (P = 0.032). Additionally, lower incidence of mechanical ventilation (P < 0.001), ICU admission (P = 0.001), and development of ARDS (P = 0.015) were associated with statin treatment via Cox model analysis. Furthermore, 319 participants of the 1219 statin users with hypertension were treated with an additional angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARBs) during hospitalization; however, co-treatment was not associated with any significant benefit in the cohort through analysis using a Cox model (P = 0.074), mixed-effect Cox model (P = 0.018), or marginal structure model (P = 0.576).

Tan et al. conducted a retrospective cohort study within a Singaporean tertiary center and evaluated the association between antecedent statin use and a number of clinical outcomes within COVID-19 patients [47]. They used logical treatment models with PSM to compare statin users’ (n = 40) and non-statin users’ (n = 509) risk of admission to the intensive care unit (ICU), hypoxia, mechanical ventilation, and death. A lower chance of ICU admission was independently associated with antecedent statin therapy (P = 0.028), while other clinical outcomes such as hypoxia requiring supplemental oxygen (P = 0.449), invasive mechanical ventilation (P = 0.114), and death (P = 0.488) did not significantly differ between statin and non-statin users.

In a retrospective single-center study, Vahedian-Azimi et al. evaluated the correlation between use of ACEis, ARBs, statins, and aspirin on the clinical outcomes of mortality and ICU admission in patients hospitalized with COVID-19 [48]. Atorvastatin therapy, specifically, was found to be associated with reduced mortality after adjusting for age, lockdown status, and other medications (P = 0.001).

Rodriguez-Nava et al. evaluated whether a daily statin dose of 40 mg reduced inpatient mortality due to COVID-19 in the ICU of a hospital located in Evanston, IL [49]. Confounding factors were minimized by adjusting for age, hypertension, cardiovascular disease, mechanical ventilation, disease severity, number of comorbidities, and other adjuvant therapies. The retrospective cohort study found that atorvastatin was associated with the slowest progression to death out of several target interventions [adjusted HR = 0.38; 95% confidence interval (CI) = 0.18–0.77; P = 0.008] when performing a multivariable Cox proportional hazards model. Additionally, non-statin users were shown to have a 73% faster progression to death.

In a retrospective multicenter cohort study conducted in Belgium, Spiegeleer et al. explored the association of antecedent statin and/or ACEi/ARB use with severity of symptoms and clinical outcomes in older adults infected with COVID-19 across two nursing homes (n = 154) [50]. Logistic regression models were utilized while adjusting for covariates of age, sex, functional status, diabetes, and hypertension. Statin use was found to be significantly related to the absence of symptoms during infection [odds ratio (OR) = 2.91; CI = 1.27–6.71]. A positive association between statins and serious clinical outcomes, such as death within 14 days of disease onset and prolonged hospital admission, was also observed, though it was not statistically significant (OR = 0.75; CI = 0.24–1.87).

Oh et al. conducted a population-based cohort study in South Korea to investigate whether prior and inpatient statin therapy affected COVID-19 incidence and hospital mortality in patients with COVID-19 [51]. Logistic regression analysis with PSM revealed that among 122,040 adults, statin users (n = 22,633) were 35% less likely to develop COVID-19 than non-statin users (n = 101,697) (OR = 0.65; 95% CI 0.60–0.71, p < 0.001). Hospital mortality in COVID-19 patients, however, did not differ between the statin and control groups when applying the multivariable model (OR = 0.74; 95% CI = 0.52–1.05; P = 0.094).

A nationwide observational study conducted in France by Cariou et al. sought to evaluate the association between routine statin therapy and clinical outcomes of COVID-19 inpatients across 68 hospitals with Type 2 diabetes mellitus (T2DM) [52]. Logistic regression analysis via inverse probability of treatment weighting (IPTW) with propensity score weighting was performed. The primary outcomes selected for were tracheal intubation and/or death within 7–28 days of admission. Patients who received antecedent statin therapy (n = 1192) were shown to have similar primary outcome rates as non-statin users (n = 1257) within 7 (29.8 versus 27.0%, respectively; P = 0.1338) and 28 days of admission before adjustment (36.2 versus 33.8%, respectively; P = 0.2191). After IPTW application, there was a significant association observed between statin therapy and intubation within 7 days (OR = 1.38; 95% CI = 1.04–1.83). Antecedent statin use was also significantly associated with a lower likelihood of death within both 7 (OR = 1.74; 95% CI = 1.13–2.65) and 28 days (OR = 1.46; 95% CI = 1.08–1.95).

In Wuhan, China, Fan et al. conducted a retrospective case study to investigate the association of statin use and in-hospital outcomes of 2147 patients admitted with COVID-19 across two hospitals [53]. Using a multivariate Cox model, statin users (n = 250) showed a lower risk for mortality (HR = 0.428; 95% CI = 0.169–0.907; P = 0.029), ARDS (HR = 0.371; 95% CI = 0.180–0.772; P = 0.008), and ICU admission (HR = 0.319; 95%; CI = 0.270–0.945; P = 0.032) than non-users (n = 1897) when adjusted for age, gender, admitted hospital, comorbidities, inpatient medications, and blood lipids. Similarly, before and after adjusting for covariates, a Cox regression model revealed lower mortality (unadjusted HR = 0.254; 95% CI = 0.070–0.926; P = 0.038), ARDS development (unadjusted HR = 0.240; 95% CI = 0.087–0.657; P = 0.006), and ICU admission (unadjusted HR = 0.349; 95% CI = 0.150–0.813; P = 0.015) to be linked with statin therapy. A 1:1 matched cohort (206:206) was additionally created with PSM analysis of 18 potential confounders and showed statin use to be associated with better survival on a Kaplan–Meier survival curve (P = 0.025).

Peymani et al., in their retrospective cohort analysis, studied the role of routine and inpatient statin therapy in 150 patients hospitalized with COVID-19 in the Shiraz province of Iran [54]. The association of statin therapy and rate of death was assessed using Cox proportional hazards regression models. They found statins were associated with lower risk of death (HR = 0.76; 95% CI = 0.16–3.72; P = 0.735) and lower risk of morbidity (HR = 0.85; 95% CI = (0.02, 3.93), P = 0.762), although these results were not statistically significant. Statin therapy also reduced the chances of mechanical ventilation (OR = 0.96; 95% CI = 0.61–2.99; P = 0.942) and abnormal CT scan results (OR = 0.41; 95% CI = 0.07–2.33; P = 0.312). However, these findings were also not statistically significant.

Israel et al. performed a population-based cohort study with data collected from Clalit Health Services, the largest healthcare provider in Israel, to investigate the protective effects of statins, as well as several other established drugs, on COVID-19 hospitalization [55]. They utilized two case–control matched cohorts to assess which medications had the greatest protective effect. Five control patients chosen from the general Israeli population were matched to each case (n = 6202) in the first cohort and each case in the second cohort (n = 6919) was matched to two non-hospitalized SARS-CoV-2 positive control patients. In regards to our drug of interest, routine rosuvastatin use was identified as one the therapies that most significantly reduced risk of hospitalization due to COVID-19 (OR = 0.673; 95% CI = 0.596–0.758; P < 0.001) in both cohorts. Furthermore, pravastatin use was significantly associated with lower hospitalization risk (OR = 0.673; 95% CI = 0.493–0.902; P = 0.00659) in cohort 1. Similar effects were not observed with other statins.

A retrospective study conducted by Ayeh et al. analyzed the relationship between statin use and COVID-19 clinical outcomes, defined as prolonged hospital stay (≥ 7 days) and/or invasive mechanical ventilation, in patients admitted at the Johns Hopkins Medical Institutions across Maryland, United States [56]. Univariable and multivariable analyses were performed via logistic regression, Cox proportional hazards regression, and PSM. After Cox proportional regression application, statin use showed a protective effect against hazard of death (HR = 0.92; 95% CI = 0.53–1.59), though this was not statistically significant. Historical statin use was not found to reduce duration of hospitalization or need for intubation (relative risk (RR) = 1.00; 95% CI = 0.99–1.01; P = 0.928). Rather, it was associated with an 18% increased risk of severe infection (RR = 1.18, 95% CI = 1.11–1.27; P < 0.001).

In Milan, Italy, Bifulco et al. performed a retrospective cohort study on prior and in-hospital statin therapy as related to COVID-19-induced mortality in patients admitted to Humanitas Clinical and Research Hospital (n = 541) [57]. When adjusting for confounding variables such as age, gender, and pre-existing comorbidities, the odds of all-cause mortality were shown to be insignificantly lower in statin users (n = 117) compared to non-users (n = 424) (adjusted OR = 0.75; 95% CI = 0.26–2.17; P = 0.593). Though also not statistically significant, the risk of all-cause mortality was 14% lower in statin users when excluding the 12.4% of patients (n = 67) who discontinued statin treatment due to tracheal intubation (adjusted OR = 0.86; 95% CI = 0.28–2.63; P = 0.795).

Marić et al., in their retrospective cohort study, evaluated 18,466 COVID-19 patients across 62 United States healthcare centers within the COVID-19 electronic health record (EHR) database of Cerner Real-World Data to analyze the effect of statin therapy on mortality rates of inpatients who were not previously prescribed statins [58]. PSM utilizing a 1:2 ratio and nearest neighbor method of patient demographics, comorbidities, and medication indication was used to compare the statin group (n = 2297) to the control (n = 4594). Statin drugs included were the following: atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Zypitamag, Livalo or Nikita), pravastatin (Pravachol), rosuvastatin (Ezallor or Crestor), simvastatin (FloLipid or Zocor). In the 10 cases of PSM by all three factors, a small but statistically significant reduced mortality rate was observed in patients who were prescribed statins (18.0%) compared to the matched controls (20.6%) (P < 1.00E-04 for all iterations).

A retrospective single-center study conducted by Saeed et al. enrolled COVID-19 patients with diabetes mellitus (DM) admitted to a hospital in Bronx, New York to compare risk of death during hospitalization between those who did and did not receive statin therapy [59]. Analysis via competing events regression revealed statin use (n = 983) to be associated with a 15% decrease in hospital deaths of patients with both DM and COVID-19 when compared with non-statin use (n = 1283) (24% versus 39%; P < 0.01). There was no difference in mortality observed from statin to control groups without DM (20% versus 21%; P = 0.82). In addition, PSM (HR = 0.88; 95% CI = 0.83–0.94; P < 0.01) and IPTW (HR = 0.88; 95% CI = 0.84–0.92; P < 0.01) were used to limit potential confounders, both of which showed a 12% reduced risk of in-hospital death for statin users.

In their single-center case–control study, Karampoor et al. analyzed the protective effects of lovastatin on 284 patients with severe COVID-19 admitted to the ICU of Firouzgar Hospital in Iran [60]. Participants comprised of three groups: (1) a control group of patients who did not receive lovastatin therapy (n = 92), (2) patients who received a daily dose of 20 mg lovastatin (n = 99), and (3) patients who received 40 mg lovastatin per day (n = 93). Blood samples were tested on the first day of hospitalization (T1), 3 days after hospitalization (T2), and 6 days after hospitalization (T3) in order to analyze dynamic changes upon inflammatory markers. Both lovastatin test groups exhibited statistically significantly reduced CRP, IL-6, and IL-8 levels between T1 and T3 (P < 0.05). Changes in IL-6 and IL-8 levels were found to be dose dependent; the 40 mg lovastatin group had significantly more reduced levels than the 20 mg group. Furthermore, the length of hospitalization of patients who received lovastatin was significantly lower than the control (P < 0.05). Mortality rate, however, did not statistically differ between test and control groups (P > 0.05).

3.2 Interventional studies

Ghati et al. published the results of the RESIST trial, a single-center, prospective, four-arm parallel design, open-label randomized clinical trial (RCT), that investigated the potential effects of novel statin and/or aspirin treatment on clinical deterioration and inflammatory response of patients requiring hospitalization for mild to moderate COVID-19 [61]. A total of 900 COVID-19 patients diagnosed via reverse transcription polymerase chain reaction (RT-PCR) were randomized into Group A (n = 224) to receive 40 mg of atorvastatin daily, Group B (n = 225) to receive 75 mg of aspirin daily, Group C (n = 225) to receive conjunctive atorvastatin and aspirin therapy, or Group D (n = 226) to receive the standard of care (SOC). All participants were treated with SOC in addition to statin and/or aspirin therapy, save for Group D, which received solely SOC. Groups were followed for 10 days of hospitalization or until discharge, whichever came first. The primary outcome of clinical deterioration was characterized via WHO Ordinal Scale for Clinical Improvement (WHO-OSCI) ≥ 6 and secondary outcome inflammatory response was evaluated via changes in serum inflammatory markers of CRP, IL-6, and troponin I from time zero to day 5 of enrollment. Modified intention-to-treat (ITT) analysis revealed no significant difference in WHO-OSCI among the four groups (P = 0.46). Additionally, the primary outcome was not reduced when comparing all study participants who received atorvastatin (n = 442; HR = 1.0; 95% CI = 0.41–2.46; P = 0.99) and aspirin (n = 442; HR = 0.7; 95% CI = 0.27–1.81; P = 0.46) to the control (n = 219). Secondary outcomes of serum troponin I (P = 0.55) and CRP (P = 0.89) levels showed no significant changes between interventional and conventional groups, while IL-6 levels exhibited a significant decrease with conjunctive therapy (Group C; P < 0.001) and aspirin-only therapy (Group B; P = 0.04).

A double-blind, multicenter RCT with a 2×2 factorial design known as INSPIRATION/INSPIRATION-S was conducted by Bikdeli et al. across 11 hospitals in Iran to compare clinical outcomes of ICU-admitted COVID-19 patients who received statin treatment versus a placebo [62]. Participants, all of whom had no prior indication for statin use, were randomly assigned in a 1:1 ratio to receive atorvastatin 20 mg daily (n = 303) or a matching placebo (n = 302) in addition to SOC for 30 days from the time of randomization or until the primary outcome was reached. The primary outcome of interest was a composite of venous or arterial thrombosis, extracorporeal membrane oxygenation, and all-cause mortality. The individual components of the primary outcome as well as the number of days in which mechanical ventilation was not required comprised the secondary outcome. The median duration of use of atorvastatin therapy was 21 days and placebo was 19 days (P = 0.79). The primary outcome was observed in 33% (n = 95) of the interventional group and 36% (n = 108) of the placebo group (OR = 0.84; 95% CI = 0.58–1.21; P = 0.35), which indicated a risk difference of −3.6% (95% CI = −11.2–4.0%). Of the composing factors, all-cause mortality contributed the largest impact as the risk of mortality was 31% (n = 90) in the interventional group and 35% (n = 105) of the placebo (OR = 0.84; 95% CI = 0.58–1.22). No significant differences between atorvastatin and placebo groups were found in the incidence of venous (P = 0.64) or arterial thromboembolism (P = 0.32). There were no patients from either study group that required extracorporeal membrane oxygenation treatment. Similarly, both interventional and placebo groups had a 30-day median duration of ventilator-free days (P = 0.08).

An single-blind RCT was conducted by Ghafoori et al. in 2021 in Bojnurd, Iran, on patients hospitalized with COVID-19 [63]. In this RCT, 156 participants were randomized in a 1:1 ratio into a comparison group, which received standard therapy of hydroxychloroquine 400 mg daily and lopinavir/ritonavir 400/100 mg every 12 hours, or an interventional group, which received atorvastatin 20 mg daily plus SOC. All patients were followed until discharge or death, whichever result occurred first. Survival analysis, via Cox proportional-hazards regression and Kaplan–Meier analysis, was implemented to determine the primary outcome of hospitalization duration. Other outcomes studied included ICU admission and paraclinical findings. Atorvastastin exhibited a significant association with increased mean length of hospitalization (7.72 days versus 5.06 days; P = 0.001) and heart rate (94.26 versus 87.87 per minute; P = 0.004) in comparison to SOC. Admission to the ICU was also higher in patients who received atorvastatin (18.4 versus 1.3%; P = 0.001) and the comparison group had a higher remission probability as evidenced by Kaplan–Meier analysis (P = 0.0001). After applying Cox regression analysis to adjust for age, length of hospital stay remained significantly reduced (HR = 1.70, 95% CI = 1.22–2.38; P = 0.002) and remission occurred 1.71 times sooner in the control group (HR = 1.70; 95% CI = 1.22–2.38; P = 0.002).

MEDIC-LAUMC was a small double-blind, placebo-controlled RCT conducted by Matli et al. that tested the efficacy of a five-drug protocol consisting of nicorandil, L-arginine, folate, nebivolol, and atorvastatin in the treating endothelial dysfunction in patients hospitalized with mild, moderate, and severe COVID-19 [64]. Thirty seven patients were assigned 1:1 to either the endothelial interventional group (n = 17) or placebo group (n = 20) and received their corresponding medications for 14 days. They were followed for an additional 14 days (28 days total) in hospital or as outpatients to observe outcomes. In the interventional group, participants were given 40 mg atorvastatin daily (unless previously on a statin, in which case they continued their current regimen), folic acid 5 mg daily, L-arginine 1 g thrice daily, nicorandil 10 mg twice daily, and nebivolol 2.5 or 5.0 mg once daily, depending on each patient’s heart rate upon enrollment. The primary outcome was duration until recovery, measured by WHO-OSCI, and secondary outcomes were all-cause mortality, ICU admission, and need for invasive mechanical ventilation. There was no significant association found between the combination drug and median recovery time (P = 0.854), ICU admission, or need for mechanical ventilation (P = 0.644). Furthermore, no deaths were observed in either study group during the 28-day follow up period.

3.3 Ongoing trials

The phase III COVID-STAT is a single-center, double-blinded, RCT in Egypt that is expected to enroll 220 participants who are hospitalized for COVID-19 [65]. The trial will compare the efficacy of atorvastatin 40 mg orally for a maximum of 28 days with a placebo control arm. The main goal is to analyze all-cause mortality data of atorvastatin therapy after 28 days and 6 months from initial randomization.

Another phase III RCT, NAAC, is an open-label study in India that is measuring the efficacy of a new combination drug therapy consisting of aspirin, atorvastatin, and nicorandil in moderate–severe cases of COVID-19 [66]. Progression of In-hospital mortality, length of hospital stay, (invasive and non-invasive) mechanical ventilation, ARDS, thrombotic and cardiac events, and acute kidney injury are all parameters that define primary outcomes for this study.

More recently, COLSTAT is a phase III open-label, multicenter trial conducted by Yale University that aims to evaluate the effect of colchicine/rosuvastatin combination therapy in hospitalized COVID-19 patients [67]. 1:1 randomization will be used to assign 466 patients to an interventional group, to receive combination therapy in addition to SOC, or conventional group, to receive solely standard therapy. Patients in the interventional group will be administered rosuvastatin 40 mg daily and a loading dose of 0.6 mg colchicine twice daily for 3 days, after which they will continue on a maintenance dose of 0.6 mg colchicine daily for the duration of hospitalization or 30 days. Progression to severe COVID-19 as defined by WHO-OSCI 5–8 and arterial and/or venous thromboembolic complications are the primary outcomes to be studied. Other outcomes include 30-day composite of death, respiratory failure requiring intubation, and myocardial injury.

In Côte d’Ivoire, an ongoing phase IIb open-label RCT (INTENSE-COV) is studying the benefits of using atorvastatin and telmisartan in combination with antiviral treatment, lopinavir/ritonavir to reduce viral load from the patient’s body and thereby improve clinical outcomes [68]. The three arms include SOC (lopinavir/ritonavir 200/50 mg for 10 days), lopinavir/ritonavir 200/50 mg plus telmisartan 40 mg for 10 days, and lopinavir/ritonavir 200/50 mg plus atorvastatin 20 mg for 10 days. Outcome measures will be evaluated on serum levels of C-reactive protein and detection of SARS-CoV-2 virus on PCR from a nasopharyngeal swab. Clinical improvement based on WHO-OSCI, hospital duration, oxygen supplementation, endothelial activation markers, death rates, and adverse effects will also be indicated.

STATCO19, is a phase II single-center, open-label RCT in Cambridge, Massachusetts with 300 participants that aims to compare atorvastatin 40 mg orally for 30 days (plus SOC) against SOC in hospitalized patients with COVID-19 disease [69]. The primary outcome is the portion of patients who will progress to severe or critical status requiring ICU admission and/or emergency salvage therapy, or death, as measured by scores 5–8 according to the WHO-OSCI. Secondary measurements will include clinical outcomes on day 7 and 30 and also proportions of patients who test negative on day 7 based on PCR.

Ruxo-Sim-20 RCT is another phase II single-center study that is expected to include 94 participants in Madrid, Spain who are hospitalized for COVID-19 [70]. Patients will be divided into two groups: ruxolitinib 10 mg orally for 7 days and then 20 mg for 7 days plus simvastatin 40 mg orally for 14 days and standard of care. The trial aims to evaluate the percentage of patients who develop severe respiratory failure over a course of 7 days, as denoted by scores above 5 on the WHO-OSCI. Other outcomes may include length of ICU and hospitalization times, survival rates at 1, 6, and 12 months, and adverse events to the drug combination.

4. Discussion

To date, most literature that evaluate the initial efficacy of antecedent and inpatient statin therapy on the clinical outcomes of COVID-19 hospitalization have been epidemiological and observational in nature. We recognize that this may introduce several areas of biases, most commonly though short study duration or follow up period, absence of randomization, and small sample size. We attempted to mitigate these factors in this chapter by screening for a comprehensive list of studies with robust designs that were noted to be either of “High” or “Fair” quality on the Newcastle-Ottawa Scale for quality assessment.

Among the 16 observational studies, in-hospital mortality, invasive mechanical intubation, length of hospitalization, and ICU admission were the most common parameters analyzed. Statins were shown to significantly lower mortality rate in seven studies [45, 46, 48, 52, 53, 58, 59], reduce rates of ICU admissions in three studies [46, 47, 53], lower risk of invasive mechanical intubation in two studies [46, 52], and slow progression to death in two studies [49, 53]. However, several other studies revealed no significant benefit to statin use pre- or during hospitalization in improving clinical outcomes. Six studies demonstrated similar mortality data between statin and non-statin users [47, 50, 51, 54, 57, 60]. Three studies revealed no significant difference in incidence of mechanical ventilation [45, 47, 54]. One study found no effect of statin therapy on the duration of hospital stay [50]. Surprisingly, one study even concluded that use of statins may contribute to adverse outcomes by increasing the rate of prolonged hospitalization and invasive ventilation in COVID-19 hospitalized patients [56].

Concerning the gold standard of RCTs, we described the findings from four publications that investigated the role of inpatient statin administration as a therapeutic for COVID-19. These trials were all determined to have “low risk of bias” when entered into the RoB 2.0 algorithm. The RESIST trial tested how statin therapy alone and in combination with aspirin affected clinical deterioration and inflammatory markers. Reportedly, only IL-6 levels significantly benefited from atorvastatin/aspirin conjunctive treatment [61]. The findings of the INSPIRATION/INSPIRATION-S trial showed no significant improvements of atorvastatin therapy in regard to venous or arterial thrombosis, extracorporeal membrane oxygenation, all-cause mortality, or requirement of invasive intubation [62]. Ghafoori et al. compared the standard of care for COVID-19 treatment to the experimental arm of atorvastatin with standard of care. Their results notably demonstrated that statin intervention actually significantly increased duration of hospitalization and pulse rate, as well as reduced likelihood of remission [63]. In another study, MEDIC-LAUMC found no significant improvement in median recovery time, rate of ICU admission, mechanical ventilation, or risk of mortality associated with the administration of a cocktail drug protocol that included nicorandil, L-arginine, folate, nebivolol, and atorvastatin [64]. Overall, there is currently little to no existing evidence from existing clinical trials that statin treatment has any benefit in preventing adverse clinical outcomes of COVID-19, and in one instance, it even contributed to worsened outcomes.

Finally, we reviewed ongoing clinical trials to assess future evidence impacting the use of statins in COVID-19. Of the six interventional studies described, three were in stage III [65, 66, 67], one was in stage IIb [68], and two were in stage II [69, 70]. Upon extensive search on the WHO International Clinical Trials Registry, ClinicalTrials.gov, and the NIH Clinical Center, no trials belonging to stage IV have been declared. Most prospective trials have been focused on testing the efficacy of statins as adjunctive therapy rather than a primary treatment option. Only two studies, COVID-STAT and STATCO19, are evaluating clinical outcomes associated with statin therapy alone (with standard of care) [65, 69]. Similar to published clinical trials, primary outcomes included parameters such as all-cause mortality data, ICU admission rates, intubation incidence, and progression of disease. Secondary outcomes were more concerned about serum levels, oxygen requirements, adverse effects, acute kidney injuries, and myocardial stress. While the gap in knowledge between COVID-19 treatments has certainly narrowed since the beginning of the pandemic, the therapeutic role of statins is not yet clear. There are still many questions regarding the efficacy of statins, especially on newer strains of SARS-CoV-2 like Omicron (B.1.1.529) or on post-COVID-19 syndrome. Other areas of investigation might also include a comprehensive assessment of lipophilic versus hydrophilic statins on treatment of COVID-19.

5. Conclusion

Statin drugs used alone or as adjuvant treatment for patients hospitalized with COVID-19 have revealed significantly marginal to inconclusive differences in clinical outcomes following review of multiple observational studies and clinical trials to date. Findings from forthcoming literature may provide robust evidence to further support this conclusion.

Conflict of interest

All authors have no disclosures or conflicts of interest.