One of the indirect effects of the pandemic is that some people have stopped taking preventive measures aimed at combatting chronic diseases or maintaining general health, and this has been the case with statins. “Some health professionals have even advised their withdrawal in the belief that they could worsen the effects of COVID-19,” said Masana.
NOVEMBER 4, 2020
Ongoing treatment with statins reduces COVID-19 mortality by 22% to 25%
by Universitat Rovira i Virgili
One of the treatments that have been discussed in regard to their role in the evolution of COVID-19 has been statins. These drugs help to reduce cholesterol in the blood and thus prevent cardiovascular diseases. They are currently taken by one in four people and are the most widely used medicine among the general public. Now, research by the Universitat Rovira i Virgili (URV) and Pere Virgili Institut (IISPV) led by Lluís Masana has found that people who are being treated with statins have a 22% to 25% lower risk of dying from COVID-19. The research results have been published in the European Heart Journal—Cardiovascular Pharmacotherapy.
The study was carried out through the Network of Lipid and Arteriosclerosis Units of Catalonia and collected information from 2,159 patients infected with SARS-COv-2 from 19 hospitals in Catalonia during the first wave of the pandemic from March to May. The researchers evaluated one hundred clinical variables per patient such as age, sex, previous illnesses, cholesterol levels, evolution of the virus, treatments used for COVID-19, and so on. The researchers then compared death rates of patients being treated with statins with death rates among those who were not and they also analyzed the effect of withdrawing statins when the patient was admitted to hospital.
“In our comparison, we adjusted the groups so that they were comparable in terms of age, sex and the existence of earlier illnesses,” explained Masana, who has coordinated the study from the Lipid and Arteriosclerosis Research Unit at the URV’s Department of Medicine and Surgery, which is a member of the CIBERDEM Network bringing together research groups working on diabetes and metabolism in Spain. Masana is also a researcher at the Sant Joan University Hospital in Reus.
The percentage of patients who died in the group not treated with statins was 25.4%, whereas it was 19.8% among those who were, which is to say, the treatment group had 22% lower mortality. “The data indicate that treatment with statins prevents one in five deaths,” indicated Masana. Furthermore, if treatment with this medicine continued during hospitalization, mortality fell by up to 25%, thus preventing one in four deaths.
Consequently, Lluís Masana went on to say that “not only do these findings demonstrate that treatment with statins has no negative on the evolution of COVID-19, they also show that it significantly reduces patient mortality.”
One of the indirect effects of the pandemic is that some people have stopped taking preventive measures aimed at combatting chronic diseases or maintaining general health, and this has been the case with statins. “Some health professionals have even advised their withdrawal in the belief that they could worsen the effects of COVID-19,” said Masana. In this regard, in addition the virus to directly causing death in some patients, complications and overall mortality can increase due to the withdrawal of these drugs and regular monitoring of the use of this medicine. “In the case of statins, we have demonstrated that fear of the pandemic should never be used as an excuse to suspend treatment,” concluded the researcher.
Although the research was never intended to demonstrate that administering statins to COVID-19 patients would reduce the risk of death, it does open the way for studies that may confirm this finding.
Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19
Nature Communications volume 12, Article number: 1325 (2021) Cite this article
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The coronavirus disease 2019 (COVID-19) can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections, but their benefit has not been assessed in COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1st through May 12th, 2020 with study period ending on June 11th, 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline sociodemographic and clinical characteristics, and outpatient medications. The primary endpoint includes in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use is significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.47, 95% CI 0.36–0.62, p < 0.001). We conclude that antecedent statin use in patients hospitalized with COVID-19 is associated with lower inpatient mortality.
There are many potential explanations as to how statins may have contributed to lower 30-day in-hospital mortality in our cohort, despite high prevalence of cardiovascular comorbidities in patients with antecedent statin use. Statins, which target HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, confer a significant mortality benefit in patients with atherosclerotic cardiovascular disease5,26,27, who are overrepresented in hospitalized patients with COVID-19. In addition to hyperlipidemia and other cardiovascular risk factors, inflammation has been identified as a key modulator of atherogenesis and can contribute to adverse cardiovascular events5,28,29. The potential benefits from statins extend beyond cholesterol-lowering properties, as there is a robust literature supporting the anti-inflammatory properties of statins in the preclinical and clinical arenas, suggesting that these drugs can stabilize and restore endothelial function, and lower rates of circulating inflammatory biomarkers such as CRP5,30. In this regard, patients receiving statins presented with significantly lower CRP levels in this cohort compared with those who were not on statins.
Plaque stabilization31,32 and antithrombotic properties33 are also favorable characteristics of this class of drugs. It has previously been demonstrated in several series of COVID-19 patients that pre-existing cardiovascular disease is associated with risk for clinical decompensation and severe disease13,34. Therefore, it is conceivable that antecedent statin use may confer benefit by preventing myocardial injury and infarction as well as thrombotic events, both of which may have influenced mortality and endotracheal intubation rates.
Other mechanisms, which may explain the effects of statin use in patients with COVID-19, have also been suggested. Functional membrane microdomains or lipid rafts consist of cholesterol and sphingolipids9,10,11, and viruses may gain entry to cells via receptors which are concentrated in these regions of the plasma membrane12. Thus, it has been theorized that statin-mediated reduction in cholesterol levels may sufficiently alter the makeup of these lipid rafts12, potentially preventing or reducing likelihood for viral infection or replication, and hence disease severity. Though lipid levels were not available for our entire cohort, we did find lower levels of total cholesterol and low-density lipoprotein in statin users. In addition, a recent computational docking analysis was performed to assess the interaction between an important SARS-CoV-2 protease (Mpro)35 and statins36. Interestingly, these authors found that several statins demonstrated stronger interactions with Mpro than some protease inhibitors, implicating a potential mechanism by which statins may be able to interfere with SARS-CoV-2 replication. Preclinical evidence suggests that statins (as with ACEi and ARBs) can contribute to increased ACE2 expression and epigenetic modification37. As ACE2 serves as the entry point for SARS-CoV-2 to human hosts, it remains to be completely understood how the modulation and modification of ACE2 levels may impact viral replication and infectivity.
Statin use is associated with lower disease severity in COVID-19 infection
Scientific Reports volume 10, Article number: 17458 (2020) Cite this article
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We aim to study the association of hyperlipidemia and statin use with COVID-19 severity. We analysed a retrospective cohort of 717 patients admitted to a tertiary centre in Singapore for COVID-19 infection. Clinical outcomes of interest were oxygen saturation ≤ 94% requiring supplemental oxygen, intensive-care unit (ICU) admission, invasive mechanical-ventilation and death. Patients on long term dyslipidaemia medications (statins, fibrates or ezetimibe) were considered to have dyslipidaemia. Logistic regression models were used to study the association between dyslipidaemia and clinical outcomes adjusted for age, gender and ethnicity. Statin treatment effect was determined, in a nested case–control design, through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical significance was taken as p < 0.05. One hundred fifty-six (21.8%) patients had dyslipidaemia and 97% of these were on statins. Logistic treatment models showed a lower chance of ICU admission for statin users when compared to non-statin users (ATET: Coeff (risk difference): − 0.12 (− 0.23, − 0.01); p = 0.028). There were no other significant differences in other outcomes. Statin use was independently associated with lower ICU admission. This supports current practice to continue prescription of statins in COVID-19 patients.
The COVID-19 pandemic continues to grow around the world, with more than 20 million cases worldwide1. The coronavirus infections, COVID-19, SARS and MERS, are all associated with dysregulated immune and inflammatory processes. Severe cases of COVID-19 are characterised by high circulating pro-inflammatory cytokines concentrations, as well as high neutrophil counts and lymphopenia2,3,4. COVID-19 has been associated with hyperinflammatory states, cardiovascular disease and venous thromboembolism5,6,7.
Inflammation has a potential role in the pathogenesis of dyslipidaemia8. Statins are commonly used to treat hyperlipidemia and its pleiotropic effects have been shown to reduce cytokines in various non-infective conditions9,10. Long term statin therapy correlates with better outcome in the setting of bacterial pneumonia11,12 and influenza13. A randomised controlled trial evaluating atorvastatin as a treatment for influenza showed significantly lower levels of inflammatory cytokines with treatment [NCT02056340].
Medical comorbidities such as diabetes, hypertension and cardiovascular diseases have been identified as risk factors for severe COVID-19 in numerous large case series from China, Italy and the United States14,15,16. Dyslipidaemia has not been identified as an independent risk factor17, although it is associated with diabetes and hypertension, and contributes to cardiovascular diseases. We aimed to study the association of dyslipidaemia with COVID-19 associated inflammation and the correlation between long term statin therapy and disease severity.
Within our cohort of 717 patients, one hundred fifty-six (21.8%) patients had dyslipidaemia. Individuals with dyslipidaemia were older (62.5 years, IQR 55–68 years versus 37 years, IQR 27–52 years) and more likely to be of Malay ethnicity (18.6% versus 8.9%). Approximately 24–59% of patients had coexisting diabetes, hypertension and atherosclerotic cardiovascular disease defined as history of ischemic heart disease, stroke or peripheral vascular disease. In terms of inflammatory markers, those with dyslipidaemia were more likely to have higher CRP, LDH, procalcitonin, white cell count and neutrophil count but lower lymphocyte count. Patients with dyslipidaemia were more likely to require supplemental oxygen, ICU admission and IMV. The risk of death was higher (p < 0.05). See Tables 1 and 2.
We found that statins was associated with better outcomes in COVID-19. Similar results have been reported from a large study from Hubei province, China wherein they found that statin use was associated with a lower risk of mortality in COVID-19 infections20. In another retrospective study, atorvastatin also associated with a lower risk of death in COVID-19 patients admitted to the intensive care unit21. In a study involving nursing home residents, statin use was associated with higher chances of asymptomatic infection22.
Lipids and cholesterol-rich membrane microdomains facilitates the interaction between the surface glycoprotein S of SARS-CoV and the cellular receptor angiotensin-converting enzyme 2 (ACE2)23. Cholesterol has been implicated to have a possible role in the increased risk of infection in the elderly patients wherein higher tissue cholesterol has been shown to increase the endocytic entry of SARS-CoV-2 along with increased trafficking of angiotensin converting enzyme-2 (ACE-2) in a preprint24. After cellular entry, RNA viruses require intracellular cholesterol and fatty acids for further replication. For e.g. it has been demonstrated that during the initial phase of dengue virus infection, there is an increase in intracellular cholesterol concentration. This is associated with an increase in low density lipoprotein (LDL) concentrations in cells and a concomitant increase in the enzymatic activity of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inside the cells25,26. Three decades ago, Mabuchi et al., reported that statins can effectively reduce LDL concentrations through HMG-CoA reductase inhibition27 and in the last three decades statins have become the most widely prescribed lipid lowering medication. In COVID-19, statins may help to reduce viral entry and viral transmission by inhibition of the HMG-CoA reductase in the cells which will make less cholesterol available inside cells and tissues.
In our small observational cohort, we observed a significant trend towards higher white cell counts and neutrophil counts in patients with dyslipidaemia. A key pathological process that leads to cardiovascular disease is inflammation. Statins have been shown to have significant pleiotropic, anti-inflammatory and immunomodulatory effects28,29,30,31,32,33,34,35,36, independent of its ability to reduce low-density lipoprotein36. Even in rheumatological disease statins are known to modulate the inflammatory response37. Additional to its beneficial effects in cardiovascular disease, statins may be beneficial in patients with bacterial sepsis38,39, community acquired pneumonia40 and influenza13. Severe outcomes in COVID-19 is associated with higher markers of inflammation and a “cytokine storm”41,42,43. Statins have the potential to block the molecular mechanisms, including NF-κB and NLRP3 inflammasomes and TLR signalling which are responsible for the “cytokine storm” in severe COVID-19 patients44,45,46.
We found dyslipidaemia patients had a significant trend towards a higher innate immune response shown by higher white cell counts and neutrophil counts. Statin use was independently associated with lower requirement for ICU admission. This supports current practice to continue prescription of statins in hyperlipidemia and other metabolic disorders in COVID-19 patients. The effect of statin use and intensification on COVID-19 disease severity and atherosclerotic events after recovery needs to be studied in larger observational studies or ideally in randomised controlled trials.