Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients
Tóm tắt
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients. After initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93), P = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72), P = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61–2.99), P = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07–2.33), P = 0.312]. Although we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19.
Tài liệu tham khảo
Drozdzal S, et al. FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy. Drug Resist Updat. 2020;53:100719.
Sureda A, et al. Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management? Eur J Pharmacol. 2020;882:173288.
Shojaei S, et al. Autophagy and SARS-CoV-2 infection: a possible smart targeting of the autophagy pathway. Virulence. 2020;11(1):805–10.
Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
Organization, W.H. Clinical management of severe acute respiratory infection when novel coronavirus (NCoV) infection is suspected. Geneva: WHO; 2020.
Rello J, et al. Clinical phenotypes of SARS-CoV-2: implications for clinicians and researchers. Eur Respir J. 2020;55(5):2001028.
Varga Z, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8.
Gavriilaki E, Brodsky RA. Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily. Br J Haematol. 2020;189(6):e227–30.
Tang N, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844–7.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–42.
Lee KCH, Sewa DW, Phua GC. Potential role of statins in COVID-19. Int J Infect Dis. 2020;96:615–7.
Subir R, Jagat JM, Kalyan KG. Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19). Diabetes Metab Syndr. 2020;14(5):1225–9.
Rizk JG, et al. Pharmaco-Immunomodulatory therapy in COVID-19. Drugs. 2020;80(13):1267–92.
Zhang XJ, et al. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab. 2020;32(2):176–87 e4.
Adhyaru BB, Jacobson TA. Safety and efficacy of statin therapy. Nat Rev Cardiol. 2018;15(12):757–69.
Dastghaib S, et al. Simvastatin induces unfolded protein response and enhances temozolomide-induced cell death in glioblastoma cells. Cells. 2020;9(11):2339.
Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160–4.
Lim S, et al. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol. 2013;167(5):1696–702.
Schneider MP, et al. Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels. J Hypertens. 2011;29(9):1757–64.
Katsiki N, Mikhailidis DP, Banach M. Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels. J Hypertens. 2011;29(12):2493–4 author reply 2494.
Zhang L, et al. Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus. Atherosclerosis. 2012;223(1):78–85.
Adel A, Abdel-Salam Z, Nammas W. Low-dose statin therapy improves endothelial function in type 2 diabetic patients with normal serum total cholesterol: a randomized placebo-controlled study. J Clin Hypertens. 2010;12(10):820–5.
Yang B, et al. Statin ameliorates endothelial dysfunction and insulin resistance in Tibet women with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci. 2016;20(6):1185–91.
Nakamura T, et al. Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease. J Cardiol. 2020;75(3):270–4.
Zhu Z, Fang Z. Statin protects endothelial cell against ischemia reperfusion injury through HMGB1/TLR4 pathway. Int J Cardiol. 2016;203:74.
Li P, et al. Inhibition of aberrant MicroRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP Cyclohydrolase 1 in vivo. Circulation. 2016;134(22):1752–65.
Cerda A, et al. Role of microRNAs 221/222 on statin induced nitric oxide release in human endothelial cells. Arq Bras Cardiol. 2015;104(3):195–201.
Ali F, et al. Statin-mediated cytoprotection of human vascular endothelial cells: a role for Kruppel-like factor 2-dependent induction of heme oxygenase-1. J Thromb Haemost. 2007;5(12):2537–46.
Momin A, et al. The association between saphenous vein endothelial function, systemic inflammation, and statin therapy in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2007;134(2):335–41.
Ahmadi M, et al. Pleiotropic effects of statins: a focus on cancer. Biochim Biophys Acta Mol basis Dis. 1866;2020(12):165968.
Han F, et al. Atorvastatin ameliorates LPS-induced inflammatory response by autophagy via AKT/mTOR signaling pathway. J Cell Biochem. 2018;119(2):1604–15.
Peng S, et al. Atorvastatin inhibits inflammatory response, attenuates lipid deposition, and improves the stability of vulnerable atherosclerotic plaques by modulating autophagy. Front Pharmacol. 2018;9:438.
Gu W, et al. Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma. Respirology. 2017;22(3):533–41.
Simpson S, et al. Radiological Society of North America Expert Consensus statement on reporting chest CT findings related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA. Radiology. 2020;2(2):e200152.
Kleinbaum DG, Klein M. Survival analysis. Berlin: Springer; 2010.
Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Philadelphia: LWW; 2000.
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41–55.
Rubin DB. Multiple imputation for nonresponse in surveys, vol. 81. Hoboken: Wiley; 2004.
Hariyanto TI, Kurniawan A. Statin therapy did not improve the in-hospital outcome of coronavirus disease 2019 (COVID-19) infection. Diabetes Metab Syndr. 2020;14(6):1613–5.
Yang D, et al. COVID-19 & chronic renal disease: clinical characteristics & prognosis. QJM. 2020. https://doi.org/10.1093/qjmed/hcaa258.
Saeed O, et al. Statin use and in-hospital mortality in diabetics with COVID-19. J Am Heart Assoc. 2020:e018475.
Tan WYT, et al. Statin use is associated with lower disease severity in COVID-19 infection. Sci Rep. 2020;10(1):17458.
Song SL, et al. Statin use is associated with decreased risk of invasive mechanical ventilation in COVID-19 patients: a preliminary study. Pathogens. 2020;9(9):759.
Urbach D, et al. Associations of medications with lower odds of typical COVID-19 symptoms: cross-sectional symptom surveillance study. JMIR Public Health Surveill. 2020;6(4):e22521.
Mitacchione G, et al. Impact of prior statin use on clinical outcomes in COVID-19 patients: data from tertiary referral hospitals during COVID-19 pandemic in Italy. J Clin Lipidol. 2020. https://doi.org/10.1016/j.jacl.2020.12.008.
Butt JH, et al. Association between statin use and outcomes in patients with coronavirus disease 2019 (COVID-19): a nationwide cohort study. BMJ Open. 2020;10(12):e044421.
Van De Garde EM, et al. Statin treatment and reduced risk of pneumonia in patients with diabetes. Thorax. 2006;61(11):957–61.
Khurana VBH, Caldito G, Owens MW. Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans. Chest. 2007;131:1282–8.
Jacobson JR, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005;288(32–36):L1026–32.
Golomb BA, et al. Reduction in blood pressure with statins: results from the UCSD statin study, a randomized trial. Arch Intern Med. 2008;168(7):721–7.
Furberg CD. Natural statins and stroke risk. Circulation. 1999;99(2):185–8.
Feldman C. The role of statins in respiratory diseases. Clin Pulm Med. 2009;16(2):95–100.
Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.
Terblanche M, Smith TS, Adhikari NKJ. Statins, bugs and prophylaxis: intriguing possibilities. Crit Care. 2006;10(5):168.
Terblanche M, et al. Statins and sepsis: multiple modifications at multiple levels. Lancet Infect Dis. 2007;7(5):358–68.
Mehrbod P, et al. Evaluation of antiviral effect of atorvastatin on H1N1 infection in MDCK cells. Afr J Microbiol Res. 2012;6(27):5715–9.
Mehrbod P, et al. Simvastatin modulates cellular components in influenza a virus-infected cells. Int J Mol Med. 2014;34(1):61–73.
Kwong JC, Li P, Redelmeier DA. Influenza morbidity and mortality in elderly patients receiving statins: a cohort study. PLoS One. 2009;4(11):e8087.
Vandermeer ML, et al. Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study. J Infect Dis. 2012;205(1):13–9.
Inoue I, et al. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of mRNA levels for interleukin-1, interleukin-6, cyclooxygenase- 2 and p22phox by regulation of peroxisome proliferator-activated receptor (PPAR) in primary endothelial cells. Life Sci. 2000;67(8):863–76.
Mehrbod P, et al. Statins reduce the expression of proinflammatory cytokines in influenza A virus infected CrFK cells. Acta Virol. 2012;56(4):353–5.
Lee CS, et al. Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic-polycytidylic acid-induced pneumonia. Eur Respir J. 2013;41(5):1147–56.
Yuan S. Statins may decrease the fatality rate of Middle East Respiratory Syndrome infection. mBio. 2015;6(4):e01120–15.
Virani SS. Is there a role for statin therapy in acute viral infections? Cardiology Magazine. Washington, DC: American College of Cardiology; 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19
Reiner Ž, et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch Med Sci. 2020;16(3):490–6.
Moeller R, et al. Effect of statins on SARS-CoV-2 infection. medRxiv. 2020;20152272.
Mehrbod P, et al. The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections. Virulence. 2019;10(1):376–413.
Yeganeh B, et al. Autophagy activation is required for influenza A virus-induced apoptosis and replication. Biochim Biophys Acta, Mol Cell Res. 2018;1865(2):364–78.
Zeki AA, Kenyon NJ, Goldkorn T. Statin drugs, metabolic pathways, and asthma: a therapeutic opportunity needing further research. Drug Metab Lett. 2011;5(1):40–4.
Thong L, MacSharry J, Murphy DM. The effects of statin therapy on the human airway. Drug Metab Lett. 2016;10(2):75–82.
Ghavami S, et al. Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53. PLoS One. 2011;6(1):e16523.
Ghavami S, et al. Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins. Biochim Biophys Acta. 2014;1843(7):1259–71.
Qin XT, et al. Effect of atorvastatin on ACE2 expression in pressure overload induced cardiac hypertrophy in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2008;33(5):438–42.
Li YH, et al. Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats. J Geriatr Cardiol. 2013;10(2):151–8.
Suski M, et al. Influence of atorvastatin on angiotensin I metabolism in resting and TNF-α -activated rat vascular smooth muscle cells. J Renin-Angiotensin-Aldosterone Syst. 2014;15(4):378–83.
Tikoo K, et al. Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem Pharmacol. 2015;93(3):343–51.
Warner FJ, et al. Angiotensin converting enzyme-2 (ACE2) and its possible roles in hypertension, diabetes and cardiac function. Lett Pept Sci. 2003;10(5):377–85.
Aguilar C, F Ventura, L Rodríguez-Delfín. [Atorvastatin induced increase in homologous angiotensin I converting enzyme (ACE2) mRNA is associated to decreased fibrosis and decreased left ventricular hypertrophy in a rat model of diabetic cardiomyopathy]. Rev Peru Med Exp Salud Publica. 2011;28(2):264–72.
Shin YH, et al. The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts. Heart Vessel. 2017;32(5):618–27.
Min JJ, et al. Effects of pravastatin on type 1 diabetic rat heart with or without blood glycemic control. J Diabetes Res. 2018;2018:1067853.
Schaafsma D, et al. Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts. Respir Res. 2011;12(1):113.
Schaafsma D, et al. The mevalonate cascade as a target to suppress extracellular matrix synthesis by human airway smooth muscle. Am J Respir Cell Mol Biol. 2011;44(3):394–403.
Kreuter M, et al. Statin therapy and outcomes in trials of nintedanib in idiopathic pulmonary fibrosis. Respiration. 2018;95(5):317–26.
Kreuter M, et al. Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis. Thorax. 2017;72(2):148–53.
Vedel-Krogh S, Nielsen SF, Nordestgaard BG. Statin use is associated with reduced mortality in patients with interstitial lung disease. PLoS One. 2015;10(10):e0140571.