Protective Effects of Statins Administration in European and North American Patients Infected with COVID-19: A Meta-analysis
Severe acute respiratory syndrome coronavirus 2 has spread rapidly throughout the world, becoming an overwhelming global health emergency. The array of injuries caused by this virus is broad and not limited to the respiratory system, but encompassing also extensive endothelial and systemic tissue damage. Since statins effectively improve endothelial function, these drugs may have beneficial effects in patients with coronavirus disease 2019 (COVID-19). Therefore, this investigation aimed to provide an updated overview on the interplay between statins and COVID-19, with particular focus on their potentially protective role against progression toward severe or critical illness and death. A systematic electronic search was performed in Scopus and PubMed up to present time. Data on statins use and COVID-19 outcomes especially in studies performed in Europe and North America were extracted and pooled. A total of seven studies met our inclusion criteria, totaling 2,398 patients (1,075 taking statins, i.e., 44.8%). Overall, statin usage in Western patients hospitalized with COVID-19 was associated with nearly 40% lower odds of progressing toward severe illness or death (odds ratio: 0.59; 95% confidence interval: 0.35–0.99). After excluding studies in which statin therapy was started during hospital admission, the beneficial effect of these drugs was magnified (odds ratio: 0.51; 95% confidence interval: 0.41–0.64). In conclusion, although randomized trials would be necessary to confirm these preliminary findings, current evidence would support a favorable effect of statins as adjuvant therapy in patients with COVID-19. Irrespective of these considerations, suspension of statin therapy seems highly unadvisable in COVID-19 patients.
* Mairi Pucci and Diletta Onorato contributed equally to this work.
22 January 2021 (online)
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- 1 Satija N, Lal SK. The molecular biology of SARS coronavirus. Ann N Y Acad Sci 2007; 1102: 26-38
- 2 Mackay IM, Arden KE. MERS coronavirus: diagnostics, epidemiology and transmission. Virol J 2015; 12: 222
- 3 Zhu N, Zhang D, Wang W. et al; China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382 (08) 727-733
- 4 Weiss SR, Leibowitz JL. Coronavirus pathogenesis. Adv Virus Res 2011; 81: 85-164
- 5 Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 2020; 324 (08) 782-793
- 6 Lippi G, Sanchis-Gomar F, Henry BM. COVID-19: unravelling the clinical progression of nature's virtually perfect biological weapon. Ann Transl Med 2020; 8 (11) 693
- 7 Donoghue M, Hsieh F, Baronas E. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000; 87 (05) E1-E9
- 8 Wrapp D, Wang N, Corbett KS. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367 (6483): 1260-1263
- 9 McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020; 19 (06) 102537
- 10 Conti P, Ronconi G, Caraffa A. et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 2020; 34 (02) 327-331
- 11 Levi M, Thachil J. Coronavirus disease 2019 coagulopathy: disseminated intravascular coagulation and thrombotic microangiopathy-either, neither, or both. Semin Thromb Hemost 2020; 46 (07) 781-784
- 12 Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020; 507: 167-173
- 13 Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020; 46 (07) 763-771
- 14 Thachil J, Srivastava A. SARS-2 coronavirus-associated hemostatic lung abnormality in COVID-19: is it pulmonary thrombosis or pulmonary embolism?. Semin Thromb Hemost 2020; 46 (07) 777-780
- 15 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
- 16 Calabrese F, Pezzuto F, Fortarezza F. et al. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European Pulmonary Pathologists. Virchows Arch 2020; 477 (03) 359-372
- 17 Aggarwal G, Lippi G, Lavie CJ, Henry BM, Sanchis-Gomar F. Diabetes mellitus association with coronavirus disease 2019 (COVID-19) severity and mortality: a pooled analysis. J Diabetes 2020; 12 (11) 851-855
- 18 Aggarwal G, Cheruiyot I, Aggarwal S. et al. Association of cardiovascular disease with coronavirus disease 2019 (COVID-19) severity: a meta-analysis. Curr Probl Cardiol 2020; 45 (08) 100617
- 19 Lippi G, Wong J, Henry BM. Hypertension in patients with coronavirus disease 2019 (COVID-19):: a pooled analysis. Pol Arch Intern Med 2020; 130: 304-309
- 20 Gil C, Ginex T, Maestro I. et al. COVID-19: drug targets and potential treatments. J Med Chem 2020; (e-pub ahead of print) DOI: 10.1021/acs.jmedchem.1020c00606.
- 21 Yuan S, Chan CC, Chik KK. et al. Broad-spectrum host-based antivirals targeting the interferon and lipogenesis pathways as potential treatment options for the pandemic coronavirus disease 2019 (COVID-19). Viruses 2020; 12 (06) 628
- 22 Sanchis-Gomar F, Perez-Quilis C, Favaloro EJ, Lippi G. Statins and other drugs: facing COVID-19 as a vascular disease. Pharmacol Res 2020; 159: 105033
- 23 Beltrán-García J, Osca-Verdegal R, Pallardó FV. et al. Oxidative stress and inflammation in COVID-19-associated sepsis: the potential role of anti-oxidant therapy in avoiding disease progression. Antioxidants 2020; 9 (10) E936
- 24 Zeiser R. Immune modulatory effects of statins. Immunology 2018; 154 (01) 69-75
- 25 Yoon SJ, Yoon YW, Lee BK. et al. Potential role of HMG CoA reductase inhibitor on oxidative stress induced by advanced glycation endproducts in vascular smooth muscle cells of diabetic vasculopathy. Exp Mol Med 2009; 41 (11) 802-811
- 26 Lim S, Sakuma I, Quon MJ, Koh KK. Differential metabolic actions of specific statins: clinical and therapeutic considerations. Antioxid Redox Signal 2014; 20 (08) 1286-1299
- 27 Tikoo K, Patel G, Kumar S. et al. Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem Pharmacol 2015; 93 (03) 343-351
- 28 Wösten-van Asperen RM, Bos AP, Bem RA. et al. Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome. Pediatr Crit Care Med 2013; 14 (09) e438-e441
- 29 Henry BM, Benoit S, Lippi G, Benoit J. Circulating plasma levels of angiotensin II and aldosterone in patients with coronavirus disease 2019 (COVID-19): a preliminary report. Prog Cardiovasc Dis 2020; (e-pub ahead of print) DOI: 10.1016/j.pcad.2020.07.006.
- 30 Ju A, Hanson CS, Banks E. et al. Patient beliefs and attitudes to taking statins: systematic review of qualitative studies. Br J Gen Pract 2018; 68 (671) e408-e419
- 31 Zhao Z, Du S, Shen S. et al. Comparative efficacy and safety of lipid-lowering agents in patients with hypercholesterolemia: a frequentist network meta-analysis. Medicine (Baltimore) 2019; 98 (06) e14400
- 32 Wang B, Van Oekelen O, Mouhieddine TH. et al. A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward. J Hematol Oncol 2020; 13 (01) 94
- 33 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62 (10) 1006-1012
- 34 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
- 35 De Spiegeleer A, Bronselaer A, Teo JT. et al. The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents. J Am Med Dir Assoc 2020; 21 (07) 909.e2-914.e2
- 36 Mestre-Gómez B, Lorente-Ramos RM, Rogado J. et al; Infanta Leonor Thrombosis Research Group. Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis. J Thromb Thrombolysis 2020; (e-pub ahead of print) DOI: 10.1007/s11239-020-02190-9.
- 37 Daniels LB, Sitapati AM, Zhang J. et al. Relation of statin use prior to admission to severity and recovery among COVID-19 inpatients. Am J Cardiol 2020; (e-pub ahead of print) DOI: 10.1016/j.amjcard.2020.09.012.
- 38 Nguyen AB, Upadhyay GA, Chung B. et al. Outcomes and cardiovascular comorbidities in a predominantly African-American population with COVID-19. medRxiv 2020; DOI: 10.1101/2020.06.28.20141929.
- 39 Gupta A, Madhavan MV, Poterucha TJ. et al. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Res Sq 2020; (e-pub ahead of print) DOI: 10.21203/rs.21203.rs-56210/v21201.
- 40 Rodriguez-Nava G, Trelles-Garcia DP, Yanez-Bello MA, Chung CW, Trelles-Garcia VP, Friedman HJ. Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study. Crit Care 2020; 24 (01) 429
- 41 McCarthy CP, Murphy S, Jones-O'Connor M. et al. Early clinical and sociodemographic experience with patients hospitalized with COVID-19 at a large American healthcare system. EClinicalMedicine 2020; 26: 100504
- 42 Zhang XJ, Qin JJ, Cheng X. et al. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab 2020; 32 (02) 176.e4-187.e4
- 43 Yan H, Valdes AM, Vijay A. et al. Role of drugs used for chronic disease management on susceptibility and severity of COVID-19: a large case-control study. Clin Pharmacol Ther 2020; (e-pub ahead of print) DOI: 10.1002/cpt.2047.
- 44 Argenziano MG, Bruce SL, Slater CL. et al. Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series. BMJ 2020; 369: m1996
- 45 Dreher M, Kersten A, Bickenbach J. et al. The characteristics of 50 hospitalized COVID-19 patients with and without ARDS. Dtsch Arztebl Int 2020; 117 (16) 271-278
- 46 Zeng H, Zhang T, He X. et al. Impact of hypertension on progression and prognosis in patients with COVID-19: a retrospective cohort study in 1031 hospitalized cases in Wuhan, China. medRxiv 2020; DOI: 10.1101/2020.06.14.20125997.
- 47 Grasselli G, Greco M, Zanella A. et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med 2020; 180 (10) 1345-1355
- 48 McMullan BJ, Mostaghim M. Prescribing azithromycin. Aust Prescr 2015; 38 (03) 87-89
- 49 Xu Z, Shi L, Wang Y. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8 (04) 420-422
- 50 Ding Y, Wang H, Shen H. et al. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol 2003; 200 (03) 282-289
- 51 Ng DL, Al Hosani F, Keating MK. et al. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. Am J Pathol 2016; 186 (03) 652-658
- 52 Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust 2020; 213 (02) 54.e1-56.e1
- 53 Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017; 377 (06) 562-572
- 54 Wu L, O'Kane AM, Peng H, Bi Y, Motriuk-Smith D, Ren J. SARS-CoV-2 and cardiovascular complications: from molecular mechanisms to pharmaceutical management. Biochem Pharmacol 2020; 178: 114114
- 55 Fogarty H, Townsend L, Ni Cheallaigh C. et al. More on COVID-19 coagulopathy in Caucasian patients. Br J Haematol 2020; 189 (06) 1060-1061
- 56 Gavriilaki E, Brodsky RA. Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily. Br J Haematol 2020; 189 (06) e227-e230
- 57 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
- 58 Karalis DG. Are statins safe in patients with COVID-19?. J Clin Lipidol 2020; 14 (04) 396-397
- 59 Watanabe T, Oku K, Amengual O. et al. Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 2018; 27 (02) 225-234
- 60 Gaertner S, Cordeanu EM, Nouri S, Mirea C, Stephan D. Statins and prevention of venous thromboembolism: myth or reality?. Arch Cardiovasc Dis 2016; 109 (03) 216-222
- 61 Lorizate M, Kräusslich HG. Role of lipids in virus replication. Cold Spring Harb Perspect Biol 2011; 3 (10) a004820
- 62 Glende J, Schwegmann-Wessels C, Al-Falah M. et al. Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2. Virology 2008; 381 (02) 215-221
- 63 Rodrigues-Diez RR, Tejera-Muñoz A, Marquez-Exposito L. et al. Statins: could an old friend help in the fight against COVID-19?. Br J Pharmacol 2020; 177 (21) 4873-4886
- 64 Abu-Farha M, Thanaraj TA, Qaddoumi MG, Hashem A, Abubaker J, Al-Mulla F. The role of lipid metabolism in COVID-19 virus infection and as a drug target. Int J Mol Sci 2020; 21 (10) 3544
- 65 Strandell J, Bate A, Hägg S, Edwards IR. Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction. Br J Clin Pharmacol 2009; 68 (03) 427-434
- 66 Wang G, Zhang Q, Zhao X. et al. Low high-density lipoprotein level is correlated with the severity of COVID-19 patients: an observational study. Lipids Health Dis 2020; 19 (01) 204
- 67 Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des 2012; 18 (11) 1519-1530