Download PDF
Semin Thromb Hemost 2021; 47(04): 392-399
DOI: 10.1055/s-0040-1722307
Review Article

Protective Effects of Statins Administration in European and North American Patients Infected with COVID-19: A Meta-Analysis

Diletta Onorato   *
1   Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
,
Mairi Pucci‡   *
1   Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
,
Giovanni Carpene
1   Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
,
Brandon Michael Henry
2   Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Ohio
,
Fabian Sanchis-Gomar
3   Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain
4   INCLIVA Biomedical Research Institute, Valencia, Spain
,
Giuseppe Lippi
1   Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

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.

Keywords

statins - coronavirus disease - COVID-19 - meta-analysis

* Mairi Pucci and Diletta Onorato contributed equally to this work.




Publication History

Article published online:
22 January 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Satija N, Lal SK. The molecular biology of SARS coronavirus. Ann N Y Acad Sci 2007; 1102: 26-38
    CrossrefPubMedGoogle Scholar
  • 2 Mackay IM, Arden KE. MERS coronavirus: diagnostics, epidemiology and transmission. Virol J 2015; 12: 222
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 4 Weiss SR, Leibowitz JL. Coronavirus pathogenesis. Adv Virus Res 2011; 81: 85-164
    Google Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 20 Gil C, Ginex T, Maestro I. et al. COVID-19: drug targets and potential treatments. J Med Chem 2020; 63 (21) 12359-12386
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 24 Zeiser R. Immune modulatory effects of statins. Immunology 2018; 154 (01) 69-75
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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; 63 (05) 702-703
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 34 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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; 136: 149-155
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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; 108 (06) 1185-1194
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 48 McMullan BJ, Mostaghim M. Prescribing azithromycin. Aust Prescr 2015; 38 (03) 87-89
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 53 Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017; 377 (06) 562-572
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 58 Karalis DG. Are statins safe in patients with COVID-19?. J Clin Lipidol 2020; 14 (04) 396-397
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 61 Lorizate M, Kräusslich HG. Role of lipids in virus replication. Cold Spring Harb Perspect Biol 2011; 3 (10) a004820
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar