ABSTRACT
OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.
Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Calcium Channel Blockers/pharmacology , Coronavirus Infections , Estrogens/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Pandemics , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral , Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Betacoronavirus/metabolism , COVID-19 , Down-Regulation , Glucagon-Like Peptide 1/agonists , Humans , Insulin/pharmacology , Mineralocorticoid Receptor Antagonists/pharmacology , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Thiazolidinediones/pharmacology , United Kingdom , Up-RegulationABSTRACT
BACKGROUND: The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs that up- or down-regulate ACE2 expression are, therefore, of critical research interest as agents that might promote or reduce risk of COVID-19 infection in a susceptible population. AIM: To collate evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2, and thus potentially affect COVID-19 infection. DESIGN & SETTING: Systematic review of studies published in MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library, and Web of Science from inception to 1 April 2020. METHOD: A systematic review will be conducted in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Inclusion criteria will be: (1) assesses the effect of drug exposure on ACE2 level of expression or activity; (2) the drug is included in the British National Formulary (BNF) and, therefore, available to prescribe in the UK; and (3) a control, placebo, or sham group is included as comparator. Exclusion criteria will be: (1) ACE2 measurement in utero; (2) ACE2 measurement in children aged <18 years; (3) drug not in the BNF; and (4) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool for animal studies. RESULTS: Data will be reported in summary tables and narrative synthesis. CONCLUSION: This systematic review will identify drug therapies that may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.