Currently prescribed drugs in the UK that could up or downregulate ACE2 in COVID-19 disease: A systematic review

ABSTRACT

ObjectiveTo review evidence on routinely prescribed drugs in the UK that could up or downregulate Angiotensin Converting Enzyme 2 (ACE2) and potentially affect COVID-19 disease DesignSystematic review Data sourceMEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science Study selectionAny design with animal or human models examining a currently prescribed UK drug compared to a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. Data extraction and synthesisMEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1st April 2020. Methodological quality was assessed using the SYRCLEs risk of bias tool for animal studies and Cochrane risk of bias tool for human studies. ResultsWe screened 3,360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and 102 were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were Angiotensin Receptor Blockers (ARBs) (n= 55) and Angiotensin-Converting Enzyme-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) GLP-1 agonists (n=2) and NSAIDs (n=2). ConclusionsThere is an abundance of 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 amongst 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. O_LSTStrengths and limitationsC_LSTO_LIThis review addresses a high priority patient and clinician concern C_LIO_LIGiven the limited evidence on the subject, we included human and animal models both in vivo and in vitro for a comprehensive review C_LIO_LIThis is the first systematic review specifically focussed on UK prescribed drugs that could alter ACE2 in COVID-19 disease C_LIO_LIThe heterogeneity across study designs and models meant meta-analysis was not suitable C_LIO_LIGiven the rapidly changing evidence as the pandemic progresses, it is possible that new studies have since been published. C_LI