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

Abstract

ObjectiveTo review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate 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 with 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 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.ResultsWe 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).ConclusionsThere 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.

Association of ACE inhibitors and angiotensin type II blockers with ACE2 overexpression in COVID-19 comorbidities: A pathway-based analytical study

“…Similarly, higher expression of ACE2 was also found among the Insulin administered animal models. Miller HD, et al has described the relationship between ACE2 upregulation and administration of glucagon-like peptide 1 (GLP) agonist or dipeptidyl peptidase-4 (DPP) inhibitors to treat diabetes ( Dambha-Miller et al 2020 ). Further, type 2 antidiabetic drug thiazolidinedione was also reported to up-regulate ACE2 expression In vivo and In vitro models ( Dambha-Miller et al 2020 ).…”

“…Miller HD, et al has described the relationship between ACE2 upregulation and administration of glucagon-like peptide 1 (GLP) agonist or dipeptidyl peptidase-4 (DPP) inhibitors to treat diabetes ( Dambha-Miller et al 2020 ). Further, type 2 antidiabetic drug thiazolidinedione was also reported to up-regulate ACE2 expression In vivo and In vitro models ( Dambha-Miller et al 2020 ). Thiazolidinediones improve vasodilation in diabetic patients by regulating the signaling cascade linking peroxisome proliferator-activated receptor-gamma ( ) and Renin-Angiotensin System ( Sarafidis et al 2004 ; Pal and Bhadada, 2020 ).…”

From Angiotensin II to Cyclic Peptides and Angiotensin Receptor Blockers (ARBs): Perspectives of ARBs in COVID-19 Therapy

“…The ACE2 enzyme has been identified to be the binding site of SARS-CoV-2 virus and controversy rose if the RAS system could be a therapeutic target, as an option to treat the disease by blocking the binding [ 14 ]. Recent findings have shown that ARBs have protective effects in hypertensive patients infected by SARS-CoV-2 [ 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. This article elaborates on the mechanism which triggers the hypertensive activity of angiotensin II and on the idea of considering ARBs as a tentative treatment for SARS-CoV-2 infections.…”

“…The in silico studies suggest that losartan and ARBs are a promising COVID-19 treatment. Previous clinical studies indicate a safe and protective role of the RAS inhibitors [ 57 , 58 ].…”

Some Questions to Our Chinese Colleagues Pioneering Research Into Coronavirus Disease 2019 (COVID-19)

“…Data about medication before hospital admission are lacking, thus no information can be obtained whether specific drugs render the patients more prone to a severe course of the disease. This issue, relating angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins has been extensively discussed in the meantime (13,14).…”