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

Abstract

Objective: To 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 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 to 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 1st April 2020. Methodological quality was assessed using the SYRCLE's risk of bias tool for animal studies and Cochrane risk of bias tool for human studies. Results: We 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). Conclusions: There 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.

Covid-19 and Diabetes: A Complex Bidirectional Relationship

“…As an example, it has been shown recently that Covid-19 infection management with the drug tocilizumab was not optimally achieved during hyperglycaemia in both diabetic and non-diabetic patients. Moreover, preclinical models found an indirect link between ACE2 upregulation and several anti-diabetic drugs ( 65 – 68 ). We discuss here presently used treatments both in the context of diabetic emergencies (such as DKA; see above) and for less acute management of hyperglycemia, where different regimens may be required.…”

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“…However, a better understanding is still needed of the ACE2-receptor contribution to facilitating viral entry into placental cells. [76,84] Passive immunization could be another option, due to its potential for minimizing effects of maternal viral infection in gestational products and in the fetal systemic infl ammatory response. [85] An ideal proposal would involve active immunization of pregnant women, but historically, pregnant and lactating women have not been included in such studies for safety reasons.…”