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

  1. Hajira Dambha-Miller
  2. Ali Albasri
  3. Sam Hodgson
  4. Christopher R Wilcox
  5. Shareen Khan
  6. Nazrul Islam
  7. Paul Little
  8. Simon J Griffin

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Abstract

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.

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  1. Version published to 10.1136/bmjopen-2020-040644
  2. ScreenIT

    SciScore for 10.1101/2020.05.19.20106856: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationHuman studies were evaluated using the Cochrane risk of bias tool which includes the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias.
    BlindingHuman studies were evaluated using the Cochrane risk of bias tool which includes the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Search Strategy: A systematic search in MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science was conducted from inception to the 1st April 2020.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    24,25 Strengths and limitations: We carried out a comprehensive and systematic search of the literature. To our knowledge, this is the first review on the subject. We did not include language restrictions but non-English language studies in the international literature might not have been indexed in the databases we searched. Given the rate of new publications on COVID-19, it is also possible that our search and results may not be up to date. Owing to the limited research on this novel virus, it was necessary to be as inclusive as possible and we therefore considered both animal and human models to look for any drugs acting through ACE2 with potential to affect COVID-19 outcomes. While this inclusive approach may offer insights, the heterogeneity across models makes it hard to interpret findings or translate them directly to patients. Although we were robust in our methodological approach to this review, we were also aware of the urgency to report our findings in the current pandemic. We therefore did not contact authors for more information about their studies beyond what was published. We observed frequent omission of information that would have allowed us to carry out a more detailed quality assessment. Had we pursued this information; the quality assessment of included papers may well have been higher.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.19.20106856v1 on medRxiv