Ursodeoxycholic acid and severe COVID-19 outcomes in people with liver disease: a cohort study using the OpenSAFELY platform

Biological evidence suggests ursodeoxycholic acid (UDCA) - a common treatment of cholestatic liver disease - may prevent severe COVID-19 outcomes. With the approval of NHS England, we conducted a population-based cohort study using primary care records, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. We estimated the hazard of COVID-19 hospitalisation or death between 1 March 2020 and 31 December 2022, comparing UDCA treatment to no UDCA treatment in a population with indication. Of 11,320 eligible individuals, 642 were hospitalised or died with COVID-19 during follow-up, 402 (63%) events among UDCA users. After confounder adjustment, UDCA was associated with a 21% (95% CI 7%-33%) relative reduction in the hazard of COVID-19 hospitalisation or death, consistent with an absolute risk reduction of 1.3% (95% CI 1.0%-1.6%). Our findings support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes. ### Competing Interest Statement BG has received research funding from the Bennett Foundation, the Laura and John Arnold Foundation, the NHS National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, NHS England, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI MRC, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme, he is a Non-Executive Director at NHS Digital, he also receives personal income from speaking and writing for lay audiences on the misuse of science. BMK is also employed by NHS England working on medicines policy and clinical lead for primary care medicines data. AM is a member of RCGP health informatics group and the NHS Digital GP data Professional Advisory Group, and received consulting fee from Induction Healthcare. LAT has received research funding from MRC, Wellcome, NIHR and GSK, consulted for Bayer in relation to an observational study of chronic kidney disease (unpaid), and is a member of 4 non-industry funded (NIHR/MRC) trial advisory committees (unpaid) and MHRA Expert advisory group (Womens Health). REC has shares in AstraZeneca. VM received a grant from NIHR. AS is employed by LSHTM on a fellowship sponsored by GSK. JT received an AstraZeneca grant for unrelated COVID-19 research. GFM and RS have received research funding from Intercept Pharmaceuticals and Advanz Pharma. All other authors declare no conflicts of interest. ### Clinical Protocols ### Funding Statement The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z) and MRC (MR/V015737/1, MC\_PC\_20059, MR/W016729/1). In addition, development of OpenSAFELY has been funded by the Longitudinal Health and Wellbeing strand of the National Core Studies programme (MC\_PC\_20030: MC\_PC\_20059), the NIHR funded CONVALESCENCE programme (COV-LT-0009), NIHR (NIHR135559, COV-LT2-0073), and the Data and Connectivity National Core Study funded by UK Research and Innovation (MC\_PC\_20058) and Health Data Research UK (HDRUK2021.000). LAT is funded by an NIHR Research Professorship NIHR302405. VM is funded by an NIHR Doctoral Research Fellowship (NIHR301535). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Health Research Authority (REC reference 20/LO/0651) and by the LSHTM Ethics Board (reference 21863). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data were linked, stored and analysed securely within the OpenSAFELY platform https://opensafely.org/. All code is shared openly for review and re-use under MIT open license (https://github.com/opensafely/udca_covid).