Summary of COVID-19 ursodeoxycholic acid studies

1. John et al., Ursodeoxycholic acid is associated with a reduction in SARS‐CoV‐2 infection and reduced severity of COVID‐19 in patients with cirrhosis

3,214 patient ursodeoxycholic acid prophylaxis PSM study: 42% lower mortality (p=0.28), 54% lower severe cases (p=0.03), 55% fewer moderate/severe cases (p=0.002), and 50% fewer symptomatic cases (p<0.0001).
Retrospective 3,214 veterans with cirrhosis comparing 1,607 participants taking ursodeoxycholic acid (UDCA) to 1,607 propensity score matched controls not taking UDCA. UDCA use was associated with significantly lower odds of SARS-CoV-2 infection, symptomatic COVID-19, moderate or worse COVID-19, and severe/critical COVID-19.
Apr 2023, J. Internal Medicine, https://onlinelibrary.wiley.com/doi/10.1111/joim.13630, https://c19p.org/john

2. Cui et al., Efficacy of ursodeoxycholic acid in the prevention and treatment of COVID-19 in patients with chronic hepatitis B

215 patient ursodeoxycholic acid prophylaxis PSM study: 48% faster recovery (p=0.01) and 83% fewer cases (p=0.001).
Retrospective 215 patients with chronic hepatitis B in China, showing lower risk of COVID-19 infection, milder symptoms, and faster recovery with ursodeoxycholic acid (UDCA) treatment.
Mar 2024, J. Clinical Hepatology, https://www.lcgdbzz.org/en/article/doi/10.12449/JCH240309, https://c19p.org/cui2

3. Zheng et al., The Value of Ursodeoxycholic Acid and Mesenchymal Stem Cells in the Treatment of Severe COVID-19

167 patient ursodeoxycholic acid prophylaxis study: 62% lower mortality (p=0.03).
Retrospective 167 severe COVID-19 patients showing lower mortality with ursodeoxycholic acid (UDCA). Timing and duration of treatment is unknown - UDCA patients may have been on UDCA since before COVID-19.
Jun 2024, Microorganisms, https://www.mdpi.com/2076-2607/12/7/1269, https://c19p.org/zheng10

4. Li et al., Protective effect of ursodeoxycholic acid on COVID-19 in patients with chronic liver disease

450 patient ursodeoxycholic acid prophylaxis study: 80% lower severe cases (p=0.22), 80% fewer moderate/severe cases (p<0.0001), and 11% fewer cases (p=0.05).
Retrospective propensity score matched cohort study of 225 chronic liver disease patients on UDCA therapy matched to 225 controls without UDCA in China. UDCA use was associated with lower COVID-19 infection rate (85% vs 94%), lower maximum temperature, less severe symptoms, shorter recovery time (5 vs 7 days median), and lower risk of infection on regression (OR 0.32). The results rely on patient self-report rather than lab confirmed COVID-19 diagnosis.
May 2023, Frontiers in Cellular and Infection Microbiology, https://www.frontiersin.org/articles/10.3389/fcimb.2023.1178590/full, https://c19p.org/li26

5. Li et al., Evaluating the protective effectiveness and risk factors of ursodeoxycholic acid on COVID-19 among outpatients

192 patient ursodeoxycholic acid prophylaxis PSM study: 21% fewer symptomatic cases (p=0.001), 19% fewer cases (p=0.004), and 18% lower progression (p=0.04).
Retrospective 1,040 outpatients in China showing lower COVID-19 cases, less severe symptoms, and shorter symptom duration with ursodeoxycholic acid (UDCA) use.
Jul 2024, Frontiers in Pharmacology, https://www.frontiersin.org/articles/10.3389/fphar.2024.1381830/full, https://c19p.org/li36

6. Moon et al., Association between ursodeoxycholic acid use and COVID-19 in individuals with chronic liver disease: a nationwide case-control study in South Korea

74,074 patient ursodeoxycholic acid prophylaxis PSM study: 33% lower severe cases (p=0.04) and 20% fewer cases (p<0.0001).
Retrospective 74,074 individuals with chronic liver disease in South Korea, showing lower risk of COVID-19 infection and related severe outcomes with ursodeoxycholic acid (UDCA) use. The risk reduction was dose-dependent, with greater benefits seen with higher UDCA exposure. Authors hypothesize that UDCA may reduce viral entry by downregulating the ACE2 receptor and modulate the cytokine storm implicated in severe COVID-19.
Aug 2024, Virology J., https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02464-1, https://c19p.org/moon

7. Brevini et al., FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

186 patient ursodeoxycholic acid prophylaxis PSM study: 94% lower mortality (p=0.13), 75% lower ICU admission (p=0.21), and 40% lower hospitalization (p=0.03).
Retrospective study from two registries of 1,096 COVID-19 patients with chronic liver disease, including 31 treated with ursodeoxycholic acid (UDCA). Propensity score matching was used to compare outcomes between UDCA-treated and untreated patients. The analysis found that UDCA treatment was associated with reduced hospitalization, ICU admission, ventilation, and death from COVID-19. The authors suggest that UDCA may decrease susceptibility to SARS-CoV-2 infection by downregulating the host receptor ACE2 through inhibition of the farnesoid X receptor. Authors also show that UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ; and that UDCA reduces the expression of ACE2 in the nasal epithelium in humans.
Dec 2022, Nature, https://www.nature.com/articles/s41586-022-05594-0, https://c19p.org/brevini

8. Yu et al., Ursodeoxycholic acid and COVID-19 outcomes: a cohort study and data synthesis of state-of-art evidence

115 patient ursodeoxycholic acid late treatment study: 39% faster recovery (p=0.04).
Retrospective 115 hospitalized COVID-19 patients in China showing faster time to body temperature recovery with ursodeoxycholic acid (UDCA) treatment. Results were better for higher dose treatment (300mg vs. 150mg). Authors also perform a meta analysis showing lower risk of severe/critical COVID-19 with UDCA, which is listed separately [Yu].
Jul 2024, Expert Review of Anti-infective Therapy, https://www.tandfonline.com/doi/full/10.1080/14787210.2024.2376153, https://c19p.org/yu10

9. Costello et al., Ursodeoxycholic acid and severe COVID-19 outcomes in people with liver disease: a cohort study using the OpenSAFELY platform

11,305 patient ursodeoxycholic acid prophylaxis study: 24% lower mortality (p=0.13), 19% lower hospitalization (p=0.02), and 21% lower combined mortality/hospitalization (p=0.005).
OpenSAFELY retrospective 11,320 primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) patients showing lower risk of COVID-19 hospitalization or death with ursodeoxycholic acid (UDCA) treatment.
Dec 2023, medRxiv, https://www.medrxiv.org/content/10.1101/2023.12.11.23299191, https://c19p.org/costello

10. Lee et al., Association Between Ursodeoxycholic Acid and Clinical Outcomes in Patients With COVID-19 Infection: Population-Based Cohort Study

413,226 patient ursodeoxycholic acid prophylaxis study: 57% lower severe cases (p=0.19) and 15% fewer cases (p=0.21).
Retrospective 1,675,593 patients in the Jeonbuk CDM cohort and 8,528,533 patients in the NHIS cohort, showing ursodeoxycholic acid (UDCA) intake associated with significantly lower risk of COVID-19 infection and severe COVID-19.
Aug 2024, JMIR Public Health and Surveillance, http://preprints.jmir.org/preprint/59274/accepted, https://c19p.org/lee16

11. Gao et al., Effect of Ursodeoxycholic Acid for Sars-Cov-2 Prevention in Hematological Malignancies: An Observational Real-World Study

393 patient ursodeoxycholic acid prophylaxis study: 12% fewer cases (p=0.03).
Retrospective 393 hospitalized patients with hematologic disorders in China, showing lower risk of COVID-19 with UDCA use.
Nov 2023, Blood, https://ashpublications.org/blood/article/142/Supplement%201/7308/500982/Effect-of-Ursodeoxycholic-Acid-for-Sars-Cov-2, https://c19p.org/gao6

12. Ming et al., A Retrospective Study in Patients With Varying Prescription Coverage With Ursodeoxycholic Acid and Association With Incidence of COVID-19 Diagnosis in Primary Care

8,864 patient ursodeoxycholic acid prophylaxis study: 13% fewer cases (p=0.03).
Retrospective 8,964 primary care patients prescribed ursodeoxycholic acid (UDCA) in the UK. Higher categorized UDCA adherence (≥80%) was associated with lower COVID-19 incidence (OR 0.86), whereas adherence as a continuous variable was not significant. However, adherence was measured indirectly via prescription records which may not reflect actual usage. Additionally, more adherent patients may differ systematically on unmeasured confounders (e.g., health behaviors) that influence COVID-19 risk.
Nov 2023, Microbiology and Infectious Diseases The American Medical J., https://www.emjreviews.com/microbiology-infectious-diseases/article/a-retrospective-study-in-patients-with-varying-prescription-coverage-with-ursodeoxycholic-acid-and-association-with-incidence-of-covid-19-diagnosis-in-primary-care/, https://c19p.org/ming

13. Okushin et al., Ursodeoxycholic acid for coronavirus disease 2019 prevention

94 patient ursodeoxycholic acid prophylaxis PSM study: 17% fewer symptomatic cases (p=0.81) and no change in cases (p=1).
Retrospective 94 outpatients attending a university hospital gastroenterology clinic in Japan showing no significant difference in SARS-CoV-2 infection rates between ursodeoxycholic acid (UDCA)-treated patients and control groups without UDCA treatment. However, UDCA-treated patients tended to have higher rates of subclinical infection based on serology, suggesting UDCA may reduce COVID-19 severity.
Jul 2023, J. Internal Medicine, https://onlinelibrary.wiley.com/doi/10.1111/joim.13704, https://c19p.org/okushin

14. Yu et al., UDCA May Promote COVID-19 Recovery: A Cohort Study with AI-Aided Analysis

107 patient ursodeoxycholic acid prophylaxis study: 38% improved recovery (p=0.05).
Retrospective 115 COVID-19 patients hospitalized during an Omicron outbreak in China, of which 65 received ursodeoxycholic acid (UDCA) treatment and 50 received standard care. It found that UDCA was associated with faster body temperature recovery, with a hazard ratio of 1.62 (95% CI 0.99-2.60, p=0.053) compared to standard care after adjusting for covariates. Patients receiving higher UDCA doses (≥300mg daily) had significantly faster recovery than the standard care group, with a hazard ratio of 1.82 (95% CI 1.07-3.10, p=0.028). To further analyze the exposure-response relationship, the authors developed an AI model called VirtualBody that accurately predicted individualized UDCA pharmacokinetic profiles. Additional analysis using VirtualBody-generated data found UDCA AUC, indicating total exposure over time, had a stronger correlation with clinical outcome than cumulative dose. Overall, the study suggests UDCA may shorten recovery time from COVID-19, especially at higher doses,..
May 2023, medRxiv, https://www.medrxiv.org/content/10.1101/2023.05.02.23289410, https://c19p.org/yu5

15. Ojeda‐Fernández et al., UDCA treatment against COVID‐19: Do we have enough clinical evidence for drug repurposing?

1,360 patient ursodeoxycholic acid prophylaxis study: 7% higher mortality (p=0.67), 4% lower ICU admission (p=0.96), 6% higher hospitalization (p=0.66), and 3% fewer cases (p=0.77).
Retrospective cohort study of 9,617 patients with liver disease in Italy, divided into UDCA users and non-users. UDCA exposure was not associated with reduced SARS-CoV-2 infection or improved COVID-19 outcomes including death, hospitalization, and ICU admission in this unvaccinated cohort. The large sample size provides power, but administrative data limitations include lack of important confounders like BMI and hypertension.
Aug 2023, J. Internal Medicine, https://onlinelibrary.wiley.com/doi/10.1111/joim.13711, https://c19p.org/ojedafernandez2

16. Marrone et al., Ursodeoxycholic acid does not affect the clinical outcome of SARS‐CoV‐2 infection: A retrospective study of propensity score‐matched cohorts

629 patient ursodeoxycholic acid prophylaxis study: 7% higher mortality (p=0.77).
PSM retrospective 629 hospitalized COVID-19 patients showing no significant difference in survival between 108 patients taking UDCA prior to infection compared to 521 matched controls not taking the drug. The lack of observed benefit in this retrospective inpatient cohort does not preclude potential protective effects of UDCA against infection or illness severe enough to require hospitalization.
Sep 2023, Liver Int., https://onlinelibrary.wiley.com/doi/10.1111/liv.15736, https://c19p.org/marrone

17. Liu et al., Ursodeoxycholic acid administration did not reduce susceptibility to SARS‐CoV‐2 infection in children

226 patient ursodeoxycholic acid prophylaxis study: 2% more cases (p=0.88).
Retrospective 280 Chinese families with children previously seen in a liver clinic assessing whether ursodeoxycholic acid (UDCA) reduced SARS-CoV-2 infection risk. Among infected families, the study found no significant difference in confirmed or suspected SARS-CoV-2 infections between children taking UDCA (80.9%) and those not taking it (77.6%) (p=0.843).
Jun 2023, Liver Int., https://onlinelibrary.wiley.com/doi/10.1111/liv.15660, https://c19p.org/liu12

18. Sakamaki et al., Insights from a multicenter nationwide cohort analysis in Japan on the association of underlying conditions and pharmacological interventions with COVID-19 disease severity

650,317 patient ursodeoxycholic acid prophylaxis study: 79% higher severe cases (p<0.0001).
Retrospective 650,317 COVID-19 patients in Japan showing higher risk of severe COVID-19 with UDCA use. There may be significant residual confounding because authors do not appear to have adjusted for liver diseases (details of adjustments are not provided), and UDCA use is a strong indicator of certain liver conditions.
Sep 2024, Discover Public Health, https://ete-online.biomedcentral.com/articles/10.1186/s12982-024-00225-7, https://c19p.org/sakamakiudca

19. Corpechot et al., Exploring the impact of ursodeoxycholic acid therapy on COVID‐19 in a real‐world setting

10,147 patient ursodeoxycholic acid prophylaxis study: 19% lower ICU admission (p=1) and 40% lower hospitalization (p=0.17).
Retrospective cohort study of 10,147 chronic liver disease patients in France, with 1,322 exposed to ursodeoxycholic acid (UDCA), showing lower risk of hospitalization for COVID-19 with UDCA exposure, without statistical significance (adjusted OR 0.48, 95% CI 0.20-1.19). A case-control analysis of 88 hospitalized patients and 840 matched controls showed no significant difference, and there was no significant difference for ICU admission and mortality. The study is underpowered due to the low number of COVID-19 hospitalizations.
Jan 2024, J. Medical Virology, https://onlinelibrary.wiley.com/doi/10.1002/jmv.29418, https://c19p.org/corpechot

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