UDCA treatment against COVID‐19: Do we have enough clinical evidence for drug repurposing?

Ursodeoxycholic acid (UDCA), an off-patent drug used to treat liver disease, is able to block SARS-CoV-2 entry into the cells downregulating ACE2 expression, a promising strategy to protect against infection. In this light, John et al. have recently demonstrated that in patients with cirrhosis, UDCA exposure was associated with both a decrease in SARS-CoV-2 infection and a reduction in COVID-19 severity confirming previous data published by Brevini et al. To investigate the impact of UDCA treatment in SARS-CoV-2 infection and COVID-19 outcomes in an unselected population of COVID-19 patients we used the administrative databases from Lombardy (Northern Italy), the first region of Western world to experience a rapid increase in the number of COVID-19 cases and related deaths and the most populated Italian region. The analysis included patients from the 1st and 2nd pandemic waves, were wild-type and alfa variant were predominant. This article is protected by copyright. All rights reserved.

UDCA treatment against COVID-19: Do we have enough clinical evidence for drug repurposing?
Dear Editor, Ursodeoxycholic acid (UDCA), an off-patent drug used to treat liver disease [1][2][3], is able to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the cells downregulating ACE2 expression [4], a promising strategy to protect against infection.In this light, John et al. [5] have recently demonstrated that in patients with cirrhosis, UDCA exposure was associated with both a decrease in SARS-CoV-2 infection and a reduction in coronavirus disease 2019 (COVID-19) severity confirming previous data published by Brevini et al. [4].To investigate the impact of UDCA treatment in SARS-CoV-2 infection and COVID-19 outcomes in an unselected population of COVID-19 patients, we used the administrative databases from Lombardy (Northern Italy), the first region of the Western world to experience a rapid increase in the number of COVID-19 cases and related deaths and the most populated Italian region.The analysis included patients from the first and second pandemic waves, where wild-type and alfa variants were predominant.
To test the association of UDCA exposure in the prevention of SARS-CoV-2 infection, we selected 9617 patients with a diagnosis of liver diseases alive on 1 March 2020 (for more details on data source, see the Supporting Information section).The cohort was divided into two groups: UDCA users and UDCA non-users whether they received or not at least one prescription of UDCA before entering the cohort (Fig. 1, left side).Demographic data were recorded at the time of inclusion.History of comorbidities was collected in the four years before inclusion using hospital records as primary diagnosis and up to five co-existing conditions.Exposures to medications of interest were traced in the 12 months before entering the cohort (Supplementary Materials, ATC and ICD-9-CM codes).We used logistic regression models to estimate the incidence of SARS-CoV-2 infection in the following 3 months after UDCA exposure.Odds ratios (ORs) with 95% confidence intervals (CIs) were adjusted for baseline characteristics (age, sex, pre-existing conditions and medications) and by inverse probability treatment weighting (IPTW).Baseline characteristics of the UDCA users and UDCA non-users groups, with standardized mean differences (SMD) were described before and after IPTW (Tables S2  and S3).Good balance was observed after IPTW with SMD equally or less than 0.10 (Figs.S1 and  S2).Our model demonstrated good goodness of fit (p-value for Hosmer-Lemeshow test were 0.61 and 0.08 for first and second pandemic wave, respectively) and led to a small variance of the effect estimate as the average of the inverse predicted probabilities was approximately equal to 1: IPTW [mean, median (q1, q3)] were [0.99, 0.97 (0.93, 1.05)] and [1, 0.98 (0.94, 1.04)] for first and second pandemic wave, respectively.No differences in risk of SARS-CoV-2 infection were observed between UDCA users and UDCA non-users according to the pandemic waves: first wave (OR 1.01; 95% CI 0.80-1.29)and second wave (OR 0.91; 95% CI 0.65-1.27).
We also evaluate the impact of UDCA treatment on COVID-19 outcomes in patients becoming positive for SARS-CoV-2 between 1 March 2020 and 31 May 2021 (Fig. 1, right side) using a Cox proportional hazard model.Hazard ratios (HRs) and 95% CIs were adjusted for baseline characteristics (sex, age, pre-existing conditions and medications) and by IPTW.Baseline characteristics of liver disease patients with COVID-19 according to UDCA treatment were described before and after IPTW (Table S4).Good balance was observed after IPTW with SMD equally or less than 0.10 (Fig. S3).In this analysis, 1360 patients were included: 219 UDCA users (16.1%) and 1141 UDCA non-users (83.9%).The number of events (%) and HRs for the outcomes are shown in Fig. 1.No difference was observed in the risk reduction for the association between UDCA treatment and death (HRs 1.07; 95% CI 0.79-1.44),hospitalization (HRs 1.06; 95% CI 0.83-1.36)and ICU admission due to COVID-19 (HRs 0.96; 95% CI 0.25-3.65).Our model demonstrated a good goodness of fit (p-value for

Study flowchart and impact of ursodeoxycholic acid (UDCA) exposure on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) outcomes in patients with liver diseases. ORs were adjusted for baseline characteristics (age, sex, pre-existing conditions and medications) reported in Tables S2 and S3 and by inverse probability treatment weighting (IPTW). Hazard ratios (HRs) were adjusted for baseline characteristics reported in Table S4 and by IPTW.
Hosmer-Lemeshow test = 0.40) and led to a small variance of the effect estimate (IPTW mean, median [q1, q3] = 1; 0.98 [0.95, 1.04]).
At the beginning of the pandemic, some authors stated that UDCA may have a potential benefit in the treatment of COVID-19 due to its inflammatory properties [6,7].In addition, the Chinese government recommended the use of bear bile that contains high levels of UDCA in order to treat severe and critical COVID-19 cases [8], as bear bile is used by traditional Chinese medicine practitioners to treat bronchitis and upper respiratory infections.Data published by Brevini et al. [4] and soon after confirmed by John et al. [5] turned the spotlight on the potential of UDCA treatment against COVID-19.The use of UDCA may have some advantages in terms of minimal side effects, cost (off-patent), route of administration (orally) and easy storage.In addition, as the target receptor is ACE2 on human cells, this drug should protect against future SARS-CoV-2 variants and could be an alternative to vaccination.Despite the promising data recently published [4,5], our results did not confirm any beneficial effect of UDCA neither on the prevention of SARS-CoV-2 infection nor on COVID-19 outcomes.The strength of our study is based on unselected cohort of patients exposed or not to UDCA and adjusted by IPTW to minimize the selection bias [9].However, it has to be pointed out that our analysis has the limitations typical of studies based on administrative databases, because we were unable to adjust for some relevant variables such as body mass index, glycaemia values and hypertension that are associated with an increased COVID-19 risk.
Our results refer to unvaccinated patients with liver disease thus cannot be generalized to the general population.More clinical evidence on the potential use of UDCA in COVID-19 treatment is needed taking also into account the vaccination status.Results from ongoing clinical observational and interventional studies evaluating the repurposing of UDCA in preventing SARS-CoV-2 infection and COVID-19 severity, including populations of healthy volunteers (NCT05659654, NCT05690646, NCT05685888), will shed light on this open topic.

Fig.
Fig. 1 Study flowchart and impact of ursodeoxycholic acid (UDCA) exposure on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) outcomes in patients with liver diseases.ORs were adjusted for baseline characteristics (age, sex, pre-existing conditions and medications) reported in TablesS2 and S3and by inverse probability treatment weighting (IPTW).Hazard ratios (HRs) were adjusted for baseline characteristics reported in TableS4and by IPTW.