Abstract: RESEARCH ARTICLE Identification of drugs associated with reduced severity of COVID-19 – a casecontrol study in a large population Ariel Israel1*, Alejandro A Schäffer2, Assi Cicurel1,3, Kuoyuan Cheng2, Sanju Sinha2, Eyal Schiff4, Ilan Feldhamer1, Ameer Tal1, Gil Lavie1,5†, Eytan Ruppin2†* 1 Division of Planning and Strategy, Clalit Health Services, Tel Aviv, Israel; 2Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, United States; 3Clalit Health Services, Southern District and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 4Sheba Medical Center, Tel-Aviv University, Ramat Gan, Israel; 5Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Abstract *For correspondence: dr.ariel.israel@gmail.com (AI); eytan.ruppin@nih.gov (ER) † These authors contributed equally to this work Competing interests: The authors declare that no competing interests exist. Funding: See page 12 Received: 07 March 2021 Preprinted: 14 October 2020 Accepted: 07 July 2021 Published: 27 July 2021 Reviewing editor: Frank L van de Veerdonk, Radboudumc Center for Infectious Diseases, Netherlands This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Background: Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18 to 95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two nonhospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher’s exact test. False discovery rate was used to adjust for multiple testing. Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI [0.058 to 0.458], p<0.001), ezetimibe (OR=0.488, 95% CI [0.377 to 0.622], p<0.001), rosuvastatin (OR=0.673, 95% CI [0.596 to 0.758], p<0.001), flecainide (OR=0.301, 95% CI [0.118 to 0.641], p<0.001), and vitamin D (OR=0.869, 95% CI [0.792 to 0.954], p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. Conclusions: Ubiquinone, ezetimibe, and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. Funding: This research was supported in part by the Intramural Research Program of the..