Abstract: Journal of the Endocrine Society, 2022, 6, 1–11 https://doi.org/10.1210/jendso/bvac017 Advance access publication 07 February 2022 Clinical Research Article A Randomized Trial of Sitagliptin and Spironolactone With Combination Therapy in Hospitalized Adults With COVID-19 Farhad Abbasi,1 Reuben Adatorwovor,2 Mohammad Ali Davarpanah,3 Yasaman Mansoori,4 Mehdi Hajiani,4 Farzan Azodi,5 Sepideh Sefidbakht,6 Shayesteh Davoudi,7 Farzana Rezaei,7 Shayan Mohammadmoradi,8,9 and Kamyar Asadipooya10, 2 Correspondence: Kamyar Asadipooya, MD, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Barnstable Brown Diabetes and Obesity Center, 2195 Harrodsburg Rd, University of Kentucky, Lexington, KY 40504, USA. Email: kas224@uky.edu. Abstract Context: COVID-19 may cause respiratory distress syndrome and death. Treatment of COVID-19 to prevent complications remains a priority. Objective: Our investigation sought to determine whether combination of spironolactone and sitagliptin could reduce mortality for inpatients with SARS-CoV-2 infection. Methods: This single-blind, 4-arm, prospective randomized clinical trial was conducted at Shiraz and Bushehr University of Medical Sciences hospitals between December 2020 and April 2021. We randomized hospitalized adult patients with COVID-19 pneumonia into 4 groups: control, combination therapy, sitagliptin add-on, or spironolactone add-on. The primary outcome was the clinical improvement of the patients in the hospital as measured on an 8-point numerical scale. The secondary outcomes included intubation, ICU admission, end organ damages, CT findings, and paraclinical information. Results: A total of 263 admitted patients were randomly assigned to control group (87 patients), combination group (60 patients), sitagliptin group (66 patients), and spironolactone group (50 patients). There were no significant differences in baseline characteristics, except for higher age in control group. The intervention groups, especially combination therapy, had better clinical outcomes (clinical score on fifth day of admission: 3.11 ± 2.45 for controls, 1.33 ± 0.50 for combination, 1.68 ± 1.02 for sitagliptin, and 1.64 ± 0.81 for spironolactone; P = 0.004). However, the mortality rate was lower in patients who received spironolactone (21.84% control, 13.33% combination, 13.64% sitagliptin, 10.00% spironolactone; P = 0.275). Our intervention reduced lung infiltration but not the area of involvement in lungs. Conclusion: Sitagliptin and spironolactone can potentially improve clinical outcomes of hospitalized COVID-19 patients. Key Words: COVID-19, ACE2, spironolactone, DPP4 inhibitor Abbreviations: ACE2, angiotensin-converting enzyme 2; ADAM17, disintegrin and metalloproteinase domain-containing protein 17; BMI, body mass index; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CT, computed tomography; DPP4, dipeptidyl peptidase-4; ESR, erythrocyte sedimentation rate; ICU, intensive care unit; IL-6, interleukin-6; INR, international normalized ratio; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; PT, prothrombin time; PTT, partial thromboplastin time; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane protease serine 2, WHO, World Health Organization. Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the cause of coronavirus disease 2019 (COVID-19), has generated huge workloads for healthcare facilities since late 2019. It also has..