A Randomized Trial of Sitagliptin and Spironolactone With Combination Therapy in Hospitalized Adults With COVID-19

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.

Metainflammation in COVID-19.

A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2) levels which potentiate the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DPP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2), support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARSCoV- 2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DPP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DPP4) inhibitors and spironolactone/ eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.