ABSTRACT
Background: Early treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to prevent progression to severe coronavirus 2019 disease (Covid-19) is an important component of the comprehensive response to the Covid-19 pandemic. Persons with overweight and obesity are at increased risk of poor short- and long-term sequelae of SARS-CoV-2 infection. Prior to its use for diabetes, metformin was used as an anti-viral medication. Methods: The COVID-OUT trial was a phase 3, factorial randomized, double-blinded placebo-controlled trial in non-hospitalized adults aged 30-85 years with overweight or obesity (n=1280) testing metformin immediate release titrated to 1500 mg/day, ivermectin 430 mcg/kg/day for 3 days, or fluvoxamine 50 mg twice daily within 3 days of confirmed SARS-CoV-2 infection and fewer than 7 days of symptoms. The primary endpoint was progression to severe Covid-19, defined as: hypoxia <=93% on home oximeter or healthcare utilization for Covid-19: emergency department visit, hospitalization, or death. Analysis was adjusted for SARS-CoV-2 vaccination, other trial medications, and used concurrent controls only. Results: The median age was 46 years, 54% female, 52% vaccinated, median body mass index (BMI) was 30 kg/m2 (interquartile range, 27 to 34 kg/m2). The adjusted odds ratio for the primary endpoint was 0.84 (95% confidence interval (CI), 0.65 to 1.09) for metformin;1.04 (95%CI, 0.74 to 1.44) for ivermectin;and 0.90 (95%CI, 0.63 to 1.30) for fluvoxamine. In pre-specified secondary analysis of the healthcare utilization components of the composite outcome, metformin had lower odds of emergency department visit, hospitalization, or death: 4.3% (27/627 with complete follow-up) versus 7.5% (47/628 with complete follow-up);adjusted odds ratio 0.60 (95%CI, 0.37 to 0.98). Conclusions: No medication reached significance for the primary endpoint. Participants receiving metformin had a 40% lower odds of emergency department visits, hospitalizations, or death due to Covid-19 (secondary endpoint). Available, inexpensive outpatient treatment with few contraindications is still needed to prevent worsening health disparities from Covid-19. Anti-viral properties of metformin could contribute insights into whether its anti-adipokine actions and associations with chronic disease outcomes are due to effects on the virome.