1643-P: Can 14 Days of Metformin Prevent Post-COVID Diabetes?

Introduction and Objective: COVID-OUT was a decentralized, randomized, placebo-controlled, quadruple-blinded, partial factorial trial of metformin vs. exact-matching placebo to treat acute SARS-CoV-2 infection. We present the results of metformin vs. placebo on the outcome of new-onset type 2 diabetes (T2DM) in the 10 months after randomization. Methods: Adults age 30-85 with a body mass index (BMI) >= 25kg/m2 were eligible if enrolled within 3 days of a documented SARS-CoV-2 infection. Dosing: immediate-release metformin hydrochloride or exact-matching placebo: 500mg on day 1; 500mg twice per day on days 2-5; 500mg in the AM and 1,000mg in the PM on days 6-14. The primary outcome was severe COVID-19 within 14 days. Overall, 1221 consented for long-term follow up with monthly surveys asking participants if they had been diagnosed with Long COVID or other conditions (including new-onset T2DM). The pre-specified primary analytic model was Cox proportional hazards regression adjusted for baseline vaccination status and other study drugs, with a secondary post-hoc model further adjusted for pre-randomization weight gain, BMI, SARS-CoV-2 variant, ethnicity, and comorbidities. Results: 1,136 (94%) completed long-term follow-up surveys, of whom 22 (1.9%) reported new-onset T2D (24.3 cases/1,000 person years). The diagnoses occurred steadily between 60-300 days after randomization. Among those randomized to metformin 1.4% (8/571) developed new-onset diabetes compared to 2.5% (14/565) randomized to placebo, absolute risk reduction 1.1%. The hazard ratio for new onset T2DM comparing metformin to placebo was 0.58 (95% CI: 0.24 - 1.32) in the primary analytic model and 0.50 (95% CI: 0.19 - 1.24) in the secondary model with additional baseline covariates. Conclusion: This outcome is consistent with prior results from this trial and the ACTIV-6 trial that starting 14 days of metformin to treat acute SARS-CoV-2 lowers the risk of post-infectious sequelae. Metformin reduced SARS-CoV-2 in two RCT’s, and observational data have reported that metformin exposure during acute SARS-CoV-2 benefits the gut microbiome. Disclosure C. Bramante: None. C. Enright: None. E.J. Lemus Wirtz: Employee; Current; Analysis Group, Inc. D. Liebovitz: None. H. Belani: None. D.R. Boulware: Other - Study drug donation; Current; Mycovia. J.B. Buse: Consultant; Current; Aardvark Therapeutics, Altimmune, Alveus Therapeutics, Amgen Inc., Antag Therapeutics, Aqua Medical, AstraZeneca, Boehringer Ingelheim International GmbH. Other - Consultant and clinical trial support; Current; Corcept Therapeutics. Consultant; Ended; Dexcom, Inc. Consultant; Current; Eli Lilly and Company. Consultant; Ended; embecta. Consultant; Current; General Medicines Inc. Other - Consultant and clinical trial support; Current; GentiBio. Consultant; Ended; Insulet Corporation. Consultant; Current; Kayothera. Other - Consultant and stock options; Current; Metsera. Other - Expert witness; Ended; Medtronic. Other - Consultant and investigator; Current; Novo Nordisk. Consultant; Current; Recordati S.p.A, Sparrow Pharmaceuticals. Consultant; Ended; Tandem Diabetes Care, Inc. Consultant; Current; Vertex Pharmaceuticals Incorporated, vTv Therapeutics, Zealand Pharma A/S. T.A. Murray: None. J.M. Nicklas: Consultant; Current; 23andMe, Inc. Research Support; Current; Eli Lilly and Company. Research Support; Ended; Pfizer Inc. Research Support; Current; Novo Nordisk, Cleerly Inc. Funding National Institutes of Health (K23DK124654), National Institutes of Health (UL1TR002494), National Institutes of Health (K24AI184270), National Institutes of Health (UL1TR002489), National Institutes of Health (K23HL133604)