Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus

Background: Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19. Methods: We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. Results: In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. Conclusions: These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.