Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

IMPORTANCE: Type 2 diabetes (T2DM) and obesity are significant risk factors for mortality in Covid19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. OBJECTIVE: We sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. DESIGN: Retrospective review of de-identified claims from UnitedHealth Group’s Clinical Discovery Database. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin and tumor necrosis factor alpha (TNFα) inhibitors as home medications in individuals with T2DM and obesity, controlling for comorbidities, medications, demographics, and state. Heterogeneity of effect was assessed by sex. SETTING: The database includes all 50 states in the United States. PARTICIPANTS: Persons with at least 6 months of continuous coverage from UnitedHealth Group in 2019 who were hospitalized with Covid-19. Persons in the metformin group had > 90 days of metformin claims in the 12 months before hospitalization. RESULTS: 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). There was no significant reduction in mortality among men. TNFα inhibitors were associated with decreased mortality, by propensity matching in a limited model, OR 0.19 (0.0378, 0.983). CONCLUSIONS: Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin’s reduction of TNFα in females over males, and suggests that metformin conveys protection in Covid-19 through TNFα effects. Prospective studies are needed to understand mechanism and causality.