Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis

Bramante, Carolyn T; Ingraham, Nicholas E; Murray, Thomas A; Marmor, Schelomo; Hovertsen, Shane; Gronski, Jessica; McNeil, Chace; Feng, Ruoying; Guzman, Gabriel; Abdelwahab, Nermine; King, Samantha; Tamariz, Leonardo; Meehan, Thomas; Pendleton, Kathryn M; Benson, Bradley; Vojta, Deneen; Tignanelli, Christopher J

BACKGROUND: Type 2 diabetes and obesity, as states of chronic inflammation, are risk factors for severe COVID-19. Metformin has cytokine-reducing and sex-specific immunomodulatory effects. Our aim was to identify whether metformin reduced COVID-19-related mortality and whether sex-specific interactions exist. METHODS: In this retrospective cohort analysis, we assessed de-identified claims data from UnitedHealth Group (UHG)'s Clinical Discovery Claims Database. Patient data were eligible for inclusion if they were aged 18 years or older; had type 2 diabetes or obesity (defined based on claims); at least 6 months of continuous enrolment in 2019; and admission to hospital for COVID-19 confirmed by PCR, manual chart review by UHG, or reported from the hospital to UHG. The primary outcome was in-hospital mortality from COVID-19. The independent variable of interest was home metformin use, defined as more than 90 days of claims during the year before admission to hospital. Covariates were comorbidities, medications, demographics, and state. Heterogeneity of effect was assessed by sex. For the Cox proportional hazards, censoring was done on the basis of claims made after admission to hospital up to June 7, 2020, with a best outcome approach. Propensity-matched mixed-effects logistic regression was done, stratified by metformin use. FINDINGS: 6256 of the 15 380 individuals with pharmacy claims data from Jan 1 to June 7, 2020 were eligible for inclusion. 3302 (52·8%) of 6256 were women. Metformin use was not associated with significantly decreased mortality in the overall sample of men and women by either Cox proportional hazards stratified model (hazard ratio [HR] 0·887 [95% CI 0·782–1·008]) or propensity matching (odds ratio [OR] 0·912 [95% CI 0·777–1·071], p=0·15). Metformin was associated with decreased mortality in women by Cox proportional hazards (HR 0·785, 95% CI 0·650–0·951) and propensity matching (OR 0·759, 95% CI 0·601–0·960, p=0·021). There was no significant reduction in mortality among men (HR 0·957, 95% CI 0·82–1·14; p=0·689 by Cox proportional hazards). INTERPRETATION: Metformin was significantly associated with reduced mortality in women with obesity or type 2 diabetes who were admitted to hospital for COVID-19. Prospective studies are needed to understand mechanism and causality. If findings are reproducible, metformin could be widely distributed for prevention of COVID-19 mortality, because it is safe and inexpensive. FUNDING: National Heart, Lung, and Blood Institute; Agency for Healthcare Research and Quality; Patient-Centered Outcomes Research Institute; Minnesota Learning Health System Mentored Training Program, M Health Fairview Institutional Funds; National Center for Advancing Translational Sciences; and National Cancer Institute.