Minneapolis, MN—While diabetes appears to increase the risk of severe effects and death in patients with diabetes, the common drug therapy, metformin might offer some protection, at least in women.

The large retrospective cohort analysis published in The Lancet Healthy Longevity suggests that metformin was associated with significantly reduced COVID-19 death risks in women.

University of Minnesota Medical School–led researchers explain that metformin, widely used to manage blood sugar levels in patients with type 2 diabetes, reduces inflammation proteins like TNF-alpha that appear to make COVID-19 worse.

“Observational studies like this cannot be conclusive but contribute to growing bodies of evidence. Seeing a bigger association with protection in women over men may point towards inflammation reduction as a key way that metformin reduces risk from COVID-19. However, more research is needed,” said principal investigator Carolyn Bramante, MD, MPH, who is an assistant professor in the Department of Medicine at the University of Minnesota Medical School. "A large database covering different geographic areas is rarely available. We were fortunate to have the opportunity to do this research alongside UnitedHealth Group.”

Background information in the study points out that type 2 diabetes and obesity, which involve chronic inflammation, are risk factors for severe COVID-19. Metformin has cytokine-reducing and sex-specific immunomodulatory effects, it notes, leading to the effort to identify whether metformin reduced COVID-19-related mortality and whether sex-specific interactions exist.

For the study, deidentified claims data from UnitedHealth Group (UHG)’s Clinical Discovery Claims Database were accessed. Data on patients were eligible for inclusion if they were adults and had type 2 diabetes or obesity (defined based on claims); at least 6 months of continuous enrolment in 2019; admission to a hospital for COVID-19 confirmed by PCR; and manual chart review by UHG, or reported from the hospital to UHG.

Defined as the primary outcome was in-hospital mortality from COVID-19. Researchers also examined independent variables, including home metformin use, defined as more than 90 days of claims during the year before admission to the hospital. Covariates considered were comorbidities, medications, demographics, and state.

Most, 52.8% of the 6,256 eligible cases involved women. The analysis found that 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).

The study found, however, that 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). On the other hand, no significant reduction in mortality among men (HR 0.957; 95% CI, 0.82-1·14; P = 0.689 by Cox proportional hazards) was determined.

“Metformin was significantly associated with reduced mortality in women with obesity or type 2 diabetes who were admitted to hospital for COVID-19,” the researchers conclude. “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.”

“While effective therapies to mitigate the harm of the SARS-CoV-2 virus are being developed, it is important that we also look to and evaluate commonly used medications with good safety profiles for their potential to combat the virus,” added Deneen Vojta, MD, executive vice president, Enterprise Research and Development, UnitedHealth Group.

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