Type 2 diabetes and obesity are considered important risk factors for severe Covid-19. Visceral adipocytes secrete many proinflammatory and coagulopathic molecules that are implicated in Covid-19 morbidity. These include interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and D-dimer. TNF-alpha contributes to insulin resistance, and its levels are higher in people with type 2 diabetes. Moreover, levels of anti-inflammatory cytokine, IL-10 are lower in type 2 diabetes and obesity. Metformin, a widely used drug for managing type 2 diabetes, decreases TNF-alpha and IL-6, and increases IL-10. The investigators thus conducted a retrospective cohort analysis to find out whether metformin could reduce Covid-19-related mortality and whether sex-specific interactions exist. They evaluated de-identified claims data from United Health Group (UHG)s Clinical Discovery Claims Database. Patient data were eligible for inclusion if they were aged ≥18 years, had type 2 diabetes or obesity, at least 6 months of continuous enrolment in 2019, and admission to hospital for Covid-19 confirmed by polymerase chain reaction, manual chart review by UHG, or reported from the hospital to UHG.

Out of 15,380 people with pharmacy claims data from January 1 to June 7, 2020, 6,256 were eligible for inclusion. Of these, 3,302 (52.8%) were females. In unadjusted analyses, metformin use was associated with decreased mortality. Moreover, metformin was associated with reduced mortality in women by Cox proportional hazards [hazard ratio (HR): 0.785, 95% confidence interval (CI): 0.650–0.951)] and propensity matching [odds ratio (OR): 0.759, 95% CI: 0.601–0.960, p=0.021). Apart from reducing TNF-alpha, other mechanisms that could underline the potential role of metformin in reducing the severity of Covid-19 are modulation of angiotensin-converting enzyme 2 receptor, reduction in release of inflammatory cytokine, improvement in neutrophil to lymphocyte ratio, decrease in glycemia, mast cell stabilisation, reduction in thrombosis, and improvement in endothelial function.

In this study, a link was reported between intake of metformin and reduction in mortality in women with type 2 diabetes or obesity who were admitted to hospital for Covid-19. A strong sex-specific response to metformin in Covid-19 patients indicates that TNF-reduction may be the main way by which it reduced mortality inthis patient population. However, prospective studies are required to further elucidate the underlying mechanism.

Reference

1. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Available at: https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(20)30033-7/fulltext Accessed on 10 Dec 2020