Metformin, neutrophils and COVID-19 infection

In recent commentaries, possible mechanisms of action of metformin which may have conflicting effects in COVID-19 has been proposed [1], [2], [3]. In this commentary, a possible role of metformin in COVID-19 on neutrophils, the first line of defense against microbial, fungal and viral infections is proposed. Although a controlled neutrophilic response is needed to combat infection, uncontrolled neutrophilic response can be deleterious [4].

A longitudinal study in 548 patients from China reported that a progressive increase in neutrophil count or neutrophil lymphocyte ratio was associated with a fatal outcome [5] and a similar report have been published from Poland [6]. In an autopsy study of COVID-19 patients, neutrophil infiltration in pulmonary capillaries, extravasation of neutrophils into the alveolar space, and neutrophilic mucositis has been reported [7].

Neutrophil extracellular traps (NETs) first described in 2004 [8], are extracellular chromatic webs released from neutrophils and contains deoxyribonucleic acid (DNA), histones, microbicidal proteins, (neutrophil elastase and myeloperoxidase) [9]. Recent reports have shown that that sera from patients with COVID-19 have elevated levels of NETS such as cell-free DNA, myeloperoxidase (MPO)-DNA, and citrullinated histone H3 (Cit-H3), highly specific markers of NETs and these were associated with markers of inflammation [10]. If controlled, NETs are beneficial in the host defence against pathogens [10]. However, if excessive NET formation occurs it has the potential to trigger inflammatory cascade that has been associated with cytokine storm [10], ARDS [11] and microthrombosis [12] all causes of fatality in COVID-19.

Metformin has been shown to reduce neutrophil count in polycystic ovarian disease [13] and reduce neutrophil lymphocyte ratio in patients with diabetes [14]. It has also been shown to ameliorate NETosis in patients with diabetes [15] and pre-diabetes independent of glucose control [16]. Metformin has been associated with a decrease in neutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein released by neutrophils and is known to be elevated in patients with diabetes [17]. Animal studies have shown that metformin reduces post myocardial infarction injuries by reducing cardiac remodelling and myocardial neutrophil activity [18]. Metformin has also been seen to reduce neutrophil and macrophage infiltration in hyperoxia induced lung injury in neonatal rats [19].

While beneficial mechanistic links through neutrophils can be suggested with the use of metformin, it is important to realise that a relatively high rate of mortality in patients with co-existing diabetes has been reported in COVID-19 [20]. A vast majority of these patients would have been on metformin. Until we have real world data on the effects of metformin use in COVID-19 patients with diabetes, no conclusive judgement with regards to its overall usefulness, neutral or detrimental effects can be made.

Funding

The author is supported in part by Ministry of Health, Clinician Scientist Award [MOH-000014]; and National Medical Research Council Centre Grant [NMRC/CG/017/2013].

Declaration of Competing Interest

The author declare that there is no conflict of interest.