Corona virus infectious disease (COVID-19) has now been recognised as a new pandemic with high mortality [1]. The risk and severity of infection are particularly high in subjects with comorbidities, such as old age, diabetes mellitus (DM), hypertension, respiratory tract diseases, cancer or coronary heart disease [2, 3]. DM is of paramount importance, given that subjects with COVID-19 and DM have increased mortality [3, 4]. Recent information from Italy has confirmed that approximately two thirds of subjects who died by COVID-19 had DM [5]. It now remains to be determined whether chronic diabetic complications play a role in this association. For instance, some thoughts have already arisen in relation to the diabetic foot [6], partly mediated by diabetic neuropathy [7].

In this context, it is useful to examine the role of anti-diabetic treatment and whether this has any effect on COVID-19 infection. Recently, it has been proposed that dipeptidyl peptidase 4 (DPP-4) inhibitors could play a crucial role in decreasing the risk of complications in subjects with DM and COVID-19 [8]. We would like to offer some thoughts on the potential role of two traditional oral antidiabetic agents, metformin and pioglitazone. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Metformin is a classical antidiabetic agent, which seems to have additional beneficial actions, even on viral infections, notably on hepatitis C virus (HCV) [9,10,11]. HCV, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), is a ribonucleic acid (RNA) virus, which leads to liver injury [1]. Overall, it seems that metformin could be helpful in reducing insulin resistance in subjects infected by those viruses, thus affecting the cellular response to the infections [9,10,11]. For this positive result, it seems that the activation of adenosine monophosphate-activated protein kinase (AMPK) is responsible, which could become beneficial for the infected subject [9,10,11]. Moreover, according to a randomised controlled trial, metformin therapy reduces liver fibrosis in patients with HCV and human immunodeficiency virus (HIV)-HCV [11]. Additionally, some studies have shown that it could also have a protective role on the liver [10, 12]. Of relevance, SARS-Cov 2 may lead to liver dysfunction [13, 14], allowing the speculation that metformin could be shown to offer some liver protection in DM subjects with COVID 19. Obviously, this speculation needs to be examined.

Pioglitazone is another classical antidiabetic agent with pleiotropic anti-inflammatory properties [15]. Interestingly, this agent has proven to be helpful in the management of viral diseases [16, 17]. In a randomised controlled trial, pioglitazone reduced HCV viral load, even in subjects who did not receive specific antiviral treatment [17]. Furthermore, pioglitazone is a drug of choice for non-alcoholic fatty liver [18, 19]. Taken together, this evidence appears to encourage, at least in theory, new therapeutic vistas for pioglitazone in COVID 19 treatment, indicating an option to improve liver injury caused by SARS-CoV-2 infection. Nonetheless, there is a considerably long way to go before this assumption is substantiated.

In conclusion, it is essential to find an effective therapy for the new pandemic. In this endeavour, it is worth reconsidering the therapeutic potential of older drugs, including metformin and pioglitazone.