Do novel drugs for diabetes help in COVID-19? Another brick in the wall?

To the Editor:

Recently we have read an interesting report concerning a mild course of novel coronavirus disease 2019 (COVID‐19) in children. The disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is defined by its high infectiousness, with 2 263 056 cases registered as of 18 April 2020. Surprisingly, its most severe course, with mortality of 6.8% (154 827 lethal cases up to 18 April 2020), almost exclusively affects adults. Children below the age of 10 usually remain asymptomatic or develop mild symptoms, with case fatality rate nearly 0%.

The reason for mild presentation of COVID‐19 in children remains unclear. Although several ideas have been discussed so far, there is still no definitive explanation for this issue. Here we propose a new hypothesis that might have practical implications.

The binding and entering of SARS‐CoV‐2 to the host cells require the interaction between viral spike protein and its cellular receptor – angiotensin‐converting enzyme 2 (ACE2) molecule. Formerly, another molecule, dipeptidyl peptidase 4 (DPP4), has been identified as an accessory functional receptor for the other Coronaviridae, especially Middle East respiratory syndrome (MERS)‐CoV.

DPP4 is widely expressed on the surface of various cell types, including respiratory epithelia. Noteworthy, although DPP4 was initially studied mainly in the context of adipose tissue, obesity, and diabetes, it has been found to be involved in pathomechanisms of various processes, including inflammation, angiogenesis, and carcinogenesis.

What is the rationale for postulated link between DPP4 and lower susceptibility to COVID‐19 in children? It has been found that DPP4 may also be released in a soluble form. Possibly, the latter might act as a decoy receptor for viral spike proteins, decreasing the virulence of SARS‐CoV‐2.

Two observations seem to support this hypothesis. First, it was proven that the level of soluble DPP4 negatively correlated with patient's age. Furthermore, as shown in a small proof‐of‐concept study, children were slightly less sensitive to DPP4 inhibitor – alogliptin, compared to adults, possibly due to the increased level of soluble DPP4.

One can speculate that DPP4 inhibitors could block an alternative entry site for SARS‐CoV‐2, thus being beneficial for COVID‐19 patients. On the other hand, while binding also to soluble DPP4, they could decrease its putative neutralizing/antiviral potential. Therefore, since DPP4 inhibitors, the aforementioned gliptins, are commonly used in diabetics, we are wondering whether any clinician has already gathered and would like to share their experience with these drugs in COVID‐19 patients. All in all, is this another brick in the wall?

CONFLICT OF INTEREST

None declared.