COVID-19 infection and diabetes
The global pandemic caused by the new Sars-Cov-2 (COVID-19) began in
China in November 2019 and quickly became a global problem, representing
a health emergency. To date, about 6.15 million positive cases and
372,000 deaths have been recorded with over 260 countries affected (1).
COVID-19 infection can range from asymptomatic or slightly symptomatic
to more severe stages such as multi-organ dysfunction resulting in fatal
lung injury and thrombus formation. Studies show that people with
pre-existing chronic diseases such as diabetes are at increased risk of
infection and serious complications. To date, there are no direct
antivirals and effective vaccines against Sars-Cov-2 (2). During the
current global COVID-19 pandemic, diabetes has been identified as an
important risk factor for the development of severe Sars-Cov-2 viral
pneumonia (3).
Epidemiological data indicate that the risk of a fatal outcome caused by
COVID-19 infection is up to 50% higher in patients with diabetes (4).
There are many factors that may increase the risk of serious
complications for the diabetic patient with COVID-19 such as the
presence of a deficient immune system, an inadequate fibrinolytic
cascade, an overactive inflammatory state, and secondary cardiovascular
disease caused by diabetes.(5). In addition, it should be considered
that the Sars-Cov-2 virus uses the angiotensin 2 conversion enzyme
protein (ACE2) to penetrate the epithelial cells of the lung. ACE2 has a
protective role especially with regard to inflammation of the
respiratory tract. COVID-19 infection in the most severe stages reduces
the expression of ACE2, this is one of the causes of hyperinflammation
and respiratory failure (6-7), moreover diabetes also changes the
expression of ACE2, and this can cause an even more complicated and
serious clinical situation. Finally, the viral infection itself can
cause a worsening of the diabetes disease with a more difficult
glycaemia to control (8). A fundamental aspect to highlight is that the
DPP-4 protein (therapeutic target of glyptins) has been identified as a
functional receptor for the virus responsible for MERS (9), a virus
similar to that of COVID-19, to date it is not certain that it is also a
functional receptor for Sars-Cov-2, investigations in this direction are
underway. Moreover, diabetes patients have an altered expression of the
DPP-4 protein, this factor may contribute to overactive inflammation,
which could further complicate the clinical situation. Based on the
considerations expressed, it emerges that the management of the patient
with diabetes and COVID-19 positive is extremely delicate. The
recommendations indicate that drug treatment for diabetes should not be
discontinued during viral infection if there are no particular
contraindications, however for some antidiabetes drugs such as glyptins
there is evidence in the literature showing their potential additional
therapeutic role against COVID-19 infection.
Gliptins agents and potential efficacy against COVID-19
Gliptins (sitagliptin, vildagliptin, etc..) are DPP-4 inhibitors with
undoubted therapeutic efficacy in the anti-diabetes field. Recently for
this class of drugs evidence has shown extra pancreatic pleiotropic
activity of glycemic normalization. The DPP-4 protein has several
actions, in particular it plays an important role in the regulation of
the immune system by activating T cells and regulating CD86 expression,
and is responsible for increasing inflammation in patients with
diabetes. It should also be noted that the activity of DPP-4 can
influence the function of several cytokines, chemokines and growth
factors. Some studies have suggested that a higher mortality rate and
complications in people with diabetes and MERS infected may be
associated with a dysregulated immune response mediated by the DPP-4
protein (10-11), so a potential therapeutic role of glyptins in fighting
COVID-19 infection is also to be assumed. However, to date, the effects
of DPP-4 inhibition on the immune system and inflammation are still not
fully understood.
A meta-analysis has shown that upper respiratory tract infections do not
increase significantly with inhibitory treatment of DPP-4 (12), moreover
MERS-CoV uses DPP-4 to enter host cells (13), but it is not known
whether Sars-Cov-2 uses the same protein to enter the cell as well, in
addition to ACE-2, If this were demonstrated, the use of glyptin could
decrease the risk of Sars-Cov-2 infection, but for now it is only a
hypothesis. The potential benefit in the treatment of Sars-Cov-2
infection with DPP-IV inhibitors remains to be investigated. To date, it
is not entirely clear whether DPP-IV inhibition may play an important
role in controlling inflammation in patients with diabetes and COVID-19,
but it may be a potential target to prevent and reduce the risk and
progression of acute airway complications that a patient with diabetes
may have in addition to COVID-19 infection
(14).
Conclusions
The COVID-19 global pandemic represents one of the greatest health
challenges in the history of mankind. Patients with comorbidities such
as diabetes may be at greater risk of complications if infected with
COVID-19. Treatment of diabetes in a patient with COVID-19 must be
carefully managed, for some anti diabetes agents such as gliptins there
is evidence of extra pancreatic pleiotropic effects and glycemic
normalization, which could be an added value in the fight against
COVID-19 infection in the patient with diabetes.