It became clear relatively soon after the outbreak of the COVID-19 pandemic that diabetes mellitus is an important risk factor for severe disease courses and is associated with increased mortality. In a review, David W. Williams et al (Cardiff, UK), discuss possible biological mechanisms that could make infection with SARS-CoV-2 particularly dangerous for patients with diabetes.
Patients with diabetes are more likely to have severe forms of COVID-19, require more intensive care and ventilation than patients with other comorbidities, and their mortality rate is significantly higher than that of COVID-19 patients without diabetes. In addition, diabetics often have additional risk factors such as obesity, hypertension, coronary heart disease, or renal failure.
In addition to this less favourable risk profile, other complex mechanisms could also contribute to an unfavourable course of COVID-19 in people with diabetes. Poorly controlled diabetes with hyperglycemia is associated with increased systemic inflammation with release of pro-inflammatory cytokines and increased oxidative stress. In addition, diabetes is associated with relative immunodeficiency, which together increase the severity of viral and bacterial infections.
ACE2 receptors are used by SARS-CoV-2 to enter the host cell. Hyperglycemia leads to reversible glycolysis of these receptors, which could make it even easier for the coronaviruses to enter, leading to more serious infections. Strict glycamic control could therefore be an important preventive factor before and at the beginning of COVID-19.
Upregulation of ACE2 receptor expression has also been observed among drugs commonly used in diabetes such as ACE inhibitors, angiotensin receptor blockers, ibuprofen and thiazolidinediones (glitazones). So far, the use of these drugs has not been shown to be an independent risk factor for severe COVID-19 courses, so there is no recommendation to discontinue them.
ACE2 receptors are also found on pancreatic beta cells, making them potential targets for SARS-CoV-2. Infection-related dysfunction could lead to new onset diabetes and increase the risk of hyperglycemia and diabetic ketoacidosis in people with diabetes.
The DPP-4 receptor is used by MERS-CoV as an entry portal and DPP-4 antibodies appear to be able to suppress this corona infection. Whether this also plays a role in SARS-CoV-2 has not yet been conclusively clarified.
The possible influence of drugs that are frequently used in diabetes is also being discussed:
This group of drugs could have a positive influence on the course of severe COVID-19 disease for a variety of reasons. By promoting diuresis and natriuresis, the heart and lungs are relieved, myocardial and renal function is improved by switching to a more energy-efficient metabolism, and the drugs have anti-inflammatory effects. A phase-III trial with dapagliflozin (10 mg/d) in COVID-19 patients with and without diabetes is currently investigating whether this is actually the case.
However, the increased risk of ketoacidosis among SGLT-2 inhibitors, which is already elevated in COVID-19, and a possible upregulation of ACE2 receptors are cause for concern.
There is currently no clinical data on the possible influence of this group of substances on the course of COVID-19 - but a retrospective case-control study and an open randomised trial with linagliptin are underway.
This group of compounds could have a positive effect on COVID-19 in two ways. Firstly, these substances could lead to a downregulation of ACE2 receptors in the cardiopulmonary system and the liver. Secondly, they could improve overall metabolic health with a reduction in endovascular inflammation. However, there have not been any studies on this so far.
The bottom line is that relatively little is known about the specific influence of individual antidiabetics on the course of COVID-19, and corresponding clinical trials with the different substance classes would be desirable, the authors write.
Sources:
1. David M. Williams et al; Diabetes and Novel Coronavirus Infection: Implications for Treatment; Diabetes Ther (2020); online first; https://doi.org/10.1007/s13300-020-00858-2
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357277/pdf/13300_2020_Article_858.pdf