A team of scientists, which included University researchers, found that dexamethasone, a steroid used to treat severe cases of COVID-19, is less effective to treat COVID-19 for those with diabetes and other risk factors. The discovery suggests that further research is necessary to understand how to better treat diabetic and at-risk patients with COVID-19.
Dexamethasone is an anti-inflammatory and immunosuppressive steroid used to treat critically-ill, COVID-19 patients who require supplemental oxygen or ventilators. The steroid suppresses the immune system, alleviating the damage done to the lungs in patients with an overactive immune response, a bodily response that can be deadly. Besides COVID-19, dexamethasone has been used to treat severe pneumonia, asthma and other conditions.
“What makes this paper special is that there aren’t that many drugs that are proven to treat COVID-19,” said Dariusz Brzezinski, University Medical School research scientist and team member. “That’s why dexamethasone is interesting because it’s been proven to help those severe cases.”
For their research, scientists from the University School of Medicine, University of South Carolina and Poland relied on the LabDB Laboratory Information Management System, a database that tracks the structures of proteins. One such plasma protein, serum albumin, is known to transport drugs throughout the bloodstream, including dexamethasone. Serum albumin has different active sites to which drugs can bind in order to be carried throughout the body.
Wladek Minor, lead researcher and a Harrison Distinguished Teaching Professor in the Medical School, explained that by studying and refining the structure of dexamethasone as well as serum albumin, the team of scientists discovered that the steroid’s transport may influence its effectiveness in patients.
“We started to look at this structure [of dexamethasone] and because we were working on albumin,” Minor said. “We found that dexamethasone binds to the same side as some drugs … If the person is taking some other drug, there is a competition for the active site. If his active site is already occupied, [dexamethasone and albumin] cannot bind together.”
Minor and the team of researchers demonstrated for the first time how dexamethasone binds with serum albumin for transport. Their new research indicates that other drugs and the hormone testosterone may compete with dexamethasone for the limited sites on serum albumin, resulting in drug displacement. In drug displacement, a drug administered at a high concentration can displace another drug, like dexamethasone, at the binding site, limiting its potential effectiveness. The scientists found that the testosterone molecule binds to albumin in the same way that dexamethasone does, further suggesting a competition between the two.
Those with diabetes have been found to have more severe symptoms of and complications with COVID-19. Diabetic patients often have high blood sugar levels which may modify serum albumin, affecting the binding site of dexamethasone.
In analyzing data from 373 patients at a hospital in Wuhan, China, the researchers also discovered that patients with high blood sugar levels as well as patients with lower than normal levels of albumin made up the majority of those who died from COVID-19.
“Apparently if you have a higher level of albumin, you can survive,” Minor said. “The level of albumin in the case of women is higher than the case of men, and this explains why women have a higher chance to survive.”
Further research is still needed to understand how best to treat COVID-19 patients affected by diabetes and high risk factors, like low levels of albumin. The researchers propose that clinical studies investigate alternative ways of administering dexamethasone to these patients.
“[Studies] could try to administer small doses of dexamethasone over a longer period of time,” Brzezinski said. “This way if you’re not transporting that much dexamethasone, then [there] won’t be that much free dexamethasone in the body, so it won’t have negative effects.”
Increasing the dosage of dexamethasone for diabetic and at-risk patients may seem like an easy solution to override competing drugs, but too much dexamethasone over a long period of time can be harmful to the body.
“The other idea is that you can administer dexamethasone not through injection … but through inhalers,” Brzezinski said. “And this way you don’t have albumin, you have a different way of transport and you’re avoiding the problem altogether.”
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