People with diabetes and/or high blood pressure develop COVID-19 symptoms that are worse than average. Danish researchers will investigate whether the medicine taken for these conditions is the cause. So far, studies indicate that the medicine used to lower many people’s blood pressure may have both benefits and drawbacks.
This was confirmed by a slew of worrying figures from China and Italy. Diabetes and high blood pressure seemed to be strongly correlated with worsening the trajectory of COVID-19 and increasing mortality. Filip K. Knop, Chief Physician and Head of the Center for Clinical Metabolic Research at Herlev and Gentofte Hospital, noticed this too.
“When the first wave of COVID-19 hit Denmark, we found that many of the people who were hospitalized had diabetes or hypertension at both our hospital and others in the Capital Region. They experienced the most severe symptoms, and many died. At the time, various hypotheses were advanced about RAS inhibitors, the medicine that many of these people take to lower high blood pressure and how it affects the trajectory of COVID-19,” he says.
To learn more, Filip K. Knop and colleagues will soon monitor more than 200 people hospitalized with COVID-19, who all take blood pressure-lowering medicine daily.
Medicine may facilitate the virus entering the body
Most people with type 2 diabetes also have high blood pressure. Some therefore take RAS (renin-angiotensin system) inhibitors, which include the angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers.
Because if you have diabetes or high blood pressure, your renin-angiotensin system (RAS) is strained. This system regulates blood pressure and fluid balance in the body through the kidneys by converting the hormone angiotensin I to angiotensin II. This binds to receptors in the walls of blood vessels, which narrow and increase blood pressure.
Conversely, RAS inhibitors cause the vessels to relax and thus reduce blood pressure.
“However, concern arose that the RAS inhibitors, which increase the quantity of a cell membrane protein called ACE2, could aggravate COVID-19 because SARS-CoV-2 uses ACE2 to penetrate into the cells. And thus, the RAS inhibitors could potentially both increase the infectivity of SARS-CoV-2 and worsen the trajectory of the disease, because the virus could more easily enter the cells and replicate,” says Filip K. Knop.
A medicine with benefits and drawbacks
Filip K. Knop says that studies of other influenza viruses and in another coronavirus outbreak, the SARS epidemic in the early 2000s, have shown that ACE2 may also play a more beneficial role by converting angiotensinogen into smaller forms of the hormone, which relaxes the blood vessels and also protects inflamed tissue. The RAS inhibitors and an increased level of ACE2 may therefore actually be beneficial because they can reduce the damage to the lungs caused by viral infections and thus mitigate the trajectory of the disease.
“This means that a clinical dilemma arose for the people who take RAS inhibitors: Should we stop them from taking the medicine because it facilitates COVID-19 entering the cells and the subsequent replication of the virus? Or should treatment continue because this may protect the lungs from the damage caused by the virus?” says Filip K. Knop.
These are exactly the questions Filip K. Knop and his team will address in the study.
“We thought that carrying out a quite pragmatic and simple but randomized study following all the rules that can clarify these details might be interesting,” he says.
Trial will identify the nuances
The randomized clinical trial will recruit an estimated 215 people taking RAS inhibitors who are hospitalized due to COVID-19 and randomly assign them to two groups. One group will continue taking RAS inhibitors, and the other group will stop taking them. All the participants will be followed up for 30 days through interviews, medical records and blood and urine samples. The trajectory of COVID-19 will primarily be assessed based on how many days each participant is hospitalized and whether the hospitalization ends in death. Second, the researchers will monitor how lung failure develops and whether the participants end up in an intensive care unit and need ventilator or other respiratory treatment.
Filip K. Knop and his colleagues are not the first to study the effects of RAS inhibitors on COVID-19. Studies have been carried out in China, the United States and Denmark. Most have been observational, but the results so far have indicated that the blood pressure-lowering medicine is not especially inappropriate.
“Currently, there are no definite conclusions. However, the observational data from the registry studies and the hospital records indicate that people taking RAS inhibitors do not die excessively when hospitalized,” says Filip K. Knop.
“However, a randomized clinical trial like ours may reveal some signals that other types of studies cannot. Although RAS inhibitors may turn out not to influence the trajectory of COVID-19, the participants may still have small but clinically relevant differences in how they experience COVID-19 with or without these inhibitors,” he adds.
Good for society but impractical for researchers
Filip K. Knop explains that when the Danish researchers started the trial several months ago, there was not much evidence in this field. Today, the number of trials is increasing worldwide. But even if the Danish trial with RAS inhibitors ends up refuting the hypothesis about the negative aspects of the medicine, doctors in acute departments can use the outcome in clinical practice.
“Excess mortality among people with diabetes and/or hypertension may have several explanations, such as obesity and an increased risk of cardiovascular disease. However, the medicine may also increase the risk of complications of severe and acute illness during hospitalization. It is therefore important to know what to recommend about medicine when they are hospitalized. In such a vulnerable situation, the little things may help push them over the edge or enable them to survive,” explains Filip K. Knop.
The first participants are enrolled in the trial, and recruitment will continue as long as COVID-19 continues to spread, which it probably will for years.
“Paradoxically, although having so few inpatients with COVID-19 is great for Denmark and society, the lack of participants is impractical for us. But we also know that this virus will not simply disappear right away. So we have been allowed to extend the study and the grant for 2 years. We then have to hope that the participants arrive for the sake of the study, a few at a time, but that they will come,” says Filip K. Knop.
In March 2020, the Novo Nordisk Foundation awarded a grant to Filip K. Knop for research on people with COVID-19 and high blood pressure and/or diabetes. The trial protocol The Effect of Discontinuing Inhibitors of the Renin-angiotensin System in Patients with COVID-19 is in press in Trials.
