On March 21, epidemiologist Haleema Shakur-Still got a WhatsApp message from Temitayo Shokunbi, a colleague at the University of Ibadan in Nigeria. He asked about starting a trial for treating COVID-19 patients with the drug hydroxychloroquine. At the time, several trials were already in the works to investigate the effectiveness of the antimalarial to counter SARS-CoV-2, the virus that causes COVID-19, so Shakur-Still didn’t think starting another one on the antimalarial would add much new information. She offered Shokunbi an alternative: test aspirin, statins, and anti-hypertensive drugs instead. These medications, Shakur-Still reasoned, could counter the intense inflammation and other tissue damage associated with COVID-19.
A growing amount of data shows that intense inflammation, blood clots, and stroke are some of the most severe symptoms of COVID-19. Decades of research have also shown that aside from lowering cholesterol, statins decrease inflammation, reduce blood clots, and prevent damage to endothelial tissue—the thin layer of cells that line blood vessels and other organs. That tissue also appears to be affected by COVID-19. There’s also some evidence that statins act as antivirals. Because of those effects, epidemiologists such as Shakur-Still and other researchers want to see if statins could be a readily available treatment for COVID-19, a disease that has, so far, sickened more than 7.3 million people worldwide and killed 416,000.
Shakur-Still says Shokunbi told her: “Low- and middle-income countries are in for a potential catastrophe because of weak health infrastructure. Whatever can help needs to be done.”
With Shokunbi on board, Shakur-Still, who works at the London School of Hygiene and Tropical Medicine, and her collaborators got to work devising a trial that will begin in the next few weeks. In it, COVID-19 patients coming to a treatment center either in Pakistan or Nigeria will be randomly assigned to receive aspirin, the cholesterol-lowering drug simvastatin, the anti-hypertensive losartan, a combination of the drugs, or standard of care. Another trial in Cambridge, Massachusetts, will test a similar cholesterol-lowering drug called atorvastatin, and there are a few other clinical trials underway that will look at the effects of statins on COVID-19.
“Effective treatments are needed urgently,” Shakur-Still writes in an email to The Scientist. “Even a modest reduction in mortality from an inexpensive and widely available and practicable treatment that adds little additional burden to hospital staff working in overstretched health systems would be helpful.”
Statins’ effects on inflammation and blood clots
Data to suggest that statins may reduce the severity of COVID-19 or prevent death from it are limited. A small, observational study of 150 individuals in their 80s published on medRxiv in mid-May shows that those who took statins for cardiovascular disease before coming down with COVID-19 fared better than individuals of a similar age who were not on statins. From the results, “it seems like statins are beneficial in this population, and we know they are safe and cheap,” says study coauthor Anton De Spiegeleer of Ghent University in Belgium. “And it’s all that we have.”
The results of that study also suggest that a combination of a statin and an antihypertensive drug could have even more benefit than statins alone, but more work needs to be done to confirm that link, De Spiegeleer says. David Kass, a cardiologist at Johns Hopkins School of Medicine who was not involved in the work, is more reserved about the conclusions and says there could be other reasons, such as overall health, lifestyle, or genetics, that could account for why participants on statins fared better after they became infected with SARS-CoV-2.
We have known for a long time that statins do more than lower cholesterol. It’s those other effects, the ones they weren’t designed to have but do have, that could affect the coronavirus.—David Kass, Johns Hopkins School of Medicine
One of the consequences of severe SARS-CoV-2 infection is widespread inflammation in the lungs—also called acute respiratory distress syndrome, or ARDS. Research has shown statins can ameliorate ARDS, Shakur-Still says. Simvastatin, for example, reduced lung inflammation and lung injury in mice with ARDS. It also quelled lung inflammation in healthy human volunteers who had inhaled an endotoxin. That’s one reason she and her colleagues are testing simvastatin in their clinical trial to treat COVID-19.
How exactly statins reduce the inflammation of ARDS isn’t clear, though studies have shown that the drugs can suppress inflammatory cytokines, such as interleukin-6, and target the cell signaling molecules so that they are broken down before entering endothelial tissue. Acting in those ways, statins could shore up the integrity of the barrier that separates the lungs’ endothelial tissue, which lines blood vessels, from their epithelial tissue, which surrounds the air sacs, or alveoli, that help us breathe. Maintaining that barrier between the tissue types would keep inflammatory molecules out of the lungs, explains David Fedson, a retired physician and former director of medical affairs at the European vaccine company Aventis Pasteur MSD. Other drugs, such as antihypertensives, might have a similar effect. This type of treatment protocol is an example of an emerging concept in infectious disease research called disease tolerance, in which treatments target the host’s response to infection, rather the virus itself.
Along with reducing inflammation, statins might also prevent blood clots, another consequence of SARS-CoV-2 infection. A small study of 21 patients admitted to intensive care at Baylor St. Luke’s Medical Center in Houston found that more than half developed blood clots while being treated for COVID-19. In a separate study, patients who died of COVID-19 had nine times as many blood clots in their lungs as patients who died of the H1N1 flu, a team of doctors reported May 21 in the New England Journal of Medicine. Experimental studies and clinical trials have shown that statins can lower levels of thrombin, an enzyme in blood plasma that assists in blood clotting, and increase levels of thrombomodulin, a protein expressed on endothelial cells that reduces blood coagulation.
“We have known for a long time that statins do more than lower cholesterol,” Kass says. “It’s those other effects, the ones they weren’t designed to have but do have, that could affect the coronavirus.”
Statins’ interference with SARS-CoV-2
Statins might not only target inflammation and blood clots, but interact with viruses directly as well. The drugs reduce the amount of cholesterol in the membranes of cells, and lower levels of cholesterol can prevent viruses from successfully entering cells. A study published May 10 on bioRxiv showed that added cholesterol in the cell membrane makes it easier for SARS-CoV-2 to get inside.
When the cholesterol level in the cell membrane is high, ACE2—the receptor the virus uses to invade cells—sits at a spot on the cell surface primed for endocytosis, the process by which extracellular material (including viruses) is brought into the cell. When cholesterol is low, ACE2 is present in a region that isn’t primed for endocytosis. SARS-CoV-2 can still gain entry through a less efficient cell surface mechanism using the protein TMPRSS2, but the new work shows the endocytic pathway is the more infectious one, study coauthor Scott Hansen of the Scripps Research Institute in Jupiter, Florida, writes in an email to The Scientist. Lowering cell membrane cholesterol levels, which statins could do if taken in advance of infection, led to less virus getting into the cell, he says.
A recent computer simulation study also found that several statins could inhibit SARS-CoV-2’s main protease—an enzyme essential for viral replication and transcription. The results, the authors write in the paper describing them, indicate that statins could “directly affect the virus particle,” though there hasn’t been a study in cells to show this yet.
That effect is probably less important than statins’ role in fixing endothelial damage, says Fedson, who was not involved in the modeling study. “But we shouldn’t overlook it.”
Statins’ performance in clinical trials for infections
Although the data on COVID-19 and statins are scant, evidence from other infections, such as influenza, indicate that the drugs could have some benefit. For instance, individuals who were already taking a moderate dose of statins before coming down with the flu had a reduced risk of dying from the infection compared with those who did not take statins, and patients who took statins before or during a hospital visit for flu also appeared to have a lower risk of dying from the infection.
In addition to flu, statins have also been suggested as a treatment for Ebola. In a small study in Sierra Leone in 2014, approximately 100 individuals infected with the virus were treated with a combination of a statin called atorvastatin and an antihypertensive called irbesartan for five to six days. Some of the patients also received clomiphene, which was thought to have antiviral effects against Ebola, for two to three days. Data from the study weren’t released publicly, but individual health records, letters, and memoranda shared by clinicians who treated these patients showed that dozens of them survived the Ebola infection and were released from care. Typically, half of patients who are infected with Ebola die, according to the World Health Organization (WHO).
If we can prevent even a small number of patients getting to the stage of needing mechanical ventilation and dying, I think it will help.—Haleema Shakur-Still, London School of Hygiene and Tropical Medicine
Together, statins and antihypertensives seemed to improve survival in the patients with Ebola, Fedson says. Still, even with these seemingly promising preliminary findings, the WHO chose not to set up any additional clinical trials or other studies to follow up on the results, he notes.
There have also been randomized clinical trials using statins to treat sepsis and ARDS. In three of those trials, patients were already mechanically ventilated by the time they received statins; the drugs did not appear to reduce mortality. A small trial using statins to treat patients hospitalized with sepsis showed more promise, as a large percentage of cases did not develop into severe sepsis with multi-organ failure. There weren’t enough study participants for the team to draw statistical significance from the findings.
The WHO has turned down requests from Fedson to include statins in trials to treat patients infected with SARS-CoV-2. Letters Fedson shared with The Scientist reveal the organization’s hesitancy to support the drug treatment because of the lack of evidence showing statins will be successful against COVID-19. The Gates Foundation has also turned down a request by John Costello of First Group Healthcare in France to start a trial in several Central African countries with a combination of statins and antihypertensive drugs called ARBs. The reason, according to a letter to Costello from the Gates Foundation, is because one trial on ARBs alone is already underway and because statins didn’t work for sepsis and ARDS in previous studies of mechanically ventilated patients.
Kass says the use of statins to treat COVID-19 could go either way. “It could be that even though it’s a good thing it is not enough of a good thing to make a dent into COVID-19. It’s like putting on a rain jacket when it’s drizzling, you’re going to stay dry, but if you go out with the same rain jacket in a class four hurricane, you’re going to get soaked,” he explains. “So if COVID-19 is more like a class four hurricane for the blood vessels, then even though statins help to protect them, it may not be enough. That’s why we need to do the study.”
Shakur-Still and colleagues’ trial in Pakistan and Nigeria is a small step in that direction. But more could be done right now with statins to save lives, especially in less-developed countries, Fedson says.
Shakur-Still shares a similar sentiment. When thinking about her trial, she says, she can’t decide if she’s excited for it to start or terrified. “Speaking to colleagues in Islamabad, Pakistan, last weekend, there were no ICU beds for COVID-19 patients. This terrifies me,” she says. “However, if we can prevent even a small number of patients getting to the stage of needing mechanical ventilation and dying, I think it will help.”