Nothing in medicine is more exciting than discovering new drugs. However, this process is time consuming, expensive and not always necessary. Sometimes existing drugs can be used to treat diseases that are different from what they were developed for.
This “repurposing” approach has many advantages. Existing drugs already have a proven safety profile and may no longer be patented, making them cheap and easy to deploy.
For these reasons, the medical and scientific community decided early on in the pandemic to investigate whether existing antivirals (including lopinavir ritonavir, hydroxychloroquine, and remdesivir) – alone or alone – may improve survival in infected patients. It seems intuitive that a drug designed to fight a particular virus can be effective against a closely related virus.
One drug, many effects
The first stage in drug development is the identification of a biological target – perhaps a protein or enzyme that, if not working properly, leads to disease. Drugs are designed to interact with the target and restore its normal function.
However, it is rare for drugs to act exclusively on their desired purpose. The messengers used by cells to regulate their functions and communicate with each other are similar throughout the body – calcium, for example, is a omnipresent messenger.
Just as an antiviral drug can work against a range of similar viruses, a drug designed to alter calcium signals in a specific location is likely to cause a range of effects throughout the body. These so-called off-target effects of drugs are responsible for most of the unwanted side effects.
However, off-target effects are sometimes beneficial – and this is where statins come into play. Statins aim to lower cholesterol, and that is essential for many biological processes but can lead to heart disease if the levels are too high. Cholesterol is produced in most cells of the body through a long, complex series of chemical reactions powered by special proteins called enzymes. Cholesterol is insoluble in water, so it cannot dissolve in the blood, and instead is transported in particles called lipoproteins.
Unfortunately, some lipoproteins can get stuck in the walls of blood vessels in a process called atherosclerosis, which leads to heart attacks and strokes. Statins work by blocking an enzyme at an early stage of cholesterol production. This robs the liver of cholesterol, which makes up for it by absorbing lipoprotein particles from the blood, which means that they can no longer enter the walls of blood vessels.
The cholesterol production line is complex and branches at different stages to produce a range of biological molecules. Statins reduce their production as well as cholesterol and this is believed to contribute to statins also having an anti-inflammatory effect. Inflammation is our body’s short-term response to harmful stimuli, but extreme activation of inflammatory pathways can be life-threatening. This is what is happening in some serious cases of COVID-19.
So the anti-inflammatory effects of statins helpful in avoiding extreme inflammation in COVID-19? It’s an appealing idea, especially since lab data suggests that statins also have a direct antiviral effect by blocking the production of molecules, viruses have to multiply.
However, many attractive ideas in medicine do not work in practice. Statins can cause this harmful interactions when given with antiviral drugs used in COVID-19, and may not be suitable for some individuals, including those with liver disease or rhabdomyolysis (a rare muscle disease).
From theory to practice
Several researchers have already compared the outcomes of COVID-19 infections in patients taking statins with those who don’t. The results were reassuring and generally suggested that statin use does not cause harm. And in one of the largest studies of its kind, statin use was associated with fewer deaths. But while the results of these studies are interesting and important, they cannot answer the question of whether statins can treat COVID-19.
This is because patients who take statins are likely to be (on average) different from those who don’t. The fact that some people are on a drug can indicate that they are sicker, or whether they are getting better health care, or whether they are particularly concerned about disease prevention. If we know and can measure these differences, we can adjust our analysis to take them into account. But we are very unlikely to know about all such differences, and this creates bias.
Such studies also cannot tell us about the potential of statins to treat individuals who would not usually use the drug. For this, we need randomized controlled trials in which patients are assigned to receive a statin or a placebo entirely by chance. This ensures that there are (on average) no differences between the treatment (statins) and control (placebo) groups of patients, and allows a fair test of the effect of the drug on the patient’s clinical condition.
Such trials are underway. When we have their results, we can tell you how useful statins could be in the treatment of COVID-19.
Peter Penson, Associate Professor of Pharmacology and Pharmacy Practice, Liverpool John Moores University and Maciej Banach, Professor of Cardiology, Lodz Medical University, and Visiting Professor, University of Alabama at Birmingham