“A study published in the International Journal of Infectious Diseases found that hospitalized patients with COVID-19 presenting with high inflammatory markers and low severe acute respiratory syndrome SARS-CoV 2 (SARS-CoV-2) antibody levels exhibited the highest morality risk.”
Dr. Sylvia Mink, Private University of the Principality of Lichtenstein
“In the near future, the story of drugs like Ozempic may no longer be primarily about weight loss and diabetes.”
Daniela J. Lamas, M.D., Contributing Opinion Writer, New York Times
In September 2024, the Centers for Disease Control and Prevention reported deaths from COVID-19 dropped by about 69% in 2023—moving COVID-19 from the fourth to the tenth leading cause of death in the U.S. Vaccinations against COVID-19 contributed importantly to this positive development, but many other factors also played a role, including reduced virulence of newer SARS-CoV-2 variants and improved treatments. In this Germ Gems post, I provide an overview of the medicines to treat SARS-CoV-2 infection, including the relatively small number that proved effective, others that were clear failures, and several on the horizon that have potential.
COVID-19 treatment phases. In the early stages of the COVID-19 pandemic (2020-2021), it became clear that the main goal of treating patients with SARS-CoV-2 infection was to keep them out of the hospital but, if admitted, out of intensive care units. Scientists therefore conducted research on different drugs that possessed antiviral activity, that is, drugs that inhibited the replication of the virus. This early research required a substantial infrastructure and involved multidisciplinary teams of scientists, including members from the pharmaceutical industry. In my opinion, these researchers accomplished amazing results.
In a relatively short period of time, three products emerged that gained Federal Drug Administration (FDA) approval: remdesivir (FDA approval October, 2020); paxlovid (nirmatrerelavir/ritinovir) (FDA emergency use authorization [EUA] December, 2021); and molnupiravir (FDA EUA December, 2021). All three antiviral drugs are still in use; each has pluses and minuses.
From my perspective, paxlovid has emerged as the drug of choice for the treatment of outpatients with COVID-19. That said, a patient’s physician should always guide the decision about which antiviral, if any, should be used for treating COVID-19.
By the spring of 2020, researchers recognized that a substantial number of COVID-19 patients remained ill for prolonged periods after their acute illness. This sequela of SARS-CoV-2 infection is most commonly known as “long COVID.” (Data from a large and growing number of studies suggest that about 6-7% of adults develop long COVID, characterized by disabling fatigue and “brain fog” lasting at least three months.) Currently, the benefit of any of the approved antiviral drugs in preventing or treating long COVID is not established.
Repurposed drugs for treatment of COVID-19. In addition to testing the effects of antiviral drugs on COVID-19 outcomes, other clinical research groups employed a second approach to finding a therapy—“drug repurposing”(defined as using an existing drug for a new treatment for a medical condition for which it was not indicated before). One of the major benefits of drug repurposing is that for drugs that are already FDA approved, their safety is established.
In the first two years of the COVID-19 pandemic, two such drugs, both of which are well known antiparasitic agents, captured much attention: chloroquine and ivermectin. The efficacy of neither drug was supported in randomized controlled trials (RCTs). Another repurposed drug, fluvoxamine, approved for treatment of obsessive-compulsive disorder, also failed to convincingly improve the clinical course of COVID-19.
Drugs showing promising benefits in treatment of COVID-19. Despite the steady reduction in the number of cases of severe and fatal COVID-19, and the availability of effective antiviral drugs such as paxlovid, there remains a major need for additional drugs to treat acute COVID-19 infection, and, very importantly, to prevent and treat long COVID. With these ongoing needs in mind, reports of two such agents—metformin and GLP-1 receptor agonists—are highly promising.
Metformin is approved to treat high blood sugar levels caused by type 2 diabetes. It is the most commonly used drug for this purpose, has been around for years, is safe, and is inexpensive. As was pointed out by Harvard University’s Robert Shmerling, M.D. in an April 8, 2024 article, “Is metformin a wonder drug?,” interest in metformin has been growing for treatment of a number of medical conditions, including aging.
The results of two RCTs of metformin, led by University of Minnesota physician Carolyn Baumante, suggest that metformin is beneficial in the treatment of acute COVID-19 and appears to be associated with a lower rate of long COVID. The researchers found this clinical benefit was associated with antiviral activity of metformin.
The GLP-1 receptor agonist, semaglutide, is another drug that has captured recent attention as a potential treatment of COVID-19. Semaglutide, is the active ingredient in Ozempic and Wegovny, drugs used to treat type 2 diabetes. These drugs have become enormously popular recently because of their capacity to treat obesity. And both obesity and type 2 diabetes are well-established risk factors for poor outcomes in COVID-19 infection.
As I pointed out in my February 21, 2024 Germ Gems post, “Will the New Obesity Drugs (GLP-1 Agonists) Impact Infectious Diseases?,” semaglutide has potent anti-inflammatory properties. (See also “Wegovny Protects Against Deadly COVID Cases,” MedPage Today, August 30, 2024; and “An Obesity Drug Prevents Covid Deaths, Study Suggests,” New York Times, August 30, 2024). While the mechanism underlying the protective effects of semaglutide in patients with COVID-19 is not established, a plausible explanation is that it operates via its anti-inflammatory properties.
Inflammation as a therapeutic target in COVID-19. In the early years of the COVID-19 pandemic, the main focus of treatment of outpatients was on the virus, SARS-CoV-2. We now have three antiviral drugs approved for the treatment of acute COVID-19.
Inflammation is known to be a key contributor to morbidity and mortality of COVID-19. Both metformin and semaglutide are drugs that have established anti-inflammatory properties. Moreover, based on the early findings suggesting that metformin and semaglutide protect against severe COVID-19, these drugs could be repurposed for this goal.
In a September 16, 2024 New York Times guest essay, “Inflammation May Be the Root of Our Maladies,” Daniela Lamas, M.D. points out that dysregulation of the inflammatory process plays a pivotal role not only in infectious diseases but also in many other disorders, including heart disease and neurological disorders, like Alzheimer’s disease. And, inflammation appears to accelerate the aging process. If all of this is really true, I wonder to myself, “Why shouldn’t I start taking metformin?”
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