At the COVID-19 pandemic’s start, there were no proven, effective medications to treat the disease. In the search for therapies, repurposing existing drugs offered a faster route to answers than developing drugs from scratch. Scientists scoured drug compound catalogs for contenders that worked in ways that might show promise against COVID-19.

Metformin was just such a contender.

NCATS’ role in finding and testing metformin as a treatment for COVID-19 has spanned the entire drug development process — from early observational studies all the way to large-scale clinical trials. Now, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership’s ACTIV-6 clinical trial, overseen by NCATS, is testing metformin as an outpatient treatment for people with mild-to-moderate COVID-19. Metformin’s addition to the nationwide ACTIV-6 testing lineup could bring clarity to the drug’s value in treating COVID-19 and potentially preventing long COVID.

“By leveraging our networks and data-driven tools, we are speeding the delivery of important answers on metformin's ability to help people manage acute and long COVID symptoms,” said NCATS Director Joni L. Rutter, Ph.D. “These innovative approaches to study existing therapies could provide a foundation for integrating clinical trial and real-world data to get definitive answers from future clinical studies faster.”

The Case for Metformin in COVID-19

Metformin is a mainstay in type 2 diabetes treatment. Effective, safe and affordable, metformin does more than just moderate blood sugar levels. Metformin also suppresses key molecules that promote inflammation and blood clots. Those pro-inflammatory molecules contribute to type 2 diabetes and obesity — conditions that are primary risk factors for more severe COVID-19. Metformin may also have relevant antiviral activity. Research has shown that metformin blocks SARS-CoV-2 from replicating itself.

These properties spawned a hypothesis. If metformin reduces the inflammatory molecules that drive COVID-19 and the conditions known to increase COVID-19 risk, and if it also has antiviral activity, the diabetes drug might be repurposed as an effective COVID-19 treatment.

Observational Glimmers of Promise

Observational studies early in the COVID-19 pandemic pointed to just such potential.

In a 2020 review, NCATS Clinical and Translational Science Awards (CTSA) Program-supported researcher Carolyn Bramante, M.D., assistant professor of medicine at the University of Minnesota, and her colleagues examined electronic health records (EHRs) from adults with type 2 diabetes or obesity. They found that women taking metformin before they developed COVID-19 were significantly less likely to die after being hospitalized — although men didn’t see the same protective effect. Another 2021 observational study of EHRs found that people with diabetes who were on metformin when they developed COVID-19 were significantly less likely to die from COVID-19.

The NCATS National COVID Cohort Collaborative (N3C) enclave of EHR-derived data powered two large studies that reinforced a potential link between metformin and less-severe COVID-19 outcomes. One study of EHRs from more than 6,600 adults found that those with type 2 diabetes who were taking metformin before developing COVID-19 were less likely to be hospitalized, need mechanical ventilation or die. A second study of people with either prediabetes or polycystic ovary syndrome (a condition commonly treated with metformin) showed that metformin use was linked to less severe COVID-19.

Observational studies usually aren’t enough to change medical practice, however. Metformin would have to deliver results in large randomized, placebo-controlled trials specifically designed to answer the question of whether metformin is helpful for treating COVID-19.

Two such trials, TOGETHER and COVID-OUT, would give metformin the chance to prove itself as an effective COVID-19 treatment.

TOGETHER Trial: The First Clinical Test

Metformin’s first large randomized, placebo-controlled clinical trial was the TOGETHER trial —and it didn’t deliver clear evidence of effectiveness against COVID-19.

TOGETHER put a handful of repurposed drugs to the test as COVID-19 treatments in high-risk people in low- and middle-income countries. In TOGETHER’s metformin arm, researchers randomized high-risk adults in Brazil with COVID-19 to outpatient care with either metformin or placebo. Those on metformin took a 750-mg dose twice a day — 1,500 mg daily — for 10 days.

In their published results, the TOGETHER trial researchers found no benefit to back metformin as an outpatient treatment for early-stage COVID-19. Among the 418 people in the trial’s metformin arm, metformin didn’t significantly top placebo at reducing hospitalization or delivering better clinical improvement after 28 days.

Among those who stuck with the TOGETHER trial’s 1,500-mg dosing treatment regimen, data in the study’s appendix did show metformin presented an advantage over placebo.

COVID-OUT: Metformin Shows Promise

The 2022 COVID-OUT trial put metformin to a second test. Bramante and her fellow researchers conducted the trial at six sites in the United States. The COVID-OUT research team relied in part on grants from NCATS, as well as regulatory and logistical support from the University of Minnesota’s Clinical and Translational Science Institute, a CTSA Program-funded institution.

Participants were age 30–85 years, overweight or obese, and had a new COVID-19 diagnosis. COVID-OUT’s primary goal was to see how many people went on to develop severe disease after 14 days of outpatient treatment. Four factors defined “severe” COVID-19: low blood oxygen levels, tested by people at home; an emergency department visit; hospitalization; or death.

Like TOGETHER, COVID-OUT tested multiple repurposed drugs. Three groups of people were randomized to receive metformin in combination with fluvoxamine, ivermectin or placebo. A fourth group received placebo. Two more groups received either ivermectin or fluvoxamine with placebo.

Rather than starting at the TOGETHER Trial’s 1,500-mg daily metformin dose, COVID-OUT began lower and raised metformin doses over 6 days to reach the 1,500-mg level, where it remained through 14 days. The COVID-OUT trial also used immediate-release metformin, which has a higher systemic peak than the extended-release formulation used in the TOGETHER trial.

The COVID-OUT researchers analyzed data from 1,323 people who enrolled in the trial between December 2020 and January 2022. None of the three drugs — including metformin — significantly reduced people’s risk of severe COVID-19, compared with placebo.

Metformin’s outlook changed, however, when the researchers removed potentially problematic patient-measured oxygen levels from their definition of severe COVID-19. After the trial’s start, the U.S. Food and Drug Administration issued a safety communication on pulse oximeters’ accuracy.

When the researchers excluded low blood oxygen levels, people with COVID-19 who took metformin were 42% less likely to end up in the emergency department, hospitalized or dead. The effect was even greater when the researchers focused on the numbers for hospitalization or death — a 53% reduction with metformin.

COVID-OUT Zooms in on Long COVID

COVID-OUT’s results pointed to more than therapeutic potential in the early stages of COVID-19. In a separate research question, the investigators assessed the development of long COVID — the signs, symptoms, and conditions that linger or start after COVID-19 infection. Metformin use also showed links to lower rates of long COVID.

The COVID-OUT researchers followed study participants months after treatment. Among the 1,126 people followed long-term, 8.3% developed long COVID by 10 months. But those who took metformin for early-stage COVID-19 were 41% less likely to later develop long COVID (6.3% of people) than the people who received placebo (10.4% of people).

Metformin’s effect on reducing the risk of long COVID held regardless of people’s sex, body mass index, whether a person had been vaccinated, or the dominant SARS-CoV-2 variant during treatment. People who started metformin within three days of the start of COVID-19 symptoms were less likely to develop long COVID than those who started four or more days after their symptoms began.

ACTIV-6 Could Bring Greater Clarity

In the wake of TOGETHER and COVID-OUT, the ACTIV-6 trial could bring greater clinical-trial clarity on metformin.

ACTIV-6 is a large, randomized, placebo-controlled phase 3 clinical trial testing medications to treat mild-to-moderate COVID-19 in an outpatient setting. The trial is a public-private partnership that has already tested fluticasone, two dosages of fluvoxamine, and two dosages of ivermectin. None of those drugs delivered therapeutic benefit, compared with placebo, in ACTIV-6. A trial arm testing montelukast recently completed enrollment.

The trial’s new metformin arm opened for enrollment Sept. 5, 2023. NCATS oversees ACTIV-6, and key players in the trial’s operations include CTSA Program-funded institutions. The Duke Clinical Research Institute is the ACTIV-6 clinical coordinating center, and the Vanderbilt Institute for Clinical and Translational Research is the trial’s data coordinating center. Other CTSA Program institutions are part of the trial’s enrollment treatment network, as is the Patient-Centered Outcomes Research Institute-funded National Patient-Centered Clinical Research Network (PCORnet).

The metformin trial arm will have two primary outcomes. The first will be the time to sustained recovery from COVID-19 symptoms, assessed for up to 28 days after the start of treatment. The second will be hospitalization or death among study participants, also measured for up to 28 days. In addition, ACTIV-6 researchers will assess whether metformin prevents urgent care and emergency department visits, as well as any effects on quality-of-life measures. Those quality-of-life assessments will extend to six months after treatment begins. Researchers will use the trial’s extended follow-up to explore potential links between metformin treatment and symptoms suggestive of long COVID.

“Confronted by a global public health catastrophe, NCATS and the CTSA Program institutions have used a flexible, holistic approach to accelerate the search for effective COVID-19 treatments,” said Michael G. Kurilla, M.D., Ph.D., director of NCATS’ Division of Clinical Innovation. “By innovating in real time, we are working to deliver evidence-based COVID-19 therapies that demonstrably help people.”