Recent studies add evidence to a prior phase 3 trial, suggesting that taking the diabetes drug during acute COVID-19 reduces the risk of long-term symptoms.
Key points you should know:
- Metformin is a medication that is prescribed to help manage blood sugar levels and is often used for treating type 2 diabetes.
- A major clinical trial, which included about 1,300 participants, found that taking metformin during acute COVID-19 reduced the risk of developing Long COVID by 40%.
- A second major clinical trial, which included nearly 3,000 participants, also found a reduced risk of developing Long COVID in patients who took metformin during acute COVID-19.
- A new retrospective cohort study similarly found that higher-weight adults who took metformin during an active SARS-CoV-2 infection had a lower chance of developing Long COVID.
- In spite of this evidence, metformin is not widely used to prevent Long COVID, with many doctors unaware of this benefit.
In October 2023, the results from a major phase 3 clinical trial were published. Called the COVID-OUT trial, it found that people who took the diabetes drug metformin during an active SARS-CoV-2 infection had a 41% reduced chance of developing Long COVID compared to those given a placebo. Researchers had originally designed the trial to test whether taking metformin during acute COVID-19 could help reduce the death and hospitalization rate.
Although metformin didn’t reduce the risk of severe COVID-19 symptoms, the investigators also followed up with patients 10 months after their infection. They asked participants of the study whether any doctor had diagnosed them with Long COVID.
The study found that those who took metformin were less likely to report a Long COVID diagnosis: 10.4% of the 660 patients who received the placebo did so, versus 6.3% of patients who received metformin.
Still, two years later, many people — including healthcare providers — don’t know that taking metformin during an active SARS-CoV-2 infection might prevent Long COVID. And recent studies, including a trial testing different repurposed drugs called ACTIV-6 and a new large study from the U.K., have found more evidence that metformin may reduce the risk of Long COVID.
In fact, major medical guidelines, such as the physician resource UpToDate, currently advise against the use of metformin for acute COVID-19, citing a “lack of evidence.” This is in spite of the fact that metformin is widely used for treating type 2 diabetes and polycystic ovary syndrome, and is considered safe for most patients.
“As a public health practitioner … any smallish percentage is a huge gain in people’s lives,” said Rachel Hall-Clifford, a public health researcher at Emory University who developed Long COVID in 2022. “The safety profile for metformin speaks for itself, it’s so widely used and well tolerated.”
The safety profile for metformin speaks for itself, it’s so widely used and well tolerated.
Rachel Hall-Clifford, public health researcher with long covid
Why metformin might help prevent Long COVID
Metformin is a medication that is widely used for type 2 diabetes. It originated from a common herb called Galega officinalis that was used for centuries to treat a number of ailments. The compound metformin was isolated in 1918 and approved as a medicine in Europe in the 1950s. The FDA approved metformin for use in treating type 2 diabetes in 1994.
Metformin has also attracted considerable interest in other areas, including evidence that it may have anti-aging and anticancer properties, similar to the drug rapamycin, which is being trialed as a potential Long COVID treatment.
The COVID-OUT clinical trial was originally developed to test whether taking metformin during an active infection could prevent hospitalization or death. The researchers selected it because metformin has known antiviral and anti-inflammatory properties, which could help during the acute infection.
Many people with Long COVID develop symptoms after only a “mild” or “moderate” acute case. Since metformin impacts blood sugar, it’s plausible that it could reduce the risk of developing Long COVID.
“Blood sugar dysregulation is part and parcel of the infectious response,” said Jaime Seltzer, scientific director for the myalgic encephalomyelitis (ME) advocacy group #MEAction. In theory, taking a blood sugar regulator during an active infection could help modulate the blood sugar response alongside metformin’s antiviral and anti-inflammatory properties.
More recent findings follow COVID-OUT
In the COVID-OUT study, researchers followed up with participants 300 days after their infection and asked if a clinician had ever told them they had Long COVID, said Carolyn Bramante, the lead investigator. Developing Long COVID was a secondary endpoint for the trial, meant to offer additional insights.
When Bramante and her colleagues designed the study in 2020, they didn’t know how to define Long COVID. So, Bramante and her colleagues decided to ask about a diagnosis. “It at least reflects something that drove them to see their provider, and their provider thought was a result of their infection,” Bramante said.
In a more recent study published in the journal Diabetes Care, conducted using electronic health record data, researchers looked at patients with type 2 diabetes who were infected with SARS-CoV-2. When adjusted for different risk factors, those who were already taking metformin during their infection had a slightly reduced risk of developing Long COVID compared to those who weren’t. (Researchers discussed the results in this RECOVER webinar.)
For the ACTIV-6 trial, researchers followed up with participants six months after their infection to ask whether they were still experiencing symptoms. The trial, which has been shared in a preprint, included nearly 3,000 participants, of whom about half received metformin and half received a placebo. While this preprint has not yet been peer-reviewed, other results from the trial were published in July in JAMA Internal Medicine.
Among participants who were given the placebo, 3% said they were still experiencing symptoms 180 days after their infections, compared to 2.3% of patients who were given metformin. This difference did not meet the statistical criteria that the researchers had set to say metformin was an effective treatment.
As a secondary outcome, researchers also asked whether participants had been diagnosed with Long COVID by a clinician, similar to the COVID-OUT trial. For this question, 0.56% of patients who took metformin had received a Long COVID diagnosis, compared to 1.17% of patients who took the placebo. Here, the difference did meet statistical criteria for efficacy.
As Bramante noted, the National Institutes of Health (NIH) does not require that clinical guidelines have to use trials’ primary outcomes, and considers predetermined secondary outcomes from clinical trials to have a low risk of bias. In the NIH’s COVID-19 Treatment Guidelines, one or more randomized trials without major limitations is acceptable for high-quality evidence. Thus, the results from the COVID-OUT and ACTIV-6 trials would be considered sufficient to inform clinical guidelines.
Treating reinfections for people with Long COVID
Although there haven’t been any studies on the benefits of patients with infection-associated chronic conditions (IACCs) taking metformin during an acute SARS-CoV-2 reinfection, doctors who are familiar with the existing research and with treating IACCs will often prescribe it to people with Long COVID in the hopes of preventing their condition from getting worse.
“It’s very cheap, it’s very safe, and it’s generally well tolerated,” said Jennifer Curtin, the chief medical officer and co-founder of RTHM, a telehealth clinic that specializes in treating complex illnesses such as Long COVID. “We generally use metformin during acute COVID reinfections for patients, just to try and reduce any potential worsening.”
Metformin tends to have minimal side effects, with the most commonly reported being gastrointestinal (GI) issues, such as nausea or diarrhea. For patients who are experiencing GI upset, it can help to start with a lower dose and taper up gradually. In the COVID-OUT protocol, patients took six days to titrate up to a dose of 1,500 milligrams per day of the instant-release version of metformin, which helped with managing side effects.
One other potential side effect is lactic acidosis, which is a rare but serious complication of metformin caused by the body producing too much lactic acid. This side effect was not reported by patients in either the COVID-OUT or ACTIV-6 trials.
For Hall-Clifford, who experienced a SARS-C0V-2 reinfection last year, she found it necessary to titrate up slowly to minimize GI side effects. She continued to take metformin for several months after her infection, during which time her symptoms got much better. “I don’t know if I can directly attribute massive improvement to metformin, but I do feel like it was part of the toolkit I was using, when I really turned a corner,” she said.
For Catherine Romatowski, who has severe ME and was infected with SARS-CoV-2 in 2023, her attempts to take metformin resulted in more side effects than she could handle, and she had to stop tapering the drug at 1,000 milligrams.
Romatowski did end up developing additional symptoms after COVID-19, and in hindsight, would have tried to tolerate the full 1,500 milligrams if possible.
We generally use metformin during acute COVID reinfections for patients, just to try and reduce any potential worsening.
Jennifer Curtin, RTHM
Symptom management for Long COVID
Although there is evidence that taking metformin during an active infection can help prevent Long COVID, its evidence for treating the symptoms of the disease is much more limited.
In the Open Medicine Foundation’s TREAT-ME survey, of 140 patients who reported trying metformin for their Long COVID or ME symptoms, 53% reported no change in symptoms, while 24% reported only a mild improvement. And 11% reported that their symptoms were moderately better, while 2% reported significant improvement.
Meanwhile, a major phase 3 clinical trial, conducted in Brazil starting in 2023, found that taking metformin for Long COVID did not help with fatigue. Although these results have not yet been published, The Sick Times spoke with the study authors about the preliminary results.
This was an adaptive trial with multiple arms, which included testing metformin and another drug, fluvoxamine, for its efficacy at relieving Long COVID symptoms. Investigators tested for fatigue using the Fatigue Severity Scale.
“Metformin failed to demonstrate much better than placebo,” said Ed Mills, a health sciences professor at McMaster University and one of the investigators of the trial. According to Mills, the study’s data safety monitoring committee recommended that the trial stop the metformin arm for futility, meaning that it was highly unlikely that enrolling additional patients in the trial would yield a different outcome.
“If they didn’t notice a change, then there is a decent chance that it doesn’t affect fatigue,” Seltzer said. The benefits of blood sugar regulator drugs like metformin for IACCs probably vary according to the timing, duration, and frequency at which patients use them, Seltzer said.
In terms of symptoms, “climbs and falls in blood sugar affect orthostatic intolerance symptoms,” Seltzer said, which can in turn affect the variability of a person’s energy levels.
Still, some patients do report some other benefits to taking metformin, other than relieving fatigue.
For Melissa Mazur, who lives in Philadelphia and worked as an attorney before Long COVID forced her to resign, metformin was the only drug her primary care doctor felt comfortable prescribing for her Long COVID symptoms. It has helped to stabilize what she suspects were symptoms relating to blood sugar dysregulation.
“I was getting these weird drops of blood sugar, and it does seem like the metformin has helped to level that out,” Mazur said.
I was getting these weird drops of blood sugar, and it does seem like the metformin has helped to level that out.
Melissa Mazur, person with Long COVID
Rachel Fairbank is a freelance health journalist based in Houston, Texas. Her work has appeared in publications such as Lifehacker, Texas Monthly, Nature, National Geographic,the Houston Chronicle,the Washington Post, and the New York Times.
Editor’s note, October 29, 1:30 p.m. ET: This story has been updated to clarify references to the COVID-OUT trial’s results.
All articles by The Sick Times are available for other outlets to republish free of charge. We request that you credit us and link back to our website.
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[…] thesicktimes.org pubmed jamanetwork.com academic.oup.com […]
[…] Another study has found that the common diabetes drug metformin may help reduce the risk of Long COVID. Shared as a preprint, the electronic health records study found a 53% lower risk of developing Long COVID when the drug was prescribed within six days of SARS-C0V-2 infection. The study included the health records of 496 people (248 in the metformin group. The authors concluded that the result of this study is consistent with randomized controlled trials and observational analyses on the drug for cutting Long COVID risk, and that it could be used to help guide treatment guidelines. Read more about metformin and Long COVID in our recent feature. […]