Long COVID is still a serious problem. Millions of people deal with fatigue, brain fog, breathlessness, and other symptoms for months after their initial infection clears. Researchers have been searching for ways to prevent it. A growing body of evidence points to metformin, a cheap and widely available diabetes drug.
A major new study published in Clinical Infectious Diseases strengthens that case considerably. Here’s what it found — and why it matters.
What we already knew about metformin and Long COVID
In 2023, a landmark clinical trial called COVID-OUT made headlines. Researchers at the University of Minnesota ran a rigorous, randomized, placebo-controlled trial. They enrolled over a thousand adults with overweight or obesity who had just tested positive for COVID-19. The Parsemus Foundation provided support for the enrollment efforts for this trial and several others.
Half the participants received metformin, and half received a placebo. Participants who took metformin within seven days of COVID symptoms were about 41% less likely to develop Long COVID, and those who took it within four days had a 63% reduction in Long COVID risk. That was big news. It was the first high-quality randomized trial to show that any drug could help prevent Long COVID.
But scientists had questions. The trial enrolled a specific group of people. Participants had to start the drug soon after diagnosis. Did the benefit disappear if treatment started later? Did it only work in overweight or obese people? Would the results hold up outside of a controlled trial?
Then came ACTIV-6. This was another rigorous, randomized, placebo-controlled trial — and it extended the evidence further. ACTIV-6 included a broader population, with participants of normal weight and those who had experienced prior COVID-19 infection. The results aligned with COVID-OUT. People who took metformin during their acute COVID-19 infection were about 50% less likely to receive a clinician diagnosis of Long COVID at six months.
A second, independent analysis of electronic health records (a target trial emulation using the National COVID Cohort Collaborative database) confirmed the ACTIV-6 findings. Together, these two trials provided strong evidence that metformin can help prevent long COVID across a wider range of patients.
What the new study adds
The new Clinical Infectious Diseases paper takes a different and important approach. Instead of running a controlled trial, researchers — led by Ubonphan Chaichana of University College London — analyzed data from the UK’s primary care system. They used a dataset covering more than 624,000 overweight or obese adults who had confirmed SARS-CoV-2 infections (SARS-CoV-2 is the virus that causes COVID-19). Nearly 3,000 of those patients started metformin within 90 days of their COVID-19 diagnosis. The researchers compared their outcomes with those of individuals who did not take the drug.
The result: metformin users were 64% less likely to develop Long COVID over the following year. The absolute risk reduction was about 12.6 percentage points — a striking difference.
Randomized clinical trials, especially when double-blinded, remain the gold standard in assessing the effectiveness of treatments. Nonetheless, several things make this study especially significant:
- First, the scale. This study analyzed data from more than 624,000 patients, enabling detection of effects and patterns that might not be seen in smaller controlled clinical trials.
- Second, the treatment window. COVID-OUT required patients to start metformin within seven days of diagnosis. That’s a tight window — many people don’t seek medical care that quickly. This new study included patients who started treatment within 90 days of diagnosis. The protective effect remained strong. This suggests the benefit is not limited to those who act immediately.
- Third, the subgroup data on diabetes status. The study enrolled all overweight and obese patients regardless of diabetic status. But in practice, most people (52%) who took metformin had diabetes, while only 2.5% were diabetic in the untreated group. That’s expected — metformin is a diabetes drug, and doctors prescribe it mainly to diabetics. The researchers used statistical methods to adjust for this imbalance, and the results held up in both subgroups. COVID-OUT had already shown the drug helps regardless of diabetes status, and this study confirms that finding in a larger population.
- Fourth, the benefit held across COVID variants. COVID-OUT ran primarily during the Delta variant era. The new study covered patients infected during the pre-Alpha, Alpha, Delta, and Omicron periods. Metformin reduced Long COVID risk consistently across all of them. The Omicron-era result was actually the strongest. This suggests the drug’s protective effect does not depend on any particular variant.
Why this matters
Taken together, these findings — COVID-OUT, ACTIV-6, and now this large retrospective study — paint a consistent picture. Metformin appears to help prevent Long COVID across different populations, treatment windows, variant strains, and study designs. The consistency across such different methods is exactly what scientists look for when evaluating whether an effect is real.
Metformin is inexpensive, widely available, and has decades of safety data. It costs pennies a day. It’s already one of the most commonly prescribed drugs on the planet. If it can truly prevent Long COVID at the scale suggested by this evidence, the public health implications are enormous.
Metformin appears to help prevent Long COVID across different populations, treatment windows, variant strains, and study designs.
The latest study is observational research, which has limitations. The authors are careful to note that further research is needed to confirm causality. But when a study of over 624,000 patients closely mirrors the results of two rigorous randomized trials — and does so across multiple variants, both sexes, and people with and without diabetes — that convergence is hard to dismiss.
Evidence supports offering metformin to outpatient adults during acute SARS-CoV-2 infection. It’s up to regulatory bodies (such as the U.S. FDA) to add metformin to approved COVID treatment guidelines. Until then, metformin remains an “off-label” therapy rather than a standard of care for SARS-CoV-2.
See our web page about metformin and our other news articles about COVID-19.
