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Early treatment with metformin reduced the risk of long COVID among outpatients, according to secondary results of a negative phase III trial.

In the study of over 1,100 randomized participants, the cumulative incidence of long COVID was 6.3% in the metformin group versus 10.6% in the placebo group over 10-month follow-up (HR 0.58, 95% CI 0.38-0.88, P=0.009), reported Carolyn Bramante, MD, MPH, of the University of Minnesota in Minneapolis, and colleagues.

"Long COVID is a significant public health emergency that may have lasting health, mental health, and economic sequelae, especially in socioeconomically marginalized groups, and metformin is safe, low-cost, and widely available," they wrote in a preprint for published on SSRN, which has not yet undergone peer review.

Bramante and colleagues also tested ivermectin and fluvoxamine, but found no reduction in long COVID risk with either drug versus placebo (ivermectin: HR 0.99, 95% CI 0.59-1.64; fluvoxamine: HR 1.36, 95% CI 0.78-2.34).

The results are relevant to the current state of the pandemic since participants were enrolled during the Omicron wave and the study sample was approximately 50% vaccinated, according to the authors.

Vaccination status did correlate with metformin benefit, however, such that the unvaccinated participants appeared to experience the bulk of the reduction in cumulative long COVID risk:

• Unvaccinated: 6.3% vs 14.1% with placebo (HR 0.43, 95% CI 0.23-0.78)
• Vaccinated: 6.1% vs 7.2% (HR 0.85, 95% CI 0.46-1.56)

Bramante told 乌鸦传媒 that metformin may also be particularly effective in those with overweight or obesity (median body mass index [BMI] in this study was 30), as the subgroup with a BMI of 30 or greater saw a substantial reduction in long COVID risk (5.6% vs 12.8%; HR 0.43, 95% CI 0.23-0.78).

"There are a few reasons it might work better in persons with overweight or obesity. We know from trial and preclinical data that metformin inhibits SARS-CoV-2, and adipose tissue may be a reservoir for SARS-CoV-2," she said. "Metformin also has anti-inflammatory actions that involve reducing adipokines. This means there might be a greater opportunity for seeing a benefit over placebo if there is a greater amount of adipose tissue."

"However," she added, "there are no data to suggest it wouldn't also work in someone with a normal BMI."

Metformin has also been shown to improve T-cell immunity, Bramante said, "so it might be beneficial in someone who is immune-compromised. Also, anything that inhibits viral replication would be important in someone who is immune-compromised. Additionally, metformin wouldn't interact with other medications that someone with a complex medical history would be taking."

For the overall study population, when metformin was started in under 4 days of symptom onset, the HR for long COVID was 0.37 (95% CI 0.15-0.95), in comparison with an HR of 0.64 (95% CI 0.40-1.03) for those who started on day 4 or later.

As was previously reported, the primary results of COVID-OUT showed no benefit with metformin, ivermectin, or fluvoxamine in reducing the composite endpoint for severe COVID at day 14. Among the three repurposed drugs, however, metformin had shown the most promise, with secondary endpoints suggesting a possible benefit in reducing the risk for emergency department visits, hospitalization, or death.

In the updated analysis, the authors reported that those taking metformin were less likely to be hospitalized compared with those taking placebo at day 28 (1.34% vs 3.16%).

"The number of cases of long COVID was higher in our trial than the number of emergency department visits or hospitalizations for acute COVID-19," Bramante and team wrote. "This supports the current understanding that long COVID occurs in individuals who did not have severe COVID-19."

For this multi-site study, inclusion criteria included an age of 30 to 85, overweight or obesity, symptoms for less than 7 days, and enrollment within 3 days or less of documented SARS-CoV-2 infection.

A total of 1,323 outpatients in the multicenter, quadruple-blind, parallel group trial were randomized, and 1,125 consented to long-term follow-up, with 95% completing over 9 months of follow-up. Median age was 45 years, 56% were women, and 82.8% were white. Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID.

"This means of ascertaining long COVID was chosen as an important balance of sensitivity and specificity because the definition of long COVID is rapidly changing, fluctuating symptoms are challenging to assess, and electronic health record codes lack specificity and sensitivity," Bramante and team noted.

Those who received a primary vaccine series had a lower risk of developing long COVID (6.6%) compared with those who were unvaccinated (10.5%). Of the 57 participants who received a booster shot prior to enrollment, only one developed long COVID.

The authors acknowledged that their findings may not be generalizable to people with a normal BMI or those younger than 30, as well as those with a prior infection.

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