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Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial - The Lancet Infectious Diseases
The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95).
Vaccine slashes chance of long Covid, says study, but risk remains
In the unvaccinated group, 10.42 out of 100 people early in the pandemic (before vaccines were available) had developed long Covid one year after being infected. In the Delta variant era (defined as June 19 through Dec. 18, 2021), 9.51 out of 100 unvaccinated people were diagnosed with long Covid, compared to 5.34 out of 100 vaccinated people. When the current Omicron era began (Dec. 19, 2021), the gap widened: 7.76 out of 100 unvaccinated people but only 3.5 out of 100 vaccinated people acquired long Covid.
A break from Covid waves and a breakthrough for preventing Long Covid
But a new randomized, placebo-controlled trial of metformin has yielded exciting results—the first drug to be shown to help prevent Long Covid. Over a thousand people with mild-to-moderate Covid were randomly assigned to 2 weeks of metformin (500 mg pills, 1 on day 1, twice a day for 4 days, then 500 mg in AM and 1000 mg in PM for 9 days) or placebo. There was a 42% reduction of subsequent Long Covid as you can see by the event curve below, which corresponds to an absolute decrease of 4.3%, from 10.6% reduced to 6.3%.
Of note, the participants in the trial were fairly representative of the people who most often go on to manifest Long Covid, outpatients with a median age of 45 years and 56% were female. The low risk subgroups of people age <30 years or with a normal BMI were excluded. There were no treatment by subgroup interactions—that is there were overlapping 95% confidence intervals for the direction of benefit for metformin for all subgroups; no clear evidence that metformin worked better or worse for each.