Researchers have found that metformin, commonly used to control blood sugar levels in people with type 2 diabetes, was more effective than placebo at preventing lingering complications 10 months after a coronavirus infection, reducing the risk by an impressive 41%, they said.
Some 65m people worldwide have some degree of long Covid, which can involve chronic fatigue, brain fog, heart and lung problems, and loss of taste and smell, among other issues, reports New Scientist.
With preventative drugs and other treatment options being limited, Carolyn Bramante at the University of Minnesota and her colleagues tested the potential of several therapies, including metformin, which apart from being used to control blood sugar levels in type 2 diabetics, has been shown to limit the replication of the SARS-CoV-2 coronavirus in the lab.
The team looked at 1 126 people, aged 30 to 85, who had tested positive for SARS-CoV-2 within the past three days. They were all overweight or obese, which can raise the risk of severe Covid-19, but didn’t require hospital care for the infection.
The participants were randomised to receive a range of potential treatments, including combinations of metformin, the anti-parasitic drug Ivermectin, the antidepressant fluvoxamine or a placebo.
At a 10-month follow-up, 6.3% of those who took metformin had been diagnosed with long Covid, compared with 10.4% on placebo, suggesting that the drug prevented 41% of long Covid cases in the trial. Neither Ivermectin nor fluvoxamine reduced the risk, they said in their findings, published in The Lancet.
While metformin may prevent long Covid among those who are overweight or obese and who have a mild SARS-CoV-2 infection, the drug’s potential in other groups, or as a long Covid treatment, is unclear.
Grace McComsey, who leads the long Covid RECOVER study at University Hospitals Health System in Cleveland, Ohio, said the research was encouraging. “A 40% decrease is pretty impressive, especially considering that most of the study population was fully vaccinated and already at a lower risk of getting long Covid.”
Metformin may work as both an anti-inflammatory and by reducing SARS-CoV-2’s viral load in an infected person’s body, she added. If it is an antiviral, it “could potentially work for the treatment of those with long Covid”.
Study details
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
Carolyn Bramante, John Buse, David Liebovitz, Jacinda Nicklas, Michael Puskarich, Ken Cohen, et al.
Published in The Lancet on 8 June 2023
Summary
Background
Post-Covid-19 condition (also known as long Covid) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient Covid-19 treatment with metformin, Ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long Covid.
Methods
We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (Covid-OUT) at six sites in the USA. We included adults aged 30–85 years with overweight or obesity who had Covid-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe Covid-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long Covid diagnosis by a medical provider was a prespecified, long-term secondary outcome.
Findings
Between December 30, 2020, and January 28, 2022, 6 602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1 323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long Covid at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive Ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. 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). There was no effect on cumulative incidence of long Covid with Ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo.
Interpretation
Outpatient treatment with metformin reduced long Covid incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for Covid-19 and is globally available, low-cost, and safe.
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