Diabetes Therapy Reduces Risk of Long COVID

The long-time diabetes therapy, metformin, reduced the risk of postacute sequelae of SARS-CoV-2 infection (PASC) or long COVID by 41% in a 10-month follow-up. And it reduced the risk of emergency department visits, hospitalizations, and death due to COVID-19 by 42.3% by day 14 using the therapy compared with placebo, in a study aimed at preventive measures.

The study’s results were published in The Lancet Infectious Diseases.

“Treatment with metformin during acute COVID-19 infection reduced the risk of long COVID by day 300 by 41.3% compared with placebo, with an estimated cumulative incidence of 6.3% in the metformin group and 10.6% in the placebo group,” the investigators wrote.

The study’s participants were given the diabetes therapy in the outpatient setting. Study participants were included if they had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before trial enrollment.

“Participants who received metformin were also less likely to be hospitalized by day 28 than those who received placebo (eight [1·3%] of 596 vs 19 [3·2%] of 601; HR 0·42, 95% CI 0·18–0·95,” the investigators reported.

The study also examined ivermectin and fluvoxamine use as prophylaxis, and they wrote these therapies, “did not reduce the risk of long COVID in this trial.”

These findings may be helpful for clinicians looking for a potential novel strategy in helping to reduce the potential burden of long COVID, especially in patients who might be at a greater risk of developing the condition. A meta-analysis of 41 studies, which included 860,783 patients, found that the following risk factors were significantly associated with developing long COVID:

• Being of the female sex
• Being older
• Having a higher body mass index
• Being a smoker
• Having preexisting comorbidities
• Previous hospitalization or ICU admission

In previous reporting done by Contagion, a study demonstrated early intervention of COVID-19 therapies during the acute phase of COVID-19 infection reduced the risk of COVID-19 symptoms after 3 months. In that study, it was found that antivirals were protective against any symptoms of long COVID, and monoclonal antibodies reduced the incidence of neuro-behavioral long COVID symptoms.

Study’s Methods
The metformin trial was conducted as a randomized, quadruple-blind, placebo-controlled, phase 3 trial titled, COVID-OUT. It was conducted across 6 US sites from December 30, 2020 with the 300-day follow-up ending on Nov 27, 2022.

The primary outcome was the development of severe COVID-19 by day 14 after starting the study drug with a secondary outcome of incidence of long COVID. The investigators included a monthly follow-up for 300 days to assess if early COVID-19 treatment with the study’s therapies could prevent long COVID.

“The metformin dose was titrated over 6 days: 500 mg on day 1500 mg twice daily on days 2–5, then 500 mg in the morning and 1000 mg in the evening up to day 14. The ivermectin dose was 390–470 μg/kg per day for 3 days (median 430 μg/kg per day). The fluvoxamine dose was 50 mg on day 1 followed by 50 mg twice daily up to day 14,” the investigators wrote.

According to the investigators, there were 1323 participants in the primary, modified intention-to-treat population, and 1126 of them agreed to long-term follow-up.

Participants were characterized as having long COVID after diagnosis from a medical provider. In follow-up surveys given to participants, they were asked if a provider had diagnosed them with long COVID on days 180, 210, 240, 270, and 300.

In the group of 1126 who agreed to follow-up, they filled out at least one survey after the assessment for long COVID at day 180.

In terms of safety, there were no issues for participants without diabetes taking metformin.

"Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe," the investigators wrote.