Metformin Could Reduce Long COVID Risk in People with Overweight or Obesity

Carolyn Bramante, MD, MPH
Credit: University of Minnesota

New research from a phase 3 trial of people with overweight or obesity with COVID-19 suggests use of metformin could reduce risk of long COVID by up to 67% percent.

Results of the study, which compared use of metformin, ivermectin, and fluvoxamine against placebo therapy, indicate use of metformin was associated with a reduced cumulative incidence of long COVID, with earlier initiation associated with a greater effect and no benefit observed with ivermectin or fluvoxamine compared with placebo.¹

“Long COVID is a significant public health emergency that may have lasting physical health, mental health, and economic impacts, especially in socioeconomically marginalized groups. There is an urgent need to find potential treatments and ways to prevent this disease,” said lead investigator Carolyn Bramante, MD, MPH, assistant professor of Medicine at the University of Minnesota Medical School.² “Our study showed that metformin, a medication that is safe, low-cost, and widely available, substantially reduces the risk of being diagnosed with long COVID if taken when first infected with the coronavirus. This trial does not indicate whether metformin would be effective as a treatment for those who already have long COVID.”

Named the COVID-OUT trial, the study was designed as a decentralized, randomized, quadruple-blind, parallel-group, phase 3 trial and conducted at 6 sites in the US. The trial enrolled adults aged 30-85 years of age with overweight or obesity who a documented SARS-CoV-2 positive PCR or antigen test within the prior 3 days and were experiencing symptoms for fewer than 7 days. After enrollment, these patients were randomized in a 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.¹

The primary outcome of interest for the trial was severe COVID-19 by day 14. Investigators pointed out the a priori primary sample was a modified intention-to-treat sample. The secondary outcome of interest for the trial was long COVID diagnosis by a medical provider.¹

Overall, 6602 patients were assessed for eligibility. A total of 1431 were enrolled and randomly assigned between December 30, 2020-January 28, 2022. Of these, 1323 participants received a dose of study treatment and were included in the ITT population. A cohort of 1126 consented for long-term follow-up and completed a survey after the assessment for long COVID at day 180.¹

A diagnosis of long COVID was observed in 8.3% (n=93) of the 1126 patients who consented to long-term follow-up. Results of the investigators’ analysis suggested the cumulative incidence of long COVID by day 300 was 6.3% (95% confidence interval [CI], 4.2-8.2) in those who received metformin and 10.4% (95% CI, 7.8-12.9) in those who received placebo (Hazard ratio [HR],0.59 [95% CI, 0.39-0.89]; P = .012). Investigators pointed out this effect was consistent across prespecified subgroups and earlier administration of metformin appeared to increase the benefit, with initiation within 3 days of symptom onset associated with a 63% relative risk reduction (HR, 0.37 [95% CI, 0.15-0.95]; P = .07).¹

When examining the effects of other treatments, results indicated there was no effect on cumulative incidence of long COVID with either ivermectin (HR, 0.99 [95% CI, 0.59-1.64]) or fluvoxamine (HR, 1.36 [95% CI, 0-.78-2.34]) relative to placebo therapy.¹

In a Linked Comment, Jeremy Faust, MD, of Harvard Medical School and Brigham and Women’s Hospital, noted more research is necessary to confirm the findings of the current study, but commended investigators for their novel and “potentially landmark” findings.

“If confirmed, the findings from the study by Bramante and colleagues are profound and potentially landmark on two distinct counts,” wrote Faust.³ “First, to our knowledge, this is the first high-quality evidence from a randomized controlled trial to show that the incidence of long COVID can be reduced by a medical intervention, metformin—an inexpensive treatment with which clinicians have ample experience. Second, the authors have, perhaps inadvertently, made an important contribution to medical epistemology. If a new disease has been sufficiently well characterized by clinicians so that it can be successfully modified by a therapy compared with placebo, then the entity must, from a practical standpoint, truly exist.”