Why not metformin for long COVID in non-diabetics?

Metformin prescribed within a week of SARS-CoV-2 infection was associated with a 53-percent reduction in long COVID or death over 6 months in patients without diabetes or prediabetes, as shown in a simulation study presented at IDWeek 2024.

“Why not metformin for long COVID? Metformin is safe, inexpensive, and widely available,” said Dr Carolyn Bramante, a paediatrician and obesity medicine specialist at the University of Minnesota Medical School in Minneapolis, Minnesota, US. She noted that metformin’s only US FDA–approved indication is for diabetes.

“However, in previous studies, metformin has been shown to reduce the incidence of long COVID, with only a few contraindications or medication interactions,” she added.

Bramante and her team simulated a randomized controlled trial of metformin vs control using the US National COVID Cohort Collaborative (N3C) Electronic Health Record Database. [IDWeek 2024, abstract 578]

Long COVID was determined using a computable phenotype based on symptoms and conditions. Many of the participants were infected with the Omicron variant.

Metformin was prescribed within 6 days of SARS-CoV-2 infection. Patients in the control group, designed to mimic a placebo, had a prescription for fluvoxamine, fluticasone, ivermectin, or montelukast, which have been used off-label in COVID-19 but have shown no effect on acute COVID-19 outcomes.

Patients with a previous metformin prescription or a comparator prescription, any indication for long-term use of metformin, or a contraindication for metformin were excluded.

What is known for metformin

COVID-OUT, a previous randomized controlled trial of 1,323 patients conducted by Bramante and her team in response to the severe SARS-CoV-2 pandemic, demonstrated the benefits of metformin in preventing severe COVID outcomes, including hypoxemia, emergency department visits, hospitalization, or death associated with COVID. [N Engl J Med 2022;387:599-610]

She also led a 2020 analysis, examining electronic health records of adults with type 2 diabetes (T2D) or obesity. In this review, metformin was significantly associated with reduced mortality in women with obesity, or T2D admitted to the hospital for COVID-19. The same protective effect was absent in men. [Lancet Healthy Longev 2021;2:e34-e41]

Another study showed metformin inhibited viral replication after 48 hrs, with no cytotoxic effect in doses up to 100 µM. [Biomed Pharmacother 2022;152:113223]

Bramante said metformin has also demonstrated anti-inflammatory and antiviral properties in other trials. This led her team to conduct the simulated trial in patients without diabetes or prediabetes.

The study featured a similar racial/ethnic makeup in the metformin and control groups: 16 percent and 17 percent were Black, and 16 percent and 13 percent were Hispanic, respectively. Within 6 months, 4 percent of patients in the metformin group developed long COVID or died vs 8.5 percent in the control group (relative risk [RR], 0.47). For prescriptions made on days 0–1 relative to infection, the RR was 0.39. When metformin was prescribed on days 0–14, the RR was 0.75.

Bramante said it is important to have an active comparator to control for things that cannot be measured, such as engagement in healthcare and the placebo effect.

“Many people have been suffering from post-acute sequelae, yet we don’t have therapies for long COVID,” commented Dr Emily Erbelding from the National Institute of Allergy and Infectious Diseases, Maryland, US, who was not involved in the study.

“We now have data pointing to metformin as a therapy for long COVID, and this is important,” she added. “The findings give us a reason to consider doing a large randomized controlled study of metformin for COVID.”