Pilot Study Looks at Metformin in COVID-19

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As observational evidence grows that prior metformin use may reduce mortality in hospitalized patients with COVID-19, researchers have continued to stress that randomized trials are needed.

Now, at least, one team has begun such a pilot study of metformin, looking at its potential role to prevent worsening of COVID-19 in individuals who have not previously taken metformin but who have tested positive for SARS-CoV-2 and have a body mass index (BMI) over 25 kg/m² (over 23 kg/m² if of South Asian or Latin ethnicity).

"We have funding for the first 70 patients of the prospective study. We hope to begin enrolling this week locally and in other sites in the coming weeks," investigator Carolyn Bramante, MD, of the University of Minnesota Medical School, Minneapolis, told Medscape Medical News.

She added that participants, recruited from outpatient COVID-19 testing sites, will be randomized to 1500 mg/day of immediate-release metformin or placebo for 14 days.

Initially, in these first recruits, the researchers will look at changes in CRP, albumin, and SARS-CoV-2 viral load, as well as differences in clinical outcomes, although Bramante acknowledges that the study, entitled MET-COVID: Outpatient Metformin Use for COVID-19, isn't anywhere near large enough yet to show a significant difference in the latter outcome.

"We have done calculations and worked out that 802 people will be required [for the study to be large enough to show a difference in clinical outcomes], if we assume that metformin reduces the clinical severity of COVID-19 by 25%," she told Medscape Medical News.

Metformin is widely used for the treatment of type 2 diabetes as well as other indications.

Bramante and colleagues were among the first to document a reduction in mortality with metformin. They first reported the results of their large observational study in a preprint in June, now published online in Lancet Healthy Longevity.

What Dose and Duration of Metformin Treatment May Impact COVID-19?

The observational study included 6256 patients hospitalized with COVID-19 and used propensity matching.

A significant reduction in mortality was seen in women who had been taking metformin (defined as having at least 90 days of filled prescriptions) — an approximately 24% reduced likelihood of dying compared with similar women not taking the medication, after adjusting for confounding factors. There was no significant reduction in mortality among men, and the authors hypothesize that this may be due to a larger anti-inflammatory effect of metformin in women than in men.

"Our findings should be prospectively confirmed. With the median time to hospitalization for COVID-19 being about 1 week, it is necessary to understand the duration of metformin use that conveys benefit, and whether it prevents SARS-CoV-2 infection," the authors write.

"Our study of home metformin use...highlights the effect that medications can have early on in the disease course," they add, noting that, in the United States, metformin is normally stopped when someone is hospitalized.

However, in an accompanying editorial, Angela Dardano, MD, PhD, and Stefano Del Prato, MD, PhD, say it was not possible to determine how long study participants took metformin, whether they adhered to therapy, the dose taken, or if metformin was stopped upon admission, as practices regarding the latter vary between US hospitals.

They also cite numerous other limitations, which they acknowledge Bramante and colleagues have attempted to adjust for.

There have also been similar studies that have shown reductions in mortality among those taking metformin, which were summarized in a mini-review in August, as reported by Medscape Medical News.

However, Dardano and Del Prato stress, "This evidence is largely indirect, and based on retrospective, observational studies."

Nevertheless, there is a case for studying metformin, but it won't be easy to do, they point out.

"Randomized trials are unlikely to be initiated because of the lack of consistent investment in a potentially powerful, yet out-of-patent, drug," they say

"However, it is because of the low cost of metformin that randomized trials could prove a very high cost-effectiveness, particularly when dealing with highly expensive diseases, such as COVID-19," add the editorialists, from the University of Pisa, Italy.

Metformin for Prevention of COVID-19?

In their article, Bramante and coauthors note that, if their findings were to be reproduced, "metformin could be widely distributed for prevention of COVID-19 mortality," especially for people with diabetes or a BMI of at least 30 mg/m² "because it is safe and inexpensive."

"The ready availability and safety, even during pregnancy, of metformin make it appealing to providers, patients, and society."

To this end, they also plan to extend their trial to look at post-exposure prevention in contacts of those who test positive for SARS-CoV-2, if funding can be obtained. Participants would be randomized to 1500 mg/day of metformin or placebo for 14 days.

"We have calculated that we would need about 2900 participants for this to be adequately powered" to see differences in clinical outcomes, and that is assuming 15% of people exposed to an individual with COVID-19 would become infected, Bramante told Medscape Medical News.

Other Metformin Trials in COVID-19

According to ClinicalTrials.gov, only one other US entity, AgelessRX of Ann Arbor, Michigan, has proposed studying metformin and the SARS-CoV-2 virus The open-label study aims to assess the impact of metformin combined with naltrexone on COVID-19 symptoms compared with no treatment. It has not begun recruiting.

And two entities in Mexico City — the American British Cowdray Medical Center and Hospital Juarez de Mexico — plan to start small prospective randomized studies of metformin in patients with metabolic syndrome or diabetes hospitalized with COVID-19.

Disclosures for the authors are listed in the articles.

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