Don’t go “metformin” any premature conclusions about the results of this study just yet. But a clinical trial described in a June 8 publication in The Lancet Infectious Diseases found that those taking metformin when sick with Covid-19 were 41% less likely to have eventually developed long Covid than those taking only a placebo. In the trial, 6·3% of those who had received metformin ended up getting diagnosed with long Covid compared to 10.4% of those who had received placebo only. That’s encouraging news because the long and short of it is that doctors currently don’t have any proven treatments for long Covid at their disposal. However, there are a lot of buts, one cannot lie, about the findings from this clinical trial. So, before you “metformin” any plans to take this medication the next time you test positive for Covid-19, first take a closer look at what this study actually found.

Here’s a tweet from The Lancet Infectious Diseases on the publication and the trial, which bore the name COVID-OUT:

The goal of the COVID-OUT trial was to see whether taking metformin, fluvoxamine, or ivermectin during the acute phase of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could somehow reduce the risk of later developing long Covid. All three medications have been around for a while to treat other unrelated conditions. Metformin is a medication that’s been commonly used to treat diabetes. Fluvoxamine is a commonly-used antidepressant that showed some early promise as a treatment for Covid-19, as I’ve reported for Forbes back on March 8, 2021, but has yet to be established as an effective Covid-19 treatment. And of horse, you’ve probably heard of ivermectin. Ivermectin is a medication that’s been used for years to treat parasite infections in humans, horses, cows, and other animals. There certainly isn’t enough scientific evidence that it can be an effective treatment for Covid-19. That hasn’t kept a number of personalities and anonymous social media accounts from continuing to make all sorts of claims about ivermectin until the cows come home.

Long Covid, otherwise known as post-COVID-19 condition, by the way, has been a growing major problem since 2020. It’s where you either continue to have symptoms or develop new symptoms weeks, months, and even years after you supposedly recovered from a SARS-CoV-2. It’s a major problem because chronically suffering difficulty breathing, chest pain, fevers, headaches, chronic fatigue, “brain fog,” anxiety, stress, “pins and needles” sensations, sleep problems, joint pain, diarrhea, tummy pain, or other such symptoms kind of really sucks. It’s a major unsolved problem because when it comes to treating long Covid doctors have been sort of throwing their hands in the air, but not in a Timbaland song type of way.

Carolyn Bramante, MD, an Assistant Professor of Medicine at the University of Minnesota Medical School and the first author of The Lancet Infectious Diseases publication called metformin “an inexpensive, safe and widely available drug,” in the following tweet from the University of Minnesota Medical School:

Indeed, since metformin has been around for many years and generic versions of it are available, metformin is certainly much less expensive than a completely new medication would be. If you look at the common side effects from metformin, you’ll find things like abdominal or stomach discomfort, cough, chills, decreased appetite, and diarrhea. Although no one will say, “Yay, diarrhea,” these side effects don’t necessarily occur and the medication seems to be in general well-tolerated.

The COVID-OUT trial was a decentralized, randomized, quadruple-blind, parallel-group, phase 3 trial. That may sound like quite a mouthful. But it all makes more sense when you look at each word individually. Decentralized meant that the trial was conducted at six different locations in the United States without one location lording over the others. Randomized meant that study participants were randomly assigned to get one of six treatment combinations as soon as they were enrolled in the trial: metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Quadruple-blind didn’t mean that everyone was wearing four blindfolds throughout the trial, which would have made it a bit difficult to conduct the trial. Rather, it meant that none of the four major groups of people involved in the study—study participants, investigators, those providing medical care to the participants, and those assessing the outcomes of the participants—knew which participants were assigned to which treatment group. This helped prevent anyone from consciously or unconsciously showing any bias for or against a particular treatment, which has been a problem for some of the ivermectin studies.

To be enrolled into the trial, all participants had to be experiencing Covid-19 symptoms for fewer than seven days and had had a clearly positive SARS-CoV-2 test within the three days prior. This had to be the first time that they were diagnosed with Covid-19. Of note, all participants had to have body mass indices of over 25 kg/m2, the threshold for being in the overweight category. Recruitment for the trial occurred from December 30, 2020, to January 28, 2022. Each participant then received one of the six treatment combinations as soon as he or she was enrolled in the trial. Then each participant was asked to complete surveys 180, 210, 240, 270, and 300 days after being enrolled in the trial. The surveys asked each participant whether they had received a diagnosis of long Covid from a health care professional.

The researchers were able to initially enroll 1431 people in the trial. However, not all of them made it through the entire trial. Of the 1431 people, 1323 eventually received one of the six combinations of treatments while 1126 ended up completing at least one survey. The ages of these 1126 participants ranged from 30 to 85 years. Around 95% (1074 of the 1126 participants) were followed for at least nine months. A little over half (56·1%) of the participants were female with 44 of them being pregnant. The median age of participants ended up being 45 years while the median body mass index BMI ended up being 29·8 kg/m2.

Participants started receiving treatments as soon as they were enrolled in the trial, which meant that they were still in the midst of their SARS-CoV-2 infection. Ultimately, 564 of the participants ended up receiving a two-week course of metformin that was titrated up from 500 mg to 1000 mg over the first six days, and 562 ended up receiving a matched placebo.

By Day 300 after their initial SARS-CoV-2 infection, 93 (8·3%) of 1126 participants had been diagnosed with long Covid. However, this incidence was 41% lower (6·3% vs. 10.4%) among those who had received metformin compared to those who had received just placebo (10·4%). The difference was even greater (63% lower) among those who had started taking metformin within three days of first experiencing Covid-19 symptoms.

And surprise, surprise, there was no real difference in long Covid incidence between those who had received ivermectin and those who had received placebo. Fluvoxamine didn’t seem to have any overall positive effect as well.

So why might a medication that’s typically used to treat diabetes help prevent long Covid? Metformin is useful against diabetes because of the following sweet effects: it can decrease the amount of glucose produced by your liver, decrease the amount glucose absorbed through your intestines, and increase the response of your body tissues to insulin. Those taking metformin also often lose weight as well.

But wait, what does that all have to do with long Covid? Well, several laboratory studies have shown that metformin may work specifically against the SARS-CoV-2. It’s been found to inhibit the reproduction of the virus in cell culture and human lung tissue. Keep in mind, though, that you are more than a just bunch of cells or lung tissue. You do have feelings and other things. So just because metformin can keep the virus from reproducing in the lab doesn’t meant that it will do the same in live, whole humans.

Plus, while promising, this clinical trial was exactly one clinical trial. You should never deem something to be an effective treatment based on just one clinical trial. That would have been like calling Los Del Rio the next Beatles right after their song Macarena ascended to number one on the Billboard charts in 1996. People aren’t exactly lining up to do the Vámonos que nos vamos at weddings.

Moreover, this clinical trial did not include anyone younger than 30, with a BMI less than 25 kg/m2 or who had had COvid-19 previously. People under 30 do matter, really. So the results from this trial may not be generalizable to the rest of the population.

All in all, there needs to be more real scientific evidence before metformin can be recommended as a Covid-19 treatment. That means more studies and trials are definitely needed. Thank goodness for all the research funding that’s been allocated to study Covid-19...oh wait, that’s right, a lot of the money is no longer there.

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