#25: Metformin For Long Covid

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LongCovidMD.com

In this episode of The Medicine Cabinet series, I explain how Metformin, a drug we often associate with diabetes, helps acute covid and may help Long Covid.

Metformin is an old, relatively inexpensive medication that has many established off-label uses. I explain its mechanisms of action, who it might be right for, and I discuss the recently published COVID OUT research findings that supported metformin's use in acute infection. It reduces hospitalizations, death, and the development of Long Covid.

What does that mean for those of us who already have Long Covid? I share my opinions.

Research Links
COVID OUT metformin dose used: 500mg on Day 1, 500mg twice daily on Days 2-5 and 500mg in the AM and 1,000mg in the PM on Days 6-14

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214027/

https://www.medrxiv.org/content/10.1101/2023.06.06.23290989v1

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00299-2/fulltext#%20

https://academic.oup.com/cid/article/79/2/354/7660393?login=false

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10595158/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9111510/#:~:text=Recent%20evidence%20has%20shown%20that,has%20immunomodulatory%2C%20anti%E2%80%90inflammatory%2C

CURE-ID Database
https://cure.ncats.io/home

Chapters

• 0:00 Introduction and Overview
• 2:54 Understanding Metformin: Mechanism of Action and FDA USe
• 8:02 The COVID OUT Studies: Metformin's Impact on Acute Covid Infection
• 12:21 Metformin's Potential in Preventing Long Covid
• 18:38 Considerations for Using Metformin in Long COVID Treatment
• 25:47 Conclusion and Call to Action

Transcript

Zeest Khan (00:00)
Hi, I'm Dr. Zeest Khan, the Long COVID MD. I'm a physician with long COVID and I've applied all of my medical expertise to my recovery. Luckily, it's working and I want to share what I've learned with you. On this podcast, I help you understand your body and understand the healthcare system so you can move your own health forward.

We've got a lot to talk about, but remember, nothing I say here replaces personalized medical advice from your healthcare team. Let's get started.

Zeest Khan (00:38)
I like to keep these medicine cabinet episodes relatively short. This one is going to be a bit longer because we're talking about metformin and it's been in the news recently. There's a few recent studies published on the use of metformin in COVID and how it impacts long COVID.

So I'm gonna talk to you as always about the medication, its FDA uses, its history, its mechanism, its side effects. And then I'm gonna talk about the recent COVID OUT publications. We'll get into all of it. So this is gonna be a little bit longer of a medicine cabinet episode, but hopefully it's gonna be worthwhile and you're gonna learn a lot. So let's go.

Metformin is a drug that's been around since the 1920s. It has gained increasing interest recently as a treatment for acute and long COVID. So today I'm going to give you an explainer on why that is. Metformin is taken by over 150 million people around the world every year. It is a well -known, well -studied,

and overall safe medication that's readily available and inexpensive. So far, it's checking off a lot of great boxes. It's in the news right now because researchers based at the University of Minnesota conducted a randomized control study called COVID OUT

and published several findings in recent weeks. Together, the studies demonstrated pretty dramatically that metformin helps prevent an acute COVID infection from becoming severe and that metformin reduces the risk of developing long COVID. Those are really promising developments, so I wanna share more details about the studies. But first, as always in the Medicine Cabinet series, I'm gonna take a bird's eye view of this medication

explain its history, how it's currently used, its safety profile, and who might benefit.

Metformin is FDA approved for the treatment of type 2 diabetes, and it's available by prescription only. It was first marketed, however, in the 1950s to treat influenza. I'll talk more about this in a little bit. Metformin is what we call a pleiotropic drug, meaning it has multiple seemingly unrelated effects on the human body.

It works on several pathways, so it's been used for conditions other than diabetes for a long time. To say that another way, it's been used off -label for a long time. It's commonly prescribed to prevent diabetes in patients who are pre -diabetic. It's used to prevent diabetes in people taking certain antivirals, commonly for HIV.

And it's used to treat the symptoms of polycystic ovarian syndrome, including infertility.

Not only that, it's been used as an adjuvant treatment in some cancers to help cancer treatments like radiotherapy, chemotherapy, and immunotherapy work even more effectively. And since the 1950s, metformin has been used to combat serious diseases that develop after a viral infection. I'm talking about things like ARDS, acute respiratory distress syndrome.

which is a state that often requires mechanical ventilation and can ultimately lead to death.

How does it work? Metformin belongs to a class of drugs called biguinides derived from the compound guanidine, which is found in the French lilac flower, or lilac, depending on where you live in the US anyway. Metformin stabilizes insulin levels in the blood in three ways. One, it prevents the production of glucose in the liver,

Two, it improves the body's sensitivity to insulin. And three, it reduces the amount of sugar absorbed by the intestines.

There's another way metformin stabilizes blood sugar that makes it a drug of interest to those of us with fatiguing illnesses. Metformin activates the enzyme AMPK. That stands for adenosine monophosphate kinase. In addition to helping insulin do its job, AMPK does two more things. It helps glucose get to muscles

and it replenishes ATP when it's depleted. ATP stands for adenosine triphosphate, and it is the cellular unit of energy. It is very important in our ability to move and for our organs to function. When we talk about comparing our symptoms to

battery or a tank of gas in a car. ATP is the equivalent of that gas and that battery.

It's metformin's impact on AMPK that has made it a drug of interest to treat not only diabetes, but also obesity, aging, and cancer.

Next, it's important to know that metformin has antioxidant properties and anti -inflammatory properties. It reduces several inflammatory cytokines, including IL -6 or interleukin -6,

It also seems to have a positive effect on the gut microbiome that helps bolster the immune system. We know more and more that the gut microbiome is very important to the immune system and probably a whole branch of the immune system.

There's also evidence that metformin reduces inflammation in blood vessels, at least for people who are hospitalized with severe illness. Some studies suggest metformin significantly helps prevent the dangerous inflammatory response that viruses like COVID triggers called a cytokine storm.

That's when the inflammatory system responds robustly and maybe too robustly and that inflammatory storm or that inflammatory response itself may cause damage.

Metformin has been used to treat severe COVID infections since the beginning of the pandemic because it has known antiviral properties against several other viruses, including influenza, hepatitis B, hepatitis C, Zika, and dengue. Now some of the antiviral effects

against these viruses were found on mice models. Some effects were more significant when obesity was a factor. There is nuance to this. There are specifics to this statement, but there was enough established evidence that it was reasonable to try metformin against this viral hit when the pandemic started.

Since those early experimental days when doctors were trying everything they reasonably could to save people from dying from COVID, we found that indeed metformin inhibits the growth of SARS -CoV -2, at least in cell culture. The recent COVID OUT study, which I'm gonna talk about more in a moment,

strongly suggests that metformin inhibits the growth and replication of SARS -CoV -2 in our bodies as well.

Metformin has been so effective that current COVID guidelines recommend that a patient with diabetes who has already been using metformin and presents to the hospital with a COVID infection should remain on metformin for the duration of their hospitalization. Whether or not the patient has elevated blood sugar during their stay, metformin

stays on their medication list because it's been found to reduce the chance that the SARS -CoV -2 virus will become severe. And metformin in this patient population actually reduces mortality from an acute COVID infection.

Safety and accessibility. Metformin is a generic old drug, which means it's inexpensive and accessible. It's safe for most people to use, even if you don't have diabetes. Because it's not a potent diabetes medication, the way insulin is, the risk for developing hypoglycemia or low blood sugar is a real risk, but it's a low risk.

metformin is safe to use in pregnancy and in children.

COVID -OUT. COVID -OUT is the name of a clinical trial studying three generic medications, metformin, ivermectin, and the antidepressant fluvoxamine. It studied these three generic medications on COVID and long COVID outcomes. The name of the project is a bit of an acronym. I think that the OUT

of the name refers to the fact that the study was designed to care for people in the outpatient setting in their own homes. So participants receive the medications without having to drive into a centralized lab or research facility. This is a really innovative design that many long COVID advocates have been supporting.

And I hope it is replicated because by decentralizing the study, allowing patients to stay at home, more participants were eligible and patients did not have to drive in to a facility. So it makes sense that it would be easier to commit to the study for an extended period of time.

or for the entire duration.

Who did COVID OUT study? Who were the participants? They were patients with an acute COVID infection who were diagnosed within three days or had symptoms for no more than three days, who were overweight or had obesity. They were aged 30 to 85 and otherwise they were low risk. There was a pretty decent split between the genders and

pregnant women were also included.

COVID -out is a randomized, blinded, and placebo -controlled clinical study. This is the type we really need. So several findings of the COVID -out project hit the press recently based on the results of the group of participants who received metformin during their infection. These participants, which were several hundred,

received a 14 -day treatment with metformin that started at a kind of high dose and then tapered down. And here's what they found. I'll quote the study's abstract or quote -ish. In the COVID out phase three randomized placebo -controlled trial of outpatient treatment of COVID -19, metformin had a 42 % reduction.

in ER visits slash hospitalizations slash death through 14 days. Metformin had a 58 % reduction in hospitalizations slash death through 28 days. And Metformin had a 42 % reduction in long COVID through 10 months. End quote.

So additionally, when metformin was used in the first four days of symptom onset, it reduced the risk of developing long COVID by 63%.

That's remarkable. And it doesn't stop there. A subset of the participants were studied for viral load. Metformin reduced viral load during the acute infection by quite a bit. It was a 3 .6 fold reduction in viral load. When the researchers adjusted for variables like

baseline viral load, vaccination status, and time since their last vaccination, the results remained similar.

Lastly, the metformin group had a lower rate of rebound than the placebo group. And as a refresher, rebound is a return of symptoms or test positivity after a resolution of symptoms or test negative.

So what can we conclude? COVID out supports the use of metformin in people who are overweight and otherwise low risk who have an acute COVID infection. That's what we can pretty strongly conclude from this data. But there's a lot that's still inconclusive. But there's a lot that is still inconclusive.

we don't know how metformin compares in these measures against PaxLovid, primarily because we don't have similar clinical trials for PaxLovid. We certainly have studies demonstrating reduced mortality for high -risk patients, but the few retrospective studies on lower -risk patients that were kind of similar to this patient demographic,

Those studies demonstrated conflicting results.

regardless, for many people, Paxlovid isn't even an option when they get a COVID infection. This could be because they have an existing health issue, that's a contraindication, or because they are on medications that are not compatible with Paxlovid. Additionally, there's many patients who can't access Paxlovid.

because their doctor or provider won't prescribe it. The prescriptions are being written much more stringently now.

COVID out findings give patients a readily available, inexpensive, and effective option to minimize the risk of an acute COVID infection at home if they can't or when they can't get Paxlovid.

So at this point, you might be wondering, if I catch COVID again, should I use metformin and Paxlovid? The two drugs are technically safe to use together, meaning they don't have dangerous drug interactions. But we don't yet know if the two would work synergistically to improve COVID outcomes even more than what metformin demonstrated.

We don't know if they might inhibit one another. So the answer is we don't know yet if you should use both.

So that's metformin and that's the COVID out studies for the acute COVID infection. Now let's get to long COVID. These studies are very remarkable, like I said, that metformin reduce the risk of developing long COVID so dramatically.

But what does the COVID out study mean for those of us who already have long COVID?

I have to be clear, these published projects did not study metformin as a treatment for existing long COVID. So we can't use these studies to say that it will help us. Metformin is certainly promising though. The same unfortunately was said about PaxLavid. Metformin is certainly promising.

as a treatment for long COVID because it is effective against acute COVID. But the same is true for PaxLovid. And I'll remind you that there was a PaxLovid study for long COVID at Stanford last year. It was cut short because the results were clear early on that PaxLovid, while it was helpful to treat acute COVID, was not an effective treatment for long COVID.

Whether or not the same is true for metformin, we don't know yet. They work by very different mechanisms. So, you know, attributing one conclusion to the other is not reasonable to do yet.

I don't know if there's a plan to study metformin for long COVID, but I would certainly be disappointed if there isn't. If you know more about that, please let me know and I'll share it with the community.

So the big question, what should you do based on this information? First, if you get another COVID infection and paxlovid isn't available to you, please push for metformin. The dose used in the study will be listed here in the show notes, and I'll include them in the upcoming newsletter, and I'll talk to you more about the newsletter at the end too.

So if you get reinfected, strongly consider getting metformin. But how should you decide if metformin is worth trying for your existing long COVID symptoms? First thing, make sure you don't have a contraindication. While it does have a generous safety profile,

Metformin may not be safe for people with certain kidney conditions or heart failure. And you want to make sure that it plays well with the other medications you're taking.

Metformin is well known to cause gastrointestinal discomfort. So keep that in mind as well. You might be one of the many people who has significant GI issues from COVID. And I know that can be debilitating itself and you don't want anything to worsen it. So after you and your doctor determine that you're a candidate for metformin, the next question is to

answer. The next question to answer is how willing you are to try a medication that has theoretical value but no substantiated mechanism for treating your symptoms.

Now, a lot of medications we're using for long COVID fall into this category. And I will say that metformin is not a shot in the dark type of therapy. There is mounting evidence of its benefit against inflammation in general and against the SARS -CoV -2 virus in particular. It's also relatively inexpensive

and it doesn't have a glaring red flag side effect the way, for example, anticoagulants do. So what I basically mean is while the benefit is not verified for metformin, the benefit does have a strong theoretical and evidentiary basis, and the risk for most people is low.

I'm going back and forth here, but I'll also point out that we're making several big assumptions. We're assuming that the inflammatory cascade that metformin interrupts actually contributes to our symptoms, or we're assuming that the antiviral properties will help us, and or,

we're assuming that the antiviral properties metformin has will help us because we have persistent virus or virus that hasn't cleared or a viral reservoir that is contributing to our symptoms. While these assumptions are being actively studied and many scientists believe that they may be the cause of long COVID, for now,

they remain assumptions.

If you decide to start metformin as with any treatment you try, I recommend that you have some way of tracking symptom improvement. Is this medication helping? In what ways is it helping? And how much?

In a future episode, I'm going to dive into the ways you can track symptoms effectively and simply. But for now, I suggest deciding on one or more symptoms to track before you start metformin or another treatment and then reassess at various intervals. Which brings me to my next point. If we start metformin, how long do I stay on metformin? How long does it take for it to start working?

How long do I need to remain on it if it is working? As for many issues surrounding long COVID, I don't think we have an answer for that. You might decide to start Metformin and then check in at two months, four months, six months, reassess your symptoms, assess how you're tolerating the medication, and go from there.

In general, metformin is pretty safe to use long term.

So that's the big and small of metformin for long COVID. Consider discussing metformin with your doctor. And if you're willing, let me know what you decide. I can't advise you more specifically on how to approach this. And we might end up finding that metformin isn't worth taking for long COVID. But I have to admit, the more I learn about metformin, the more encouraged I've become.

I will share that I've been taking metformin since my COVID infection in March of this year. The nausea for me does not subside. I'm nauseated with every dose. It lasts for a few hours. And I think it's gonna be a limiting factor for my extended use, but otherwise I'm tolerating it pretty well.

Since March, I have made some wobbly but steady progress in my fatigue, but I can't say that it's from metformin alone. I'm staying on it though, as I'm staying on low dose naltrexone. I'm gonna stay on it for as long as I can tolerate at a dose that I can tolerate because it has anti -inflammatory properties.

And I think I'm going to do that until the evidence demonstrates that it is not worth taking.

What do you think? Has metformin been in your medicine cabinet? Have you had a conversation about metformin with your doctor? Does your doctor know about metformin as a possible treatment option for long COVID? If your doctor isn't familiar, you can refer them to the CureID database. I see 14 case reports using metformin for long COVID symptoms. I am

I know for a fact more than 14 people have been prescribed Metformin for long COVID symptoms. Unfortunately, people are not uploading their experiences to the database. So to remind you, CureID is a project that's led by the FDA, but it's a joint project with private sector groups, and it allows clinicians and patients

to share medications that they're using for off -label purposes. There is an entire section dedicated to long COVID that was designed with the help of long COVID advocates. I've shared my data on there. You can share your experience, but you can also extract data in real time. So you can go to the website, hit the long COVID button

and search by medication. And you'll see how many case reports report that they have been using metformin as part of their treatment.

I will link that also in the show notes and in the newsletter. So speaking of the newsletter, I am going to email a newsletter in a few days with bullet points of this episode, including references. And I hope it could be helpful in you understanding what we've discussed here.

and it might be helpful in the conversation you have with your doctor. I started the newsletter recently to supplement this podcast. for the episodes I do on treatments like the medicine cabinet series, I'm gonna organize the articles in a way that you and your doctor can use.

as a resource during your office visits. That's my goal anyway, so I'm very open to feedback and what you need to help you both comprehend information and share that information easily.

Sign up for free at longcovidmd .substack .com or by using the link on my website, longcovidmd .com. I'll ask here to refer a friend or a member of your healthcare team to the podcast and the sub stack so that we can expand our reach and educate people on how long COVID presents and the urgent need for effective solutions.

Thank you for listening to the Long COVID MD podcast. I'm Dr. Zeest Khan. I hope you're feeling well and until next time, bye for now.