Metformin

Hutan

Hutan

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Staff member
Mij said:
New CAN-PCC @CochraneCanada recommendation out yesterday, including of note Metformin for the treatment of COVID-19 infection in people with Post Covid Condition. It's potentially practice changing.

Pharmacological and non-pharmacological clinical interventions for post-COVID-19 condition

Topic: Clinical interventions for PCC
In adults with post COVID-19 condition who have a new COVID-19 infection, the CAN-PCC Collaborative suggests using metformin (conditional recommendation; very low certainty in the evidence). Remarks: The regimen of metformin that was used in the two largest RCTs in non-hospitalized adults with acute COVID-19 was 750 mg twice daily for 10 days in one study, while the other study used a gradualy increased dose (day 1: 500 mg once, day 2-5: 500 mg twice daily, day 6-14: 500 mg in the morning and 1000 mg in the evening). This recommendation specifically applies to adults and not to children and adolescents.

LINK
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Given this recommendation for the use of metformin for people with Post Covid Condition who get a new Covid-19 infection, I thought it was worth having a discussion thread for it in the Treatment section.

Relevant research threads can be found by clicking on the metformin tag, top left.
 
Direct evidence
No direct evidence on the desirable effects of metformin vs. no metformin used for people with post COVID-19 condition who have a new acute COVID-19 infection was identified (i.e., no studies, neither randomized controlled trial nor observational studies that compared metformin vs no metformin in people with post COVID-19 condition were identified).

Indirect evidence
One RCT of 1,126 outpatient adults aged 30–85 years with overweight or obesity and acute COVID-19 reported that 14-day treatment with metformin started within 7 days of symptom onset resulted in a lower cumulative incidence of post COVID-19 condition (self-reported medical diagnosis) by day 300 of follow up (6.3% (95% CI 4.2–8.2)) compared to the matched placebo group (10.4% (95% CI 7.8–12.9); HR 0.59, 95% CI 0.39–0.89; p=0.012; ARR 4.1%, 95% CI 0.9 - 7.4) (1). There was minimal change in the HR after adjustment for confounding factors such as vaccination status (1). In a sub-group analysis, the effect of metformin in reducing the risk of post COVID-19 condition was greater when metformin treatment was started before day 4 since symptom onset (HR 0.37, 95% CI 0.15–0.95) compared to patients who started metformin treatment 4 days or longer following symptom onset (HR 0.64, 95% CI 0.40–1.03) (1).
Other surrogate outcomes for quality of life / daily living from the 3 RCTs of patients with acute COVID-19 are reported in the table.
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Here's the evidence quoted for the CAN-PCC decision. It seems to be based on some evidence that metformin helps with acute Covid-19 and one RCT suggesting that treatment with metformin lowered the risk of post Covid-19 condition. I'm not sure that translates to metformin being useful in people who already have post Covid-19 condition and get another Covid-19 infection, and it looks as though the authors of this guidance weren't sure either, but they figured that metformin was cheap, easily available and there weren't a lot of downsides to people being prescribed it.
 
Certainty of evidence: Very low.

I can only agree with that. Still don't understand why they only used overweight people which could bias any results towards Metformin or why Ivermectin was used in the first place. With that many different treatments I don't even know, were the studies actually truely blinded for anyone involved?

Wouldn't be suprised if it turns out to be a complete bust, similar to how initially people believed that "Paxlovid prevents LC" and it turned out that all of that research was so flawed no one should have taken it too serious and instead should have conducted better research to gain proper data.

I guess it's cheap and save, so I don't have any problems with the attitude of "at least were doing something", but I would prefer it if people were at the same time focused on getting solid data as well.
 
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I assume this is the paper suggesting that metformin reduces Long Covid, and reduces viral load.

[Preprint] Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial, 2023, Bramante et al.
SNT Gatchaman said:
In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months. Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.

Our results demonstrate, consistent with model predictions, that a safe, widely available, well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

Link | PDF (Preprint: MedRxiv)
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The thing I enjoyed is that Caroline Bramante, the principal investigator of the Metformin trials, seems to be very open with the fact that they do not know whether it works at all and that they cannot be certain that it works via antiviral effects (for LC). In fact I remember her saying in a talk that she didn't even believe that the results were statistically significant but that a colleague convinced her of something else.
 
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For what it's worth I tried this with my third infection. I got long covid from my second infection.

My long COVID wasn't fully resolved by the time I got my third infection. I was probably 60 to 70% my pre COVID level.

I got boosted and got novavax for the first time and for the first time in four years my ME didn't relapse. I then got COVID about 11 days later. I had started Metformin before my third infection because I've had terrible pain in my hands and spine as a symptom of long covid. My Dr suggested it was worth a shot. It feels like very bad tendonitis I guess in my spine it's like weakness and pain at a specific set of spinal junctions/vertebrae. Never had it before and still hope to find a treatment as it really reduces my qol.

I titrated Metformin from 500mg to 1500mg over 5 days. But as I increased the dose my brainfog worsened, I experienced nausea and the nausea became severe as time went on. I then started to experience quite severe depression as well on the verge of tears worrying about things that aren't worth thinking about. Whilst it could be from COVID I've recovered quite quickly and had a mild infection. I took a break from Metformin for 24 hours felt loads better and then 30 to 40 mins after restarting it the depression and some of the nausea came back. So that's sealed it as causative for me.

So that's just my two cents. The really strange thing is that I haven't experienced the same sort of brainfog and fatigue - I haven't got any - that I did from my second COVID infection. Also when I got COVID the first time I was booster again got COVID 12 days post booster and had a mild non breakthrough infection which resulted in bad brainfog and physical fatigue that didn't lift 3 weeks later. So I was therefore expecting to experience brainfog and fatigue but I haven't.

Hopefully someone finds this useful.
 
I forgot to add that when I started merformin for my LC and specifically my painful hands (no diagnosis yet) I experience a viral herx aches pains fatigue and malaise that evening and overnight but felt better and had way more energy + physically less weak the day after.

I took Metformin for a few days at low doses 200 to 300mg but it gave me very bad insomnia which is a common issue. So I had to stop. But again I felt stronger.

So I think as an immune modulator it does have efficacy and the ability to improve symptom state in some people. But it's not straightforward I think that's the bottom line.

Also in the study for Metformin and acute COVID it helped obese women a lot more than it did healthy women and men. But time to viral clearance was superior to paxlovid and molnu by day 10.
 
First study now out in preprint looking at acute COVID (LC results to follow).

Metformin on Time to Sustained Recovery in Adults with COVID-19: The ACTIV-6 Randomized Clinical Trial
Carolyn T. Bramante; Thomas G. Stewart; David R. Boulware; Matthew W. McCarthy; Yue Gao; Russell L. Rothman; Ahmad Mourad; Florence Thicklin; Jonathan B. Cohen; Idania T. Garcia del Sol; Juan Ruiz-Unger; Nirav S. Shah; Manisha Mehta; Orlando Quintero Cardona; Jake Scott; Adit A. Ginde; Mario Castro; Dushyantha Jayaweera; Mark Sulkowski; Nina Gentile; Kathleen McTigue; G. Michael Felker; Sean Collins; Sarah E. Dunsmore; Stacey J. Adam; Christopher J. Lindsell; Adrian F. Hernandez; Susanna Naggie; the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators

IMPORTANCE
The effect of metformin on reducing symptom duration among outpatient adults with coronavirus disease 2019 (COVID-19) has not been studied.

OBJECTIVE
Assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2.

DESIGN, SETTING, AND PARTICIPANTS
The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, 2991 participants age >=30 years with confirmed SARS-CoV-2 infection and >=2 COVID-19 symptoms for <=7 days, were included at 90 US sites.

INTERVENTIONS
Participants were randomized to receive metformin (titrated to 1500 mg daily) or placebo for 14 days.

MAIN OUTCOMES AND MEASURES
The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving study drug. Secondary outcomes included time to hospitalization or death; time to healthcare utilization (clinic visit, emergency department visit, hospitalization, or death). Safety events of special interest were hypoglycemia and lactic acidosis.

RESULTS
Among 2991 participants who were randomized and received study drug, the median age was 47 years (IQR 38-58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.3% reported >=2 doses of a SARS-CoV-2 vaccine. Among 1443 participants who received metformin and 1548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR] 0.96; 95% credible interval [CrI] 0.89-1.03; P(efficacy)=0.11). For participants enrolled during current variants, the aHR was 1.19 (95% CrI 1.05-1.34). The median time to sustained recovery was 9 days (95% confidence interval [CI] 9-10) for metformin and 10 days (95% CI 9-10) for placebo. No deaths were reported; 111 participants reported healthcare utilization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81-1.75; P(efficacy)=0.135). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. Five participants in each group reported having hypoglycemia.

CONCLUSIONS AND RELEVANCE
In this randomized controlled trial, metformin was not shown to shorten the time to symptom resolution in adults with mild to moderate COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population.


Link | PDF (Preprint: MedRxiv) [Open Access]
 
The first time I was on metformin (for diabetes) I kept going hypoglycemic, so I stopped taking it. The second time I had a leg go black and four areas of skin fell off, resulting in ulcers. This was the same leg that had been badly damaged by a fall and subsequent surgery. While metformin is generally well tolerated, its possible that in some with post pathogen syndromes it might be an issue.
 
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