Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial

Bramante, Carolyn; Buse, John B.; Liebovitz, David; Nicklas, Jacinda; Puskarich, Michael A.; Cohen, Kenneth R.; Belani, Hrishikesh; Anderson, Blake; Huling, Jared D.; Thompson, Jennifer L.; Pullen, Matthew F; Wirtz, Esteban Lemus; Siegel, Lianne; Proper, Jennifer; Odde, David J.; Klatt, Nichole R.; Sherwood, Nancy E.; Lindberg, Sarah; Karger, Amy B.; Beckman, Kenneth B.; Erickson, Spencer M.; Fenno, Sarah L.; Hartman, Katrina; Rose, Michael R.; Mehta, Tanvi; Patel, Barkha P.; Griffiths, Gwendolyn; Bhat, Neeta; Murray, Thomas A.; Boulware, David R.

doi:10.2139/ssrn.4375620

Cited by 13 publications

(12 citation statements)

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“…Modulating and decreasing the initial immune inflammatory response in COVID-19 may be beneficial in reducing the incidence of Long COVID. A recent preprint indicated a 42% relative decrease (6.3% vs. 10.6%) in the incidence of Long COVID in participants who received early outpatient COVID-19 treatment with the drug metformin with known anti-inflammatory effects (290) compared to a matched placebo control group (291).…”

Section: Long Covidmentioning

confidence: 99%

A review of cytokine-based pathophysiology of Long COVID symptoms

Low¹,

Low

Akrami

2023

Front. Med.

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The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

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Section: Long Covidmentioning

confidence: 99%

A review of cytokine-based pathophysiology of Long COVID symptoms

Low¹,

Low

Akrami

2023

Front. Med.

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“…3 More recently, metformin has attracted attention because of its capacity to partially prevent long COVID, showing a 42% relative reduction in a placebocontrolled randomized trial. 4 Last but not least, this biguanide has also been utilized for the treatment of antipsychoticinduced weight gain, acne vulgaris, polycystic ovarian syndrome, etc. 2 The mechanism of action is not fully elucidated, although its therapeutic effects are believed to derive from an insulin-sensitizing action.…”

Section: Water Pollutantmentioning

confidence: 99%

“…It is estimated that >150 million people each year take this drug, by far the most prescribed glucose-lowering oral medicine worldwide . More recently, metformin has attracted attention because of its capacity to partially prevent long COVID, showing a 42% relative reduction in a placebo-controlled randomized trial . Last but not least, this biguanide has also been utilized for the treatment of antipsychotic-induced weight gain, acne vulgaris, polycystic ovarian syndrome, etc .…”

Section: A Highly Prescribed Drug–a Ubiquitous Water Pollutantmentioning

confidence: 99%

Is the Environmental Risk of Metformin Underestimated?

Lertxundi

Domingo-Echaburu

Barros

et al. 2023

Environ. Sci. Technol.

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“…Regarding the role of pharmacological therapies, it is worth considering repurposing antihyperglycaemic medications, such as metformin, SGLT2-inhibitors, and GLP1 receptor agonists, as potential treatment strategies for long COVID. In a recent preprint, metformin has been shown to reduce the risk of long COVID by 63% if started within four days of symptom onset [16] . The postulated benefits of metformin include alleviation of inflammation [17] and inhibition of SARS-CoV-2 viral replication in vitro [18] .…”

Section: Introductionmentioning

confidence: 99%