Metformin Good news for females?

M

We know that old age is a risk factor for severe COVID-19 and one finding is old-age of the immune system.

We have suggested that macrophages may be an important line of defence.

It has been suggested that the diabetes drug metformin can rejuvinate macrophages to promote remyelination.

Therefore, metformin should offer advantage to the diabetics who get COVID-19.

It seems there is in females

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with COVID-19. Bramante C, Ingraham N, Murray T, Marmor S, Hoversten S, Gronski J, McNeil C, Feng R, Guzman G, Abdelwahab N, King S, Meehan T, Benson B, Pendleton K, Vojta D, Tignanelli CJ. MedRXiv doi: https://doi.org/10.1101/2020.06.19.20135095

Metform in reduced COVID-19 death risks by 21 per cent to 24 per cent among the females who had become infected with the virus and had already been taking metformin.

“This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in COVID-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.”

Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex. Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNF-alpha inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983). Conclusions Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in Covid-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.

I wonder what will happen in MS?

Does this mean that men should not be part of any metformin trials?

What do you think?

About the author

MouseDoctor

12 comments

  • Out of interest regarding metformin were this to be used in Ms how have the trials dealt with the very common side effect of diarrhoea amongst its trial participants?

  • I have come across mention of metformin use for remylination before, but it was argued “then why does a person with diabetes and ms still progress”… maybe they progress, but slower cos the metformin is repairing the damage and if no metformin the progression would be worse?

    Is it a really bad thing that all ms patients take metformin? Whats to lose at this stage?

  • An investigation into the SFK-AMPK signaling axis and its role in CNS myelination
    M. Narine1,2, A. Volz1, I. Tzvetanova3, H. Colognato1,2
    1Department of Pharmacological Sciences, Stony Brook University, Stony Brook, US
    2Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, US
    3Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, DE

    Src family kinases (SFK) are a family of non-receptor tyrosine kinases that integrate and transduce information
    about the extracellular environment to regulate downstream intracellular processes. The SFK member Fyn is
    needed for normal myelin production, with a global knockout of Fyn or loss of Fyn kinase activity resulting in
    severe hypomyelination. Conversely, we found that constitutive activation of Fyn in oligodendrocytes (via loss of
    C-terminal Src Kinase (Csk), a negative SFK regulator) leads to increased myelin wrapping (hypermyelination) in
    the brain and spinal cord. Hypermyelination in Csk knockouts was, surprisingly, not accompanied by detectable
    changes in MAPK or mTOR pathway activity, two pathways known to control the extent of myelin wrapping.
    Instead, Csk loss was accompanied by a 7-fold increase in AMP-kinase (AMPK) transcripts. AMPK acts as the
    metabolic sensor in the cell and is activated during energy intensive processes (e.g., myelination) to regulate the
    activity or expression of proteins involved in ATP synthesis. Exogenous activation of AMPK can be achieved with
    metformin, a drug used to treat type 2 diabetes. We found that metformin treatment of oligodendrocyte
    progenitor cells increases the expression of myelin proteins (MBP, CNP) and accelerates the generation of
    mature oligodendrocytes. Studies to evaluate the ability of metformin to influence myelination and/or myelin
    repair are currently underway. The ability to manipulate the SFK-AMPK signaling axis may prove to be beneficial
    in the development of remyelination therapies aimed at combating demyelinating diseases such as Multiple
    Sclerosis.

    Ampk

    5′ AMP-activated protein kinase or AMPK or 5′ adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low

    Activation of AMPK signifies low energy within the cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell.[12]

    https://en.wikipedia.org/wiki/AMP-activated_protein_kinase

    Fasting activates Ampk too

  • I don’t understand why it’s working less in man than in women. What makes the difference? What do I miss?

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