Is metformin a super-drug?

I

Barts-MS rose-tinted-odometer: ★★★★★ (skoda baby pink Wednesday #cca49a)

Should we all be taking metformin? As you know metformin is being tested in a remyelination therapy trial in MS; it rejuvenates senescent oligodendrocyte precursors making them more likely to make myelin. 

The biology of metformin is fascinating as it also activates NRF2 the master transcription factor for programmed cell survival, which downregulates NFKappa-B the master pro-inflammatory transcription factor. I was surprised to find this paper below which shows the anti-ageing effects of metformin are not only limited to the brain but the thymus and the immune system as well. 

Please note that ketogenic diets and fumarates (dimethyl fumarate and diroximel fumarate) also transactivate NRF2 and are potentially anti-ageing. It is a great pity Biogen pulled the plug on the DMF secondary progressive MS trial. I think we should revisit fumarates in progressive MS in combination with other potential agents that target mechanisms that drive smouldering MS. 

The question I have is that in addition to a ketogenic diet should we all start taking metformin like so many other biohackers* are doing?

*Biohacking, also known as human augmentation or human enhancement, is do-it-yourself biology aimed at improving performance, health, and wellbeing through strategic interventions.

Fahy et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. 2019 Dec;18(6):e13028. doi: 10.1111/acel.13028. Epub 2019 Sep 8.

Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (-2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from -1.6 year/year from 0-9 month to -6.5 year/year from 9-12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

51 comments

  • Prof G,

    Isn’t the therapeutic landscape for MS becoming too complicated? We now have multiple licensed drugs which knock out B cells (and another dozen DMTs doing other things). But such therapies aren’t great at addressing smouldering MS ie the real MS. There are a staggering amount of trials testing therapies for remyelination eg metformin, neuroprotection eg simvastatin and cladribine, aberrant plasma cells (Sizomus), and testing the hypothesis that MS is viral (using anti-virals). This blunderbuss approach suggests that MS researchers don’t properly understand the disease and are generating hypotheses and testing therapies willy nilly in the hope that something sticks. Can you see a time when an MS patient will be prescribed 4-5 therapies to address the different aspects of MS, or is a Black Swan event more likely ie the cause / trigger of MS will be identified and treated with one therapy?

    • Well SID
      MS researchers research different things, based on their interest and is not a single cyborg collective with a single view.

      Can we see a time when MS patients are prescribed 4-5 differnt things, as we not there already you may have a DMT then something for symptoms pain, spasticity, bladder, etc. However if the damage is done you need protectiives and repairers. It is called biology. Having treatment options will be called progress….but the best way to deal with MS is to stop it in its tracks before the damage is done This is the only time one therapy is going to work because you are dealing with multiple systems that need different solutions

      Likewise all trials are based on a hypothesis and this is called science….

      The first metformin trial is metformin + clemastine based on the data from the Franklin Lab that metfromin rejuvenates the macrophages/oligo and clemastine is the repair….this trial will suffere if there is not DMT in the mix…I dont know the protocol. Then there is octupus

      The simvastatin phase III is based on the phase II and does not a clear mechanistic reason based on my talks, however, the cholesterol pathway is the number one dysregulated in neurodegenerative diseases. This trial will suffer if there is no DMT in the mix.

      The cladribine trial is an immune therapy.

      The sizomus trial is based on CNS lymphoma data and the view that CNS plasma cells are part of the process. This is a safety study

      The anti-viral trials, anti-HERV…em

      • David (on the basis that you don’t respect my anonymity),

        The point I was making was that MS research has been going on for some 60 years, but the number of possible MS triggers / drivers / mechanisms keeps getting bigger and more and more potential diverse therapies are being identified and trialled. Usually, it works the other way eg Sherlock Holmes has ten possible suspects, but whittles it down to one. MS research does seem like an ever growing gravy train where any hypothesis is thrown on the table and then tested (using up precious resources). If the Octopus trial fails, will heads roll (given the MS Smart trial)? If Metformin / clemastine fail to promote remyelination, will heads roll (given the failure of Bexarotene)? I look forward to the day when the blog can report a successful trial relating to neuroprotection, remyelination or repair.

        • As H.L. Mencken so memorably said “For every complex problem there is an answer that is clear, simple, and wrong.” Occam’s razor certainly does not apply when it comes to MS.

        • What would your suggestion be instead?

          Seeing that we have not yet found the solution, keeping on trying sure beats giving up in my book. That trials cost resources is somehow tautological, no?

          • My suggestion would collaboration between MS research centres. Many operate in silos on their pet projects. The individual centres run their little trials which are underpowered and have no chance of being taken forward eg lamotrigine. So resources are wasted. The proof of the pudding is in the eating. We still have no licensed therapies for neuroprotection, remyelination or repair – FACT. As we approach 2022 I find this scandalous given the money consumed to date. But I seem to be the only one who seems dissatisfied with the lack of progress.

          • Collaboration between centres equal octupus and MS stat2. You will have no licenced therapies until Pharma do it,

          • I can get behind that recommendation whole-heartedly. There are a lot of studies that could be done that way comparably cheaply.

            Where I disagree: I think EVERYONE is dissatisfied with the lack of progress but what does repeating it help?

        • @MD1, please respect the privacy of people who post as not all of us are out of the closet. This is something that is causing me anxiety, please don’t dox us D:!

          • Fear not! Sid (Not their real name) is still in their proverbial closet, but perhaps you have it the wrong way round who was outed them or me.

            We made the name of Sid.

          • ANON causes anxiety to a lot of people when he/she goes around sending misleading articles and telling every single pwMS here if they are not on IRTs their life is forever doomed. I call MD’s approach on the too mild side and ANON-like behavior needs to be moderated.

          • “ ANON causes anxiety to a lot of people when he/she goes around sending misleading articles and telling every single pwMS here if they are not on IRTs their life is forever doomed.”

            I guess it depends on what your definition of “life is doomed” is, but realistically 95% of MS patients are probably doomed to severe mental and/or physical disability eventually without a powerful IRT sufficiently early in the disease course. This blog is actually one of the few MS spaces where people can point out this unpleasant fact without being shouted down.

          • A lot of these are unproven opinions, not fact. And many pwMS doing ok with appropriate treatment. It is a major problem for those being undertreated when clear evidences are presented. And sure, I respect your opinion an IRT is essential (I don’t agree), but ANON is clearly over the line when he/she making comments to people quirying about other DMTS saying “you will be SPMS and only AHscT or Alemtuzumab will save you”

        • The point of a trial is to find out whether something works
          Makes NO SENSE for heads to roll if a trial fails

        • >the blog can report a successful trial relating to neuroprotection, remyelination or repair.
          Well they have reported two successful sodium channel blocker trials for neuroprotection, at least. These are first-line treatments for central neuropathic pain anyway so I see little harm in MS patients taking them.

      • I really appreciate your posts, but you guys really need to grow up in the comment fields.

        You guys really get offended easily… You have this blog and you encourage open and honest discussions, but when people ask questions, express their opinions, and perhaps sometimes challenge you, you immediately draw your pistols loaded with intimidating ammunition.

        Keep in mind that it is pwMS who have the most reason to be upset, sad, angry and frustrated. Not MDs and researchers with million pounds salaries and careers benefiting from diseases not being figured out.

        You also have monthly Q&As, but you rarely give any proper answers.

        Stay patient and empathic, or don’t bother.

        This goes for both you and ProfG. ProfK is a fantastic exception. He’s got manners.

        • It goes both ways……Don’t try to fight the trolls, the blog masters will take away your individuality.

          I previously was able to post comments under my name, which made me feel like I was part of a community, a family. I am a very private person, no social media, nothing. However, when I found this blog, it had such a profoundly positive impact on my mental and emotional health. I wanted to give back so I began posting comments, trying to help other pwms, sharing links and research articles. Engaging in discussions with MD1 and Prof. G.

          I began to share my MS story and have my MS community follow my DMT successes and failures.

          But then one day, I tried to call out a troll on a monthly Q&A. Someone must have complained, and so with no explanation the blog masters stripped my identity away from me and would not post my comments unless they were anonymous. It was devastating! It broke my heart to loose my identity on this blog.

          But somehow they let other individuals spew hurtful and disrespecting comments. Makes no sense.

          • I have no idea what you are talking about. I know nothing about black listing anyone. If you are taking shite or bile maybe you push yourself into bin. I will look but it makes no sense your ip address is the same and you can make any name up Sid today Bob tomorrow. Try again and.dont.dis other people

        • I think all of the authors are plenty patient.

          Some of the complaints, while understandable on the face of it, really do get old – especially the ones veering on conspiracy theories.

          • Thanks for your comment (sarcasm added).

            I provide an open and honest description of my experiences and you call me a conspiracy theorist…..nice.

            No worries, I have decided to no longer share my thoughts on this blog and just go back to being a silent observer. A shame IMO, as I am sure many readers would be interested how I progress with my OCR > TERI > CLAD DMTs. Why those DMTs failed and the secondary issues I acquired from taking those DMTs. Oh well.

            It was nice was it lasted. I hope some of the people on this blog found my previous comments helpful.

          • Thank you for your comment.

            I provide an open and honest description of my experiences and you call me a conspiracy theorist…..nice.

            No worries, I have decided to no longer share my thoughts on this blog and just go back to being a silent observer.

            It was nice was it lasted. I hope some people on this blog found my comments helpful.

          • Sensitive much?

            The post didn’t accuse anyone in particular of being a conspiracy theorist. Mostly I was referring to the ‘Pharma are holding good treatments back on purpose’ camp. There is plenty wrong with Pharma incentives (me too drugs, evergreening etc.) but that one simply does not make much of any sense.

          • when it is written you cannt get the context is it a joke, is it pointed? Do you spit the dummy…posting as anon I can still tell its you

  • My GP drew the line – v nicely – at Rx metformin for me. I had already convinced him to Rx simvastatin 80mg daily. He was comfortable with that as hypertension is his research interest, I’m a 52y old male, and he could swing that past any sort of audit.

    In general practice in the UK, metformin is only commonly used for Type 2 (NIDDM) diabetics so unless I get v overweight and out of shape, it is unlikely!

    Does anyone have experience buying this online? Quality assurance is my big worry.

    • I’ll just say that lots of people in the nootropics/biohacking community use metformin. It’s pretty easy to buy online from reputable sources. Try looking through longecity or the nootropics forum on reddit.

  • Some neurologists already prescribe statins to MS patients despite the trial still being underway and I have heard that some people take metformin. Is Metformin something you are offering your patients? And if so what strength?

  • There are c130,000 MSers in the U.K. A proportion of these MSers will have T2 diabetes and be on Metformin. Surely someone (a neuro) would have noticed if MSers on Metformin were doing better than MSers not on Metformin! If Metformin was improving remyelination etc. I think word would have got round. Are any readers of this blog (with MS) on Metformin? Are they feeling any better?

    • SID…Good spot
      Yes there are people with MS with type II diabetes and people with mS, type II diabetes and metformin and even MS, type II diabetes, metformin and dead and myelin histology performed…..Maybe I will ask where this is at the moment… However did people with MS, type II diabetes and metformin make miraculous recoveries…I suspect not so be prepared for incremental effects, if they are present

    • Yes, I was for like a half year. Can’t say anything about feeling better because I think it may help in the long run, if it is any good.
      The reason I stopped is because of my personal doubt metformin was limiting my ability to build up my condition for exercising. There also is a research paper were the result showed that (in diabetics) metformin+exercise was less efficient than metfotmin alone, or metformin alone.
      Any way, the doubts made me stop taking metformin and focus more on exercising. That works fir me right now.

      Maybe in the future, when I’m switched off DMF, I give it another try as a sort of add-on therapy and see whether it really conflicts with my ability for exercise.

      My own n=1 research is hard 🙂

  • What are the real risks in taking metformin for non-diabetics?

    I know a sizeable share of the biohacking community dabbles in it but they also dabble in some things that are fairly outthere so their judgment isn’t always beyond reproach…

    • https://www.rxlist.com/consumer_metformin/drugs-condition.htm

      Compared to the risk of damage from smouldering MS – I guess each to their own but it’s definitely on the “benefit” side of the risk-benefit curve for me.

      I can get it over the counter here. I think it’s one where they are “supposed” to insist on a prescription but so many people don’t and there’s loads of elderly people here. They’d rather people had access to metformin rather than clogging up the hospitals with diabetes patients on dialysis…

      • Simon,

        “Compared to the risk of damage from smouldering MS – I guess each to their own but it’s definitely on the “benefit” side of the risk-benefit curve for me.”

        I couldn’t agree with you more. There are no licensed drugs for inactive progressive MS – the patient is expected to watch themselves become more and more disabled. BTK inhibitors look promising, but won’t be available (if successful) for 4-5 years.

        There are drugs currently in trial (Simvastatin, Metformin) which have a known safety profile. If they have some effect on limiting the damage (brain atrophy) caused by smouldering MS, then MSers can make that judgment call. If neuros can only offer advice such as “exercise”, then patients need to take control ie decide whether the potential benefits of taking unlicensed therapies outweigh the risks.

    • My sister took it after what turned out to be a mistaken preliminary diagnosis of type 2 diabetes. We think the blood test must have got mixed up with someone else’s… or some other cock-up. However it happened she was prescribed it and took it as directed. Ok for the first week then a steadily worsening and worrying set of symptoms – horrible digestive issues, headaches then a feeling of being out of body, which was so bad she couldn’t drive. Together with brain fog and balance issues, by week four she was seriously unwell. The pharmacist suspected the dosage had been too high and she demanded an urgent GP appointment to be told she must stop metformin immediately. Further blood and urine tests came back as normal and she is not diabetic or even pre-diabetic. It was a nasty experience.

  • Seems that any fasting mimetic do the same trick(rapamycin,metformin)

    So why dont you fast ?

    Cost you nothing ,as no side effects and you dont need any doctor prescription

    Fasting and the fasting mimetic metformin rejuvenate poor
    remyelination in aged rodents

    Alternate-Day Fasting Enhances Remyelination in Aged
    Rats through Functional Rejuvenation of OPCs
    remyelination in aged rodents

    On the basis of these findings, we hypothesized that reversal of
    these age-related changes in OPCs might be necessary to reinstate
    their differentiation potential.

    Although remyelination in
    ad libitum-fed animals was restricted to the border of the lesion,
    animals undergoing fasting consistently exhibited nearly complete
    remyelination (Figures 3B and 3C). The clear difference in
    the extent of remyelination between the two groups was reflected
    by a blind ranking analysis of semi-thin sections of lesions
    as well as quantification of the percentage of remyelinated
    axons within the lesions (Figures 3B, 3D, and 3E). We also
    compared g ratios of control and treatment groups but found
    no differences, suggesting that the effect of ADF is on the extent
    rather than the quality of remyelination (Figure S5A). To further
    explore fasting-enhanced remyelination in aged animals, we
    characterized the recruitment, proliferation, and differentiation
    of OPCs during remyelination. At 7 dpl, there was no difference
    in the density of OPCs within lesions of animals subjected to fasting
    or ad libitum feeding (Figures 3F–3H). However, the density of
    mature oligodendrocytes (Olig2+/CC1+) was 2-fold greater in the
    lesions of fasting animals compared with those of controls at
    both 21 and 50 dpl (Figures 3I and 3J).

    This is a paper about metformin so ask your self why do they talk about fasting?

    Why?

    Metformin Restores CNS Remyelination Capacity by
    Rejuvenating Aged Stem Cells

    https://doi.org/10.1016/j.stem.2019.08.015

    • “Fasting and the fasting mimetic metformin rejuvenate poor
      remyelination in aged rodents”

      “This is a paper about metformin so ask your self why do they talk about fasting?
      Why?”

      Maybe…because it only works in Rodents.

  • Given, Metaformin is remylination agent. Then those diagnosed with MS do not have diabetes prior to diagnosis? Is this the case. I don’t think so. Also if so, do they do better in lower EDSS scores. We already have the data and don’t need to do whole clinical trials lasting decades. To come to the conclusion, probably, No effect.

  • Why was the plug pulled for secondary progressive patients? For DMF, surely there would of been plenty of profit and a benefit to patients if it does work, considering there’s very little treatment options available for SPMS.

    • A new CEO, a review of the pipeline, a challenge to the patent (it’s now off-patent in the US), the risk associated with SPMS, etc. In the end it was a business decision, not a scientific one. I know a lot of scientists at Biogen and they wanted it to go ahead.

      • Crazy, I would of though it made business sense if anything. Millions of people on DMF would surely be good for business, unless they were worried about generics after they did all the leg work

        • I think you have just the nail on the head. We approached Biogen to do a combination therapy trial with DMF as the base and were told as much. Very disappointing.

  • I took Metformin for two weeks, half dosage, and developed severe hypoglycemia with seizures. Not for me, but I wish it had worked.

  • More of a general antiaging question. Do ketogenic diets, intermittent fasting, metformin and fumarates effect other bodies systems like cardio and pulmonary? Cancer? Vanity wise, what about skin health and wrinkles?

  • What is wrong with pseudonyms as opposed to indistinguishable Anons?

    All the Anon commentators make it extremely hard to get clear on my own head who said what.

    I really struggle trying to follow the threads as it appears there is just one Anon who is all over the place.

    At least make it so a numerical differentiator is added to every additional Anon.

    Dom

    Ps: I realise I accidentally commented on this thread as Anon! Fat thumbs but I do have a picture.

    Pps: Personally, I think that if you are going to say something you ought to take ownership of it, so it can be attributed to you. Even if it is a pseudonym.

    • If you are going to challenge repeatedly it is best to get a pseudonym so readers can make you their champion e.g. Dr Dre but it allows others to see if it is just you being a pain in the bum repeatedly and they can choose to ignore

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