Threading the needle: a strategy for taking metformin but avoiding sarcopenia (?)

Have been trying to figure out how to achieve the optimum balance for me personally. It seems that many of the readers on this forum are more “anabolic,” and are taking rapamycin. I myself am more catabolic: a thin, small-boned, osteoporotic, low-muscled older female. Searching for the right strategy to avoid sarcopenia, and hopefully build muscle. Recently did a scan that confirmed my suspicions: very low fat but very low metabolic rate, likely because there is so little muscle. (It goes without saying that I need to do more and heavier resistance training).

So, I take metformin (also a little Berberine) to keep glucose at an acceptable level (Repatha drives it up and it was slightly high even before starting that). But metformin stunts muscle hypertrophy, and that scan heightened my alarm about the metformin. What to do? Considering microdosing a GLP1 but my experience with even the tiniest starter dose of Rybelsus was a disaster – lost weight fast (not what I needed to do) and developed gallstones.

So, just found research showing that taking leucine plus sildenafil together with metformin can at least partially prevent the metformin from stunting the growth of muscle. The protocol for this combination is "
0200". It was written up in several publications such as the Journal of Obesity. As I do not eat red meat I was already taking a small intermittent dose of leucine plus tadalafil. Will increase the leucine. This seems like a low risk, low cost strategy to at least partially blunt the negative effect of the metformin.

Would appreciate having opinions and pointers on this.

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Ditch Metformin and take Imeglimin instead.
Plenty of reasons why in the Imeglimin thread, including that one.

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Seconding @cl-user wrt. imeglimin. As I recall, you have extremely low insulin levels with that elevated glucose. It is possible - just a hypothesis - that you have some beta cell defect obstructing insulin production/release. In this context, imeglimin is especially helpful as it fixes beta cell defects along a certain pathway (go to the thread for more details). Given your biomarkers you seem like a very good candidate for imeglimin based on its MOA. Not a doctor, not medical advice, YMMV.

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https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202100883R

The combination of metformin and leucine also fails to improve muscle volume. Leucine itself is a potent mTOR activator that every fitness enthusiast takes for muscle growth; however, building muscle is difficult even without taking metformin. Hypertrophy requires high levels of testosterone. If your goal is to build muscle, I suggest you ditch the metformin; otherwise, no matter how much resistance training you do, it will be a wasted effort.

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https://onlinelibrary.wiley.com/doi/10.1111/obr.13035

While low body fat helps extend lifespan for young people, the opposite is true for the elderly. This explains why Dr. Alan Green, who prescribed Rapamycin for anti-aging to over 1,500 people, didn’t even live as long as the average American life expectancy.

There is also the Editor-in-Chief of the journal AgingMikhail Blagosklonny—who was the first to publish on Rapamycin for anti-aging and one of the earliest to take it himself; yet he reportedly only lived into his 70s. Even intermittent inhibition of mTOR can be fatal for the elderly, let alone combining it with Metformin. Even David Sinclair avoids taking Metformin on workout days, so imagine the risk for seniors. The elderly actually need body fat and muscle mass to protect themselves.

As for Imeglimin, there is absolutely no reason to take it. In discussion threads regarding Imeglimin, no one can produce a single peer-reviewed paper related to anti-aging; it’s all just AI-generated nonsense. There is no point in looking into it further. Without a shred of actual anti-aging research, people are simply fantasizing about it being a replacement for Metformin.

Strange. The two sentences above are non sequiturs. Let us go ahead and assume that imeglimin is not anti-aging. It also starts with the letter “i”. And? How does it follow from that that there is “absolutely no reason to take it”? There is no connection. Has the OP asked for a way to slow aging and a drug to slow aging? No. Go and re-read the first post - not a single word about anti-aging. Instead, there is a question about controlling blood sugar without sarcopenia. So what on god’s green earth is this “anti-aging” doing here? Very odd. There may be a million and a half reasons to take it entirely and comprehensively apart from any effect on aging. If your blood glucose is too high, you may want to take imeglimin just as you may want to take metformin. We - biohackers - such as people on this site, regularly take drugs that have zero impact on aging. We take them not in hopes of slowing aging, but to prevent a disease process that might cut life short. It’s fixing a weak link. Just like a statin. The statin won’t make you age slower, but it might prevent a catastrophic failure and premature death. Scads and scads of drugs and supplements are taken for prevention purposes, or health enhancement, the famous interplay between healthspan and lifespan. In fact, there are precious few drugs with good evidence behind them - in humans - that they are anti-aging per se. If that is your standard, you may as well close down this site altogether with a note “here are some maybes: rapamycin, sglt2i, acarbose - none proven in humans”. Sum total. So the paragraph quoted I think is very silly - and also wrong inferrentially. Not only does this not address the questions OP asked, not only does one statement not follow from the other - a crude logical error - but it represents a failure to understand the purpose of biohacking at all as practiced by 100% of biohackers.

And now that we’ve disposed of this utter nonsense, getting back to imeglimin, it appears a very good candidate drug to control excess blood sugar and perhaps prevent the undesirable effects of such a condition, without one of the concerns wrt. metformin, effect on muscle - given the scenario outlined by the OP. This is what the OP asked - is there a way to thread the needle. A very sensible suggestion was to explore imeglimin as a possible way to thread that particular needle. And here we are.

By the by, the referencs to Blagosklonny and Dr. Green are wide - VERY WIDE - off the mark. Those two died not because of being underweight or sarcopenia, but as a result of lung cancer and a genetic heart condition respectively. Zero to do with weight, sarcopenia, catabolism, fat levels, muscles or any of the stuff mentioned in those other bizarre posts.

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I take metformin in 100 day cycles (100 days on 100 days off). I have noticed zero impact to my weight lifting results either way. Just an anecdote from one guy.

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anti-aging includes preventing disease processes that shorten lifespan, reducing cancer risk, or lowering all-cause mortality—these are all anti-aging measures. Your fundamental understanding is deeply flawed. Don’t be so black-and-white about everything. Moreover, there are far too many errors for me to bother correcting one by one, as this conversation is already built on a flawed foundation.

I’ve never heard high-profile longevity figures like Bryan Johnson mention or take Imeglimin. Currently, it only has data for treating diabetes and lacks any cardiovascular outcome trials (CVOT). It isn’t even mentioned in the US diabetes guidelines because it simply doesn’t meet the criteria yet.

I suggest you stop being rude to established members of the forum. It is entirely fair to argue about what is and what is not established science, but phrases such as:

Your fundamental understanding is deeply flawed. Don’t be so black-and-white about everything.

Do not add to the debate and are merely insults.

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I thought we had established that metformin is not much use for people who are not at least prediabetic and potentially only of use for people who are diabetic.

I can search out some of the papers on this, but from memory the original papers that suggested a longevity merit had a selection bias and there have been other papers identifying problems. (putting aside any effects on muscle maintenance).

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Um, that’s why it is nonsensical to dismiss imeglimin like you did as “absolutely no reason to take it”. Imeglimin was developed exactly in the context of metabolic disease centered around glucose regulation. There are studies showing efficacy in lowering glucose levels and A1c, similar to metformin but with distinct mechanisms and MOA. It is a very useful drug in the anti diabetic armamentarium. Dismissing it as “absolutely no reason to take it” is exactly “black and white” thinking. Furthermore, your understanding of anti-aging “is deeply flawed” - anti-aging has a very specific meaning in biology, as in slowing the intrinsic aging process that results in extension of max lifespan (example: rapamycin, CR), not normalizing lifespan by preventing life shortening morbidities. And if you were to be consistent in your application of the term “anti-aging” (wrongly, btw.) as meaning simply helping against life shortening, then imeglimin is absolutely “anti-aging” by your definition because it helps against diabetes and glucose disregulation. You are contradicting yourself. I pointed out that there “absolutely is a reason to take it” precisely because it is useful in ameliorating and preventing disease (metabolic disregulation). It is in clinical use in Japan. The fact that the FDA has not gotten around to clearing it for use in the USA doesn’t mean it’s not an effective medication, because - perhaps this comes as a surprise to you - not all medications have been first developed in the US. In fact, the very drug it’s being compared to here, metformin, was not developed in the US, and before it was brought over here (by Dr. Ralph DeFronzo) it was used in Europe for decades. During that time was metformin not an effective drug according to your nonsensical standards? Same here with imeglimin. It has undergone rigorous studies, been approved by regulatory agencies and is used clinically in Japan - just because the US is behind the curve (as they were once with metformin and many other drugs) does not mean people in the US (people who claim to be cutting edge biohackers), should not take advantage of non-US drugs. And what kind of idiotic point is it about Bryan Johnson using or not using any given medication?? Is he some kind of authority on medical matters or life extension (most respected researchers like Matt Kaeberlein regard him and his approach as a joke!)? And even if he were, is he supposed to take every single medication on earth for every condition otherwise it’s not a useful medication, even for conditions he does not have or are not relevant to him? This is relevant to the OP, not Bryan Johnson.

You are “not going to correct all the errors” - just as well, because the more you write the more you compromise yourself and reveal “fundamental flaws” in basic understanding of the issues. The more you write the deeper the hole you dig for yourself - as I demonstrated above - each point you made so far has been abysmally wrong. Your contributions so far have been to waste time arguing nonsensical positions dismissing the carefully thought out suggestions (like imeglimin as a potentially useful pharmaceutical) by people who have spent a lot of time carefully citing studies (for example in the imeglimin thread), all based on a dismal lack of understanding (see: your understanding of the biological concept of aging).

Given the quality of your output here, I think we are done. If you want to participate here with any added value, please familiarize yourself with the basics before dismissing the contributions of others. Ciao!

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Thank you so much for your response. I read about Imeglimin in the other threads and just sent an inquiry to Jagdish.

You were correct in your memory that I have low insulin (runs about 3 to 5 Ul/ml). After doing a lot of reading I came around to thinking I probably have a fairly rare form of “diabetes” (or prediabetes, actually) called glucokinase mody --wherein the pancreas does not respond robustly enough to glucose. Have not confirmed as testing is expensive and cannot tell what I would do differently if glucokinase mody were confirmed.

Also thank you Desert Shores for sharing your experience with metformin. Starting to wonder if recent gut/bowel issues might be metformin related-- had not understood that these issues could start up even after you had been on metformin for some time.

One of the “dirty drug” benefits of metformin is that it seems to prevent cancer recurrence (especially breast cancer) – presumably because it stops the hungry cancer cells getting ahold of glucose. so, wondering if Imeglimin would have a similar anti-cancer benefit – (?)

So appreciative of all the inputs. Thank you.

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Interesting your conclusion based on that study - that leucine and metformin don’t increase muscle mass.

While that true, it is in a atrophy model - HU or hindlimb unloading. They did improve muscle function but not size.

Well - expecting hypertrophy on a model mimicking disuse would seem a stretch. Having improved function is still pretty good.

Arguably, size isn’t really important. Function is. I’m sure at some point in sarcopenia l, size matters.

What a good reference would be is an exercising 70 year old comparing metformin to met + leucine and looking at hypertrophy. But still, it is well established that Metformin blunts the hypertrophy response even if leucine could minimize it.

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i’ll keave the debate about metformin to the other responders. But you haven’t mentioned your hormones or diet (besides not eating red mest), which play a critical role in muscle growth. You should look st some beginner weight trainibg forums: bodybuilders cycle training and diet. To build myscle you need to be in calorie surplus with a substantial amount of protein (1.2 gms per kg if body weight). After testing hormones you might speak with your dictor about supplementing low dose Testosterone during the growth phase (3-4 months). During the maintenance phase you can add metformin. If you have been diagnosed with sarcopenia you can also supplement with sarcosine, which is usually very low in people with sarcopenia.

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Is this an argument that you cannot build muscle at all (or even maintain it) without being in calorie surplus.

I accept that protein is necessary, perhaps exercise is the most important, but I am not persuaded that calorie surplus is essential and otherwise there cannot be any building of muscle.

I thought I would ask chatGPT. Sadly for some reason it would not produce a share so I have to copy all of the response:

chatGPT said:

The research answer is: no, a calorie surplus is not strictly required to increase muscle mass, but it often makes muscle gain easier and may help maximize it in some people. The strongest overall reading of the literature is:

  • Muscle gain is possible at maintenance calories or even in a deficit
  • this is more likely in beginners, people with higher body fat, and people eating plenty of protein
  • larger or prolonged deficits reduce lean-mass gains on average
  • large surpluses tend to add more fat, and the muscle advantage is often smaller than people expect (PubMed)

A useful distinction is possible versus optimal. A 2019 review on this exact question concluded that the specific surplus needed to optimize hypertrophy is still unknown, and textbook surplus recommendations have not really been validated well in resistance-trained people. The same review also noted that an energy surplus is anabolic, but the evidence does not show a clear, universally required surplus for hypertrophy in all situations. (PubMed)

There is also direct evidence for body recomposition. In a randomized trial, young men doing hard training while eating a marked energy deficit still gained lean body mass when protein was high: the high-protein group gained about 1.2 kg LBM over 4 weeks despite the deficit, while also losing more fat. That shows muscle gain can occur without a surplus under the right conditions. (PubMed)

That said, deficits do seem to hurt gains on average. A meta-analysis by Murphy and Koehler found that energy deficiency impairs lean-mass gains but not strength gains, and their meta-regression suggested that deficits of roughly 500 kcal/day were enough to prevent lean-mass gains on average in the included studies. Their practical conclusion was that people trying to build lean mass should avoid prolonged energy deficiency, and those dieting should try to avoid deficits larger than about 500 kcal/day if preserving or gaining muscle is a priority. (PubMed)

The people most likely to gain muscle without a surplus are the groups repeatedly highlighted in the literature: resistance-training novices, and overweight or obese individuals. The 2019 review explicitly states that hypertrophy in an energy deficit seems more likely in these groups. A separate systematic review in people with overweight/obesity found that resistance training plus caloric restriction was generally good for fat loss and tended to maintain lean mass rather than increase it, whereas resistance training alone was better for increasing lean mass. So recomposition is real, but in larger populations it often looks more like fat loss with muscle preservation, not massive muscle gain. (PMC)

Studies in trained lifters suggest the benefit of “bulking harder” is limited. In a 2023 trial of resistance-trained individuals, people consuming larger surpluses gained similar increases in strength and most measured muscle thicknesses, but gained more skinfold thickness/body fat. The authors’ summary was that the clearest and strongest effect of a larger surplus was more body fat, with only weak evidence of extra hypertrophy in one heavily trained muscle group. (PMC)

There is also a small pilot study in competitive bodybuilders showing that the higher-energy group gained more muscle than the moderate-energy group over 4 weeks, but they also gained more body fat. So a surplus may help in trained people pushing for maximum mass, but the trade-off is usually extra fat gain, and the evidence base is still fairly thin. (PMC)

Protein matters a lot here. The ISSN position stand says 1.4–2.0 g/kg/day is sufficient for most exercising individuals for building or maintaining muscle, and higher intakes may be especially useful during calorie restriction. In practice, many sports-nutrition reviews now place hypertrophy-focused intakes around 1.6–2.2 g/kg/day, especially when calories are not generous. (Scholar Commons)

So the best plain-English conclusion is:

You do not need a calorie surplus to gain some muscle.
But if your goal is maximal muscle gain, especially if you are already fairly lean and well trained, a small surplus is usually the safer bet than maintenance or a deficit.
If you are newer to training, carrying more body fat, and eating enough protein, you can often gain muscle without a surplus and sometimes even while losing fat.
What the literature does not support well is the idea that a large surplus is necessary; that mostly seems to raise fat gain. (PubMed)

A practical evidence-based summary would be:

  • Beginner / higher body fat: muscle gain at maintenance or modest deficit is realistic. (PMC)
  • Intermediate / advanced / lean: a small surplus is more likely to maximize gains. (PubMed)
  • Large surplus: usually more fat, unclear extra muscle benefit. (PMC)
  • Aggressive deficit: tends to blunt lean-mass gains. (mediaTUM)
  • High protein + resistance training: essential either way. (PubMed)

If you want, I can turn this into a table of the main studies with their findings and limitations.

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If you are a “hard gainer” like me, increasing calories to gain muscle just results in more fat without any significant muscle gain.

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From the OP’s description, she has little muscle mass and has trouble gaining. IMHO, she will not gain easily at maintenance calories. since body fat is not an issue for her, eating a small calorie surplus with extra protein and creatine will help her gain as long as she is doing resistance trsining. I’m sure chatgpt us right about recomposition, but you might also read how body builders put on muscle. Even those who are drug free use periodized nutrition for 8-12 weeks, a bulking cycle involving a calorie surplus, to add muscle. They wouldn’t do it if it was not successful at increasing hypertrophy.

I’m sure most (if not all) you guys know this but in case there is doubt there is literally no difference in safety profile of a drug if it is approved by EU and or Japan as compared with ones approved by FDA. If anything, drugs approved by EU and/or Japan tend to have a bit of a safer profile, so the fact that a drug has not been approved by FDA yet, it means nothing (with regards to safety) as long as it is approved in another western country.

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