44 replies to this topic

[efosse]

Hi all,

I've been taking metformin for a month and a half. I'm rather thin (170 lbs, 6ft 3) but I've always had some fat around the stomach, which is correlated with insulin resistance not to mention a host of serious health conditions. So I started taking metformin and the results have been quite positive. I've lost about 6 lbs, but more importantly the fat in my stomach has decreased noticeably (no scientific test, but I can definitely tell something is going on). I have not been taking other measurements, however.

As far as side effects, for the first week I experienced very mild diarrhea but that subsided.

I am taking 500mg 2x daily.

What have been your experiences thus far??

Best,
efosse

[tintinet]

I started at a low dose: 250 mg QD. Initially noticed profound appetite suppression. This eased in about 2 weeks, so I slowly increased dose. Now taking 500 mg TID or 1,500 mg daily in divided doses. Don't notice much anymore, but my appetite is significantly suppressed much of the time, although, in the past 8 months, high dose (1-3 grams/day) trans-resveratrol contributes.

[asnufu]

I'm at 2*850 mg daily for 6 weeks now. Have lost 2kg ~ 4lbs since starting (I'm 175cm ~ 5.8", 78kg ~ 172lbs), and am planning blood work in a month or so - will post with my 2006 blood work as soon as I get it done. I had some serious gastrointestinal irritation for the first 4 weeks or so, and some fatigue issues when I transitioned from 850 mg to 3*850 (which is why I cut back to 2*850). Things have stabilized now, though, and I only wish I had access to microarray technology so I could repeat Spindler et al's mouse assays on myself.

My girlfriend is at 3*850 mg with no problems, and for the record, we include a curcumin/piperine combo in our regimen, so moderate piperine supplementation seems to be safe with moderate MET supplementation, at least in our case [glasses] .

Btw: I'm aware of the breast cancer/piperine study referenced elsewhere, but am banking on the manifold increase in curcumin availability to outweigh any piperine downside.

[shaggy]

I used to take metformin, definately helped lean me up a bit.

I have recently dropped it though, I read reviews showing it lowered testosterone...Maybe not such a good idea, unless you are insulin restistant?

[erichb1]

Shaggy:

Would you happen to have the link showing it lowers testosterone?

[Shepard]

In women with PCOS, it's fairly well documented in its ability to lower testosterone. It also might affect testosterone in obese/diabetics due to the lowering of insulin levels which will increase SHBG.

I did contact two healthy male members of the forum who have been taking metformin and neither reported a change in testosterone or SHBG levels.

[asnufu]

Brilliant, Shepard - thanks for making that inquiry; I've been looking for controlled studies with healthy volunteers, and they all seem to use a control group of obese or insulin resistant, but non-diabetic individuals. I think those of us who are neither, and use metformin, hope to get the CR mimetic effect WITHOUT much of a drop in FT...

[bgwowk]

My girlfriend is at 3*850 mg with no problems, and for the record, we include a curcumin/piperine combo in our regimen, so moderate piperine supplementation seems to be safe with moderate MET supplementation, at least in our case [glasses] .

3*850 mg = 2550 mg per day is not moderate supplementation. That is the top end dose for diabetes therapy. There are significant risks of fatal lactic acidosis if hard physical exertion, dehydration, or trauma occurs while on therapeutic doses of metformin. There have been cases of relatively healthy people with good kidney function on metformin dying of lactic acidosis after surgery, even though metformin was stopped a day before surgery.

Metformin is an interesting drug from a disease prevention standpoint, but it should not be thought of like daily aspirin. There are risks.

[Shepard]

Metformin is an interesting drug, but it should not be thought of like daily aspirin.

This is my general feeling toward metformin, as well.

[neogenic]

http://www.lef.org/m...tformin_01.html

[shaggy]

Shaggy:

Would you happen to have the link showing it lowers testosterone?

Do a search on pubmed using keywords "testosterone, males, metformin" there's a couple of abstracts on there worth reading, especially on metformins effect on normal males.

[Shepard]

Saudi Med J. 2002 Aug;23(8):934-7.Links
    Effects of short term metformin administration on androgens in normal men.
    Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM.

    National Center for Diabetes Endocrinology and Genetics, Jordan University Hospital, Amman, Jordan.

    OBJECTIVE: To study the effect of metformin on androgens in normal men. METHODS: A total of 12 healthy males volunteered to participate in the study. A blood sample was obtained from each of them and analyzed for the following: Testosterone (total and free), sex hormone binding globulin dehydroepiandrosterone sulphate, 17-hydroxyprogesterone, luteinizing hormone, and follicle stimulating hormone. In addition, each participant was subjected to a glucose tolerance test and his insulin level was measured. Metformin 850 mg twice daily for 2-weeks was given to each subject after which the above tests were repeated. A paired t-test was used to assess the statistical significance of any observed differences before and after metformin. RESULTS: After metformin administration, there was a significant reduction in serum level of total testosterone (p=0.0001), free testosterone (P=0.002), and 17 hydroxyprogesterone (p=0.0001). There was also a significant increase in serum level of sex hormone binding globulin (p=0.009) and dehydroepiandrosterone sulphate (P=0.0008). Serum levels of luteinizing hormone and follicle stimulating hormone showed no significant changes. Similarly, there were no changes in fasting plasma glucose, fasting serum insulin, weight, or blood pressure. CONCLUSION: Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males. The clinical significance of these findings needs further investigation.

    PMID: 12235466 [PubMed - in process]

[efosse]

Hmmm... I like the last line: "The clinical significance of these findings needs further investigation." Eh.

[asnufu]

My girlfriend is at 3*850 mg with no problems, and for the record, we include a curcumin/piperine combo in our regimen, so moderate piperine supplementation seems to be safe with moderate MET supplementation, at least in our case [glasses] .

3*850 mg = 2550 mg per day is not moderate supplementation. That is the top end dose for diabetes therapy. There are significant risks of fatal lactic acidosis if hard physical exertion, dehydration, or trauma occurs while on therapeutic doses of metformin. There have been cases of relatively healthy people with good kidney function on metformin dying of lactic acidosis after surgery, even though metformin was stopped a day before surgery.

Metformin is an interesting drug from a disease prevention standpoint, but it should not be thought of like daily aspirin. There are risks.

I agree; which is why I "instructed" her to cut back to 2*850mg. This was a precautionary step, though, because I she reported no GI problems, no fatigue, and her glucose readings were low normal range.
As for the risk of lactic acidosis: although I admit that is a serious potential side-effect, I think many people suffer from a "perceived risk vs actual risk" problem in this regard

http://www.schneier....ved_risk_2.html

The actual risk, IMHO, is not that great - this is not PhenFen

http://www.ncbi.nlm....Pubmed_RVDocSum

http://www.ncbi.nlm....Pubmed_RVDocSum

and also

http://www.aafp.org/...ochrane.html#c3

That said, I think 3*850 is the top range for supplementation, and am more comfortable with 2*850mg myself. I couldn't help but notice, however, that Proteomist reported elsewhere that he uses in excess of 3g per day, probably based on body weight and tolerance, and he doesn't appear uninformed from his postings [mellow]

Edited by asnufu, 27 August 2007 - 08:09 AM.

[Mixter]

Just taking single 500mg doses on occasion, esp. after eating out and when eating late in the day to get a beneficial low-insulin stage during sleep.

If it's only about losing/controlling weight, combining proper diet and medium-high exercise with taking fiber/PGX/starch-blockers before every meal, should be very efficient for any normally healthy person. The documented insulin sensitization and glycation damage protection is very interesting though, for people with already sensible lifestyles who want to do even more in that direction.

My suggestion would be to take creatin monohydrate all the time if you use Metformin or other biguanides on a regular basis. Unless I'm totally wrong, this should mitigate any lactate raise and other side-effects of shifting metabolism toward ketosis.

[Shepard]

My suggestion would be to take creatin monohydrate all the time if you use Metformin or other biguanides on a regular basis. Unless I'm totally wrong, this should mitigate any lactate raise and other side-effects of shifting metabolism toward ketosis.

NAC should be useful, too. Oddly, this is the one area with metformin that I'm not terribly worried about in non-diabetics.

[asnufu]

I'm curious, Shepard: what *are* you concerned about if not lactate concentration and acidosis risk (apart from the potential decrease in FT) ?

[Shepard]

Mostly long-term glucoregulation. And then there is the impaired protein synthesis that I'm not necessarily too keen on, along with the interesting hormonal effects.

It's more of a nagging doubt at the back of my mind keeping me from endorsing it than anything concrete.

[bgwowk]

As for the risk of lactic acidosis: although I admit that is a serious potential side-effect, I think many people suffer from a "perceived risk vs actual risk" problem in this regard

http://www.schneier....ved_risk_2.html

The actual risk, IMHO, is not that great - this is not PhenFen

http://www.ncbi.nlm....Pubmed_RVDocSum

http://www.ncbi.nlm....Pubmed_RVDocSum

and also

http://www.aafp.org/...ochrane.html#c3

Thanks for the great links. It's been a few years since I last looked into this, so I wasn't aware of those most recent studies and emerging consensus that metformin has been getting a bad rap. Do you think that if it weren't for the problems with its predecessor drug, phenformin, the fear of metformin causing lactic acidosis might never have come up?

I completely agree about perceived risk vs. actual risk as a general social problem. Part of my motivation in cautioning people about the risks of some drugs and supplements used for preventative purposes is that a small number of fatalities due to careless use could cut off access for the rest of us, with the likely consequence of greater morbidity and mortality that no one would notice or care about.

[asnufu]

As for the risk of lactic acidosis: although I admit that is a serious potential side-effect, I think many people suffer from a "perceived risk vs actual risk" problem in this regard

http://www.schneier....ved_risk_2.html

The actual risk, IMHO, is not that great - this is not PhenFen

http://www.ncbi.nlm....Pubmed_RVDocSum

http://www.ncbi.nlm....Pubmed_RVDocSum

and also

http://www.aafp.org/...ochrane.html#c3

Thanks for the great links. It's been a few years since I last looked into this, so I wasn't aware of those most recent studies and emerging consensus that metformin has been getting a bad rap. Do you think that if it weren't for the problems with its predecessor drug, phenformin, the fear of metformin causing lactic acidosis might never have come up?

I completely agree about perceived risk vs. actual risk as a general social problem. Part of my motivation in cautioning people about the risks of some drugs and supplements used for preventative purposes is that a small number of fatalities due to careless use could cut off access for the rest of us, with the likely consequence of greater morbidity and mortality that no one would notice or care about.

Absolutely! When supplementing, you have a communal responsibility as well as a personal one, and Shepard's concerns above are taken to heart - you can't be too careful...but then again, if you're too-too careful, the eventual outcome is surely going to be death by aging and other nonSENSe [wis].

Shepard, good point about protein synthesis - do you base that on metformin possibly affecting the AMPK pathway and do you have anything to support that ? couldn't the same well hold for CR then, given that low-level stressors are likely to be the same (judging from the substantial overlap in transcription profiles/Spindler's assays) ?
Also, I can understand the concern about persistence effects with long-term use - but from what I can find, the effects should be small and beneficial, actually, if any ?

http://www.ncbi.nlm....Pubmed_RVDocSum

[Shepard]

Shepard, good point about protein synthesis - do you base that on metformin possibly affecting the AMPK pathway and do you have anything to support that ? couldn't the same well hold for CR then, given that low-level stressors are likely to be the same (judging from the substantial overlap in transcription profiles/Spindler's assays) ?
Also, I can understand the concern about persistence effects with long-term use - but from what I can find, the effects should be small and beneficial, actually, if any  ?

Yeah, I'm basing my protein synthesis speculation on the assumption that AMPK activation will inhibit protein synthesis.(1) Metformin activates AMPK in some tissues(2), but maybe not the brain. (3) I don't think it's a bad thing from an life extension perspective necessarily, but I'm not fond of it since I value skeletal muscle more than most CR practitioners. I'm unaware of the importance of brain AMPK activation in the effects of CR, or if there is some eventual drop of AMPK levels with prolonged caloric restriction. I've got a lot of things open at the moment trying to put the pieces together about the full implications of brain AMPK activation or inhibition. Looks beneficial in some aspects and not so beneficial in other aspects (especially overexpression). My glucoregulation idea ties in with the body getting used to lower gluconeogenic gene expression and what could happen if the person goes off of metformin after long-term supplementation.


1. Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise
2. Role of AMP-activated protein kinase in mechanism of metformin action
3. Metformin inhibits AMPK activation and prevents increases in NPY expression in cultured hypothalamic neurons

[asnufu]

Okay, interesting. You have to really walk a careful balance between reckless supplementation and due diligence / forward looking use of what's available. Perhaps resveratrol and metformin have potent synergistic effects. I note especially the Sirtris trials with resv + metf in combination rather than as controls, and some recent research on resv neuroprotective effects and AMPK activation in neuronal tissue, a bit counter to what you're speculating on with metf:

http://groups.google...95ec163d4?hl=en

[lucid]

Okay, interesting. You have to really walk a careful balance between reckless supplementation and due diligence / forward looking use of what's available. Perhaps resveratrol and metformin have potent synergistic effects. I note especially the Sirtris trials with resv + metf in combination rather than as controls, and some recent research on resv neuroprotective effects and AMPK activation in neuronal tissue, a bit counter to what you're speculating on with metf:

Thats a good point, I assumed that they both acted through sirtuin pathways... anyone know more about this?

[Shepard]

Perhaps resveratrol and metformin have potent synergistic effects.

Yeah, I don't know. When the resveratrol-AMPK thing came out a while back I was interested since that should indicate increased hunger, but people were reporting the opposite. Like I said, so far it looks advantageous in some areas and not in other areas (mostly overexpression or during ischemic stroke in mice). Which, ultimately doesn't really mean much.

Edited by shepard, 30 August 2007 - 02:06 PM.

[Shepard]

Thats a good point, I assumed that they both acted through sirtuin pathways... anyone know more about this?

In this instance, resveratrol activates AMPK upstream (AMPK-LKB1) and independent of SIR1.

[asnufu]

Hmm, you don't sound too sold on either metformin or resv - sobering levelheadedness, I guess, but makes me wonder; what kind of supplementation regime would be unequivocally worthwhile at this point, in your mind (apart from eating your greens [sfty] ) ?

[Shepard]

Hmm, you don't sound too sold on either metformin or resv - sobering levelheadedness, I guess, but makes me wonder; what kind of supplementation regime would be unequivocally worthwhile at this point, in your mind (apart from eating your greens  [sfty] ) ?

It's not that I'm not sold on either one, I think each has its uses and either could potentially be useful for life extension. I do think that people taking either of these compounds with the hope of having the full effects of CR are being premature. But, I'm certainly not the authority for either of these and there are people here that know more about them than I do.

As far as supplements in general go, I'm certainly not a cynic about them. My supplement regimen used to be quite extensive, and although I've cut back dramatically for a few reasons I still think some are plenty useful for various health-related reasons.

[asnufu]

Well, maybe. Even worse than that, though, is the underlying question of whether CR in humans carry any substantial benefit at all

http://groups.google...e1614e003?hl=en

See also de Grey's contrarian paper on CR, and his non-trivial arguments that the benefits are likely to be neglible, if any.

All in all, I think the effort and sacrifice in actual CR is not worth it - but if moderate supplementation can buy a few years and reduced mortality in the intervening ones, then that is worth the expense and risk, and metf/resv seem the best bets so far (spin traps and age breakers not excluded, though). In the end, SENS or a similar engineering effort is the only viable route, it seems - all this metabolic tinkering isn't going to get us off the ground anyway...

[tintinet]

Yes. Yet again, at this time, a tough call. For some among us, the question is will we live long enough to benefit from possible near future breakthroughs in anti-aging and age reversal technologies? Thus, many are motivated/tempted to use existing methods with at least some evidence they might aid longevity and prolonged enhanced health in the hopes of living just long enough to be present when aging becomes effectively treatable.

[asnufu]

True enough. The best you can do for now is to minimize mortality from pathology, while duly observing empirically established risks in doing so, and continue this until genuinely engineered pharmacological interventions become available (a la Sirtris 501 or perhaps TA-65).
I think it's thought-provoking how laissez faire de Grey is about his physical stature, subsisting by his own accord on pints of Guinness - and it's not because he's stupid either! Like CR, strenous exercise will probably help those of us who hope to look good nekkid at 70, but don't expect it to affect longevity more than marginally. Same for diet, actually, provided you're not too cancer-prone and avoid overweight...