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Experimenting with Metformin as a calorie restriction mimetic in healthy non-diabetics

metformin experiment cr mimetic

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#1 mcmanis

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Posted 07 February 2013 - 04:38 AM


Dear fellow patrons of the life extension arts,

I've been taking Metformin (in the slow release version) for about a
year and a half now, gradually ramping up the dosage in 500mg increments
to 2g - 1g in the morning, 1g in the evening. The ramp up to 2g is
recent though, just a month or so. For most of the time I've been
experimenting with Metformin (about a year and) I've been taking 1.5g - 1
gram in the morning, 500mg in the evening. I may eventually lower my
dosage back to 1.5g depending on how well my body adjusts to 2g.

To prevent long-term B12 deficiency I also supplement with 1000mcg
sublingual b12 daily plus about 750mg of calcium.

Eventually my personal experimentation sort of swept up a small group
(about 6 of us so far) of like-minded friends and family, also
non-diabetics and health-conscious. Now we're all happily
self-medicating with clinically effective doses of Metformin. Yes, we're
all very consciously thumbing our noses at the traditional FDA-approved
dogma that you should only take "medicine" to treat rather than prevent
illness / extend healthy lifespan.

While my personal experimentation eventually led me to be quite
optimistic regarding Metformin's potential to improve health and maybe
even mimic some of the benefits of calorie restriction in a healthy
subject I was initially very cautious about taking the plunge. Thanks to
the prevailing dogma there is precious little data on Metformin's
effects on healthy non-diabetics. Note that I was pretty fit to begin
with. I work out on average about 80 minutes 3 times a week in a mix of
high-intensity aerobic (3km in 10 minutes) and anerobic (mostly weight
lifting).

FWIW, I read pretty much everything I could get my hands on and even
bought the scientific handbook ("Metformin - the gold standard") to
better understand what I could expect with regards to side effects and
dosage.

I finally decided to start taking Metformin after becoming convinced
that it had an excellent safety profile. The effective dose is about 5%
of the lethal dose (based on animal studies and attempted suicides).
IMHO, the fears regarding lactic acidosis were blown way out of
proportion based on the effects of other biguanidines such as
phenformin. For Metformin you get about 1 incident of lactic acidosis
per 100,000 years of use and even that only seems to happen in patients
with advanced renal failure - exactly the population of people that are
prone to lactic acidosis regardless of whether or not they take
Metformin.

Bottom line, my interpretation of the data was that plain old exercise
looks awfully dangerous compared with Metformin. Everybody knows
exercise is good for you, but if the exact same benefits and risks
(fatal heart failure, spinal injuries, knee damage, increased risk of
lactic acidosis, etc.) were somehow packaged into a pill there's a good
chance it would never be approved according to the prevailing
hyper-conservative one-size-fits-all criteria for drug evaluation that's
choking any real progress in medicine. Imagine what the computer
industry would look like if any advance had to pass anything resembling
FDA regulation. We'd still be stuck in the 1970s.

OK, back on the subject - I had been reading up on Metformin for a
couple of years before finally deciding to self-experiment. I was
tempted by Metformin's inhibition of liver glucogenesis, activation of
AMPK, inhibition of mTOR (like rapamycin), the research that it can
induce mitochondrial bio-genesis, reduced endogenous reactive oxygen
species and associated DNA damage, statistically significant long-term
reduction in cancer and Alzheimer rates, etc. I won't bother citing all
of the research. If you're interested in the evidence, Google it.

Despite my confidence in Metformin's advantage, I decided to be extra
cautious and ramp up my dosage gradually while doing regular blood work
every couple of months - full spectrum tests (blood glucose, hba1c,
lipid levels, blood counts, liver enzymes, testosterone level, etc.),
plus more frequent testing (initially several times a day) of blood
sugar levels using a personal glucose meter.

Better safe than sorry, curiosity killed the cat and all that. Speaking
of curiosity I have to admit that played a large part in my decision to
experiment after I became sufficiently convinced I wasn't risking much
safety-wise.

The results so far:

- initial gastrointestinal discomfort which quickly subsides: I found
this initially to be significant side-effect with the regular
fast-release version of Metformin, even at small doses (e.g., 500mg).

This was significantly less of an issue with the slow release version.
This side-effect seems to go away once the bioflora in your gut
rebalances. This adverse response to a change in dosage (in both
directions) seems to have lasted just a few days for most of the
people in my small experimental group. Using the slow release version,
plus ramping up the dosage slowly seems to help one get acclimatized
with fewer side-effects.

- reduced (but still safe) levels of blood sugar (average,
post-prandial, hba1c): I had been keeping a good diet (no sugars,
complex carbs, decent amounts of protein for a weight-lifter) before
and throughout my experimentation. I wasn't expecting my average BG to
drop dramatically because I wasn't diabetic. If anything I was
concerned Metformin would tip me into hypoglycemia. Many antidiabetic
drugs are very dangerous for non-diabetics for that reason.

Thankfully to the best of my knowledge that never happened. Blood
glucose levels were decreased, but the lowest I ever measured, after
ramping up the dosage while fasting for 12 hours (while awake) was
70mg/dl.

Fasting blood glucose after sleep before I started taking Metformin
was about 90mg/dl. On Metformin around 70-80mg/dl depending mostly on
the exact timing of the test (probably something to do with the
cortisol spike after waking).

Last time I checked my hba1c I was somewhat disappointed to discover
it wasn't as low as I had expected - about 5.2% but I had been playing
with my diet back then and varying my Metformin doses. I'll be testing
again in two months after letting my body adjust to a steady
2000mg/day.

- appetite suppression and incidental calorie restriction: I experienced
a significant dose-dependent suppression of appetite and thus the
number of consumed calories. This effect was significant enough to
make me suspect that at least some of the benefits of Metformin may be
explained by the effects of "accidental" calorie restriction.

The effect is very dramatic in my case. I've tried reducing the dosage
of Metformin to 500mg or 1000mg while consuming the same amount of
calories I am comfortable with at 1500mg and the hunger eventually
drives me up the wall. This increased my respect for CRONners that
manage to basically starve themselves with nothing more than sheer
willpower. Whoever you are, wherever you are, you have my respect. I'm
personally quite sensitive to hunger and couldn't stand the effect on
my quality of life.

With Metformin reducing calories was far easier. A happy unexpected
side effect.

On a side note, this effect on my appetite improved my quality of life
significantly. Before I would have to eat every 4 hours or so to avoid
being driven to distraction by hunger - a trait my family and friends
took great amusement in, considering I've always been rather lean
("where does all that food go?"). Whenever I came over to visit my
parents they'd complain I was eating them out of house and home.

With Metformin I could comfortably go for much longer (6-8 hours)
stretches between meals. Also, the suppression of appetite seems to
dependent on the number of consumed calories. Larger meals would

suppress appetite for much longer than smaller meals. For example,
after (over-)eating out at a restaurant a few weeks ago it took about
12 hours for my appetite to return.

- testosterone: with each ramping up of the dosage there seems to be an
initial drop in testosterone characterized by low mood and sex drive.

This effect gradually subsides. I tested my test levels after having
fully adjusted (subjectively) to 1500mg/day for a few months and my
levels were actually 15% beyond the normal range. I'm guessing the
normal range doesn't take into account regular weight lifters with low
body fat though.

Note that calorie restriction has a similar effect on testosterone
levels and that in general lower testosterone is correlated with
longer lifespans. A causative relationship hasn't been proven yet but
given testesterone's strong anabolic effect this would not be
surprising. Increased anabolism would ramp up metabolism, which
usually leads to increased wear and tear if you don't upregulate
repair mechanisms by the same amount.

Anyhow, after having ramped up my dosage to 2g recently I'm pretty
sure I'm experiencing another moderate decrease in mood and sex drive.
A month later this seems to have mostly subsided. A friend and fellow
self-experimenter ramped up the dosage to 2g a few months before I did
and has since completely adjusted on all fronts. "Best time of my
life" he says. If anything he's more sexually active now than I've
ever known him to be.

- lower body fat: my body's body fat has gradually gone down
considerably. I'm currently at about 5%, down from maybe 10% before
starting Metformin.

This reduction in fat composition happened with very little conscious
effort on my part. I haven't been doing a lot of aerobics. I haven't
starved myself or dieted. I just ate when I was hungry, which happens
less frequently.

- Inhibition of both muscle growth and muscle loss: I've been lifting
weights since adolescence. I'm in my 30s now. So I'm sensitive to how
my body performs at the gym. I like my body, and the lack of desire to
see all my muscle mass wasting away was one of the reasons (besides
debilitating hunger) I could never quite stomach CRON. Call it vanity.
Call it a quality of life issue.

On Metformin I've noticed both muscle growth and muscle loss tend to
be inhibited. I've gone to very low bad fat on what is close to a
calorie restricted diet for my weight while barely loosing any muscle
mass. At least not enough to be noticeable. If anything people comment
that I seem to be bigger now but I'm certain it just looks that way
because I have lower body fat.

I have gotten a bit weaker on the major muscle groups in terms of peak
strength and reps but not nearly as much as I would have expected.
Also, the inhibition of muscle growth doesn't prevent it. If I focus
on a specific undertrained muscle group there will be a measurable
increase in strength. But I'm certainly not getting any stronger with
the big muscle groups (e.g., bench, squats, etc.) even if I try very
hard.

From my meta-research I speculate that this effect has something to do
with Metformin's influence on the mTOR pathway.

A biochemist friend of mine has argued that the loss of strength I
have experienced is well within the range of what we could expect due
to depleted levels of glycogen in my muscles and liver brought about
by the reduction in calories. Also, I'm consuming less protein so
maybe the balance point for muscle repair after a workout is lower.


- cognitive performance: like with other negative aspects of Metformin
use, I experienced an initial decrease in performance following a
ramp-up in dosage followed by a gradual return to normal after a few
weeks. The effect was most dramatic for a week or so after I increased
the dose to 1500mg/day.

I felt anxious, had trouble concentrating, kept forgetting things
(e.g., names and words on the tip of my tongue), repeated pointless
behaviors (e.g., opening the same empty cupboard over and over looking
for a lost item), failed to perceive objects that were right in front
of my eyes - which led amongst other things to an embarrassing fridge
incident. I also had a harder time expressing myself. Humor in
particular seem to be beyond my grasp.

That freaked me out a bit and I was worried I might be experiencing a
form of mild hypoglycemia but a blood test showed my BG to be in the
normal 75-85mg/dl range.

Eventually all of these symptoms subsided completely and I returned to
full cognitive performance. As far as I can tell. From my
meta-research I speculate that Metformin somehow temporarily reduced
my brain's ability to metabolise sugar. I tested normal levels of
sugar, but it felt like I was mildly hypoglycemic because my brain
cells were producing less energy with it. Perhaps the mechanism of
adaptation was the mitochondrial biogenesis I've read Metformin can
trigger. Wish I knew for sure.

- Body temperature: average waking temperature seems to have gone down
about 1-1.5 degrees Fahrenheit. Within the reference range for CRONers
but a bit on the high side for a CRONnie.

Not surprising considering I actually am restricting my calories,
though not deliberately.

- Blood pressure has gone down somewhat, mostly my diastolic though the
effect doesn't seem to be dramatic. At the Dr's office I last tested
110/58. Testing at home it's usually a bit lower (e.g., 95-105/45-55),
but that depends a bit on how relaxed I am. For anyone that thinks my
BP is too low please note that I am not prone to fainting.

Before Metformin my BP was closer to 110-120/70-80.

- Lipid levels: LDL has gone down from 81 to 61. HDL has gone up from 50
to 60. Triglycerides have gone up slightly from 41 to 57 (I suspect
this is due to increased lipolysis)

In my experimental group not everyone seemed to react the same as I did.
I advised everyone to do regular bloodwork to test how Metformin
effected their bodies in particular. For safety and of course because it
gave us more data to work with.

Gastrointestinal discomfort and a feeling of exhaustion caused one of my
friends to drop out after about a week doing just 500mg/day but most
people barely noticed the gastrointestinal effects and it seems to be
mitigated by increasing fiber intake. The initial tiredness and loss of
mood which gradually subsided seemed to effect males more than females
but this is just my impression.

Nearly everyone experienced a dose dependent reduction in appetite and a
consequent reduction in calorie intake and body fat composition but
before anyone gets any funny ideas I'd like to clarify that Metformin is
certainly not a magic weight loss pill that allows you to eat whatever
you want and still lose weight. When I dropped my dose to 1000mg/day and
ramped up my calorie intake I gained body weight (mostly muscle but also
a bit of fat) pretty quickly (3-4kg with a couple of months). A more
extreme test case was a female friend that suffers from an eating
disorder that gradually ramped up to 2000mg/day. Though her body weight
stabilized and her body fat composition changed somewhat (patterns of
fat deposits seems to have changed), her weight was not dramatically
reduced in the months when she didn't have her eating disorder under
control. Her bloodwork (blood glucose, lipid levels, etc.) did improve
significantly though. With her eating disorder under control, (mostly)
eating when she was genuinely hungry she experienced a gradual loss of
weight however.

Of course I don't have as good data for the others in my experimental
group as I do for myself. Note to anyone interpreting my personal
anecdotal experience that I may be genetically predisposed to have a
better than usual response to Metformin. According to 23andme I have a
GG genotype at rs4585:

"In this study, researchers examined metformin response in 3,920
individuals of European ancestry with type 2 diabetes. A positive
response was defined as achieving an HbA1c level below 7%. The
researchers found that individuals with the GG genotype at rs4585 (which
is equivalent to the SNP reported by the researchers) in the ATM gene
had 1.35 times higher odds of having a positive response to metformin
treatment compared to individuals with the GT genotype, and individuals
with the TT genotype had about 0.75 times the odds of having a positive
response."

Just another datapoint to those trying to evaluate my anecdotal, non
double blind, perhaps even blatantly unscientific and irresponsible
underground experimentation with a prescription drug. I wish I had a
billion dollars lying around, plus FDA approval to do a double blind
study on healthy human subjects (hardy har har!) but we have to settle
on making the most with what we have.

In any case, if it isn't clear, the sum of my meta-research and
experience leads to me to believe that Metformin is a woefully
underused, powerful health enhancing substance that can make wonderful
contributions to one's quality of life (once you get used to it) and
most likely length of life. Even if it doesn't increase maximum lifespan
like it does in many animal models, there's good reason to believe it
would improve median lifespans significantly if consumed by the general
population. It's also remarkably safe in clinically effective doses, widely
available and has a very respectable history of use.

PS: I'm posting pseudo-anonymously to avoid obvious undesirable sources of
attention. Unfortunately the first amendment doesn't hold much weight when it
comes to this sort of thing. Please respect my privacy!
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#2 Kevnzworld

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Posted 07 February 2013 - 06:15 AM

Thanks for that comprehensive review. Your results are obviously anecdotal and there is no control for confounding variables. My intial thought was the dosing was very high. I take Metformin CR, 500 mg twice a day. I am not diabetic and take it for the same reasons.
You might want t consider taking some antiglycation supplements like carnosine, benfotiamine, P5P, taurine etc to reduce you HBa1C levels. Lowering fasting and postprandial glucose levels are important, but one still has to deal with the glycation that the remaining circulating glucose creates.
You also might want to consider taking chromium to increase insulin sensitivity.
Ultimately the longevity benefits of metformin supplementation , if they exist won't be known for decades. The lower incidences of cancer and the glucose lowering effects are supported in the studies published to date.
Life Extension foundation brought the benefits of Metformin " mainstream " a few years ago. Traditional allopathic medicine has yet to embrace it. But then again it was only a few years ago that mainstream medicine " discovered " vitamin D, probiotics and testosterone supplementation.....
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#3 Andey

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Posted 07 February 2013 - 11:17 AM

Thanks for sharing

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#4 xEva

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Posted 08 February 2013 - 06:39 AM

mcmanis, welcome to the forum and thanks for your report. I found the appetite lowering effect of metformin very intriguing. Kevnzworld, have you experienced it too?

You may find this study interesting: Metformin Reduces Hepatic Expression of SIRT3, the Mitochondrial Deacetylase Controlling Energy Metabolism, 2012, http://www.plosone.o...al.pone.0049863

We show that metformin downregulates SIRT3 expression and that this results in increased mitochondrial protein acetylation.

Metformin Induces Mitochondrial Biogenesis in Hepatocytes

In the current study, we show that metformin downregulates SIRT3 expression in the liver. Metformin prevented induction of SIRT3 by glucagon and also reduced SIRT3 expression per se in mouse primary hepatocytes. A similar effect was observed in vivo. By contrast, but in agreement with previous studies, SIRT1 was upregulated by the drug. These findings indicate that metformin distinctively regulates expression of different Sirtuin family members.

metformin inhibits ATP synthesis. At the same time, SIRT3 protein expression was decreased in the hepatocyte mitochondria.

metformin can regulate mitochondrial function through a SIRT3-mediated mechanism, and this may contribute to a reduced intracellular ATP level.



#5 mcmanis

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Posted 13 February 2013 - 05:36 PM

@kevnzworld Regarding dosing, from the literature I've read the effect at 1000mg/day is pretty modest. I don't feel much of an effect at 1000mg/day. Clinically effective doses start 1500mg/day and go as high as 3000mg/day for the XR version. My current dose isn't set in stone. After a couple of months I'll do some bloodwork, and decide whether I want to stay at 2000mg/day or go back to 1500mg/day. I'm not currently considering going above 2000mg/day though.

Regarding the antiglycation supplements, is there any evidence that they reduce hba1c levels?

@xEva Going over a few of the other Metformin threads on the forum it looks like others have reported a reduction in appetite. Many thanks for the link to the study. I hadn't come across it before and found it most interesting. The dosage give to the mice (300mg/day) is about 10X higher than a typical human dose (2g a day is about 30mg/kg for an adult), though perhaps metabolically equivalent.

The main point is that it looks like there's good evidence for Metformin's mechanism of action going beyond AMPK activation. I'm not sure what to make of SIRT3 down-regulation though. SIRT3 knock-out mice don't live as long. But there's a difference between downregulating a gene and knocking it out, plus as they say in the study, the downregulation could just be a negative feedback loop from Metformin's activation of AMPK, which upregulates SIRT3. Also, they confirm that Metformin paradoxically induces Mitochondrial biogensis while downregulating some of the mechanisms known to induce it.
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#6 Kevnzworld

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Posted 13 February 2013 - 08:28 PM

@kevnzworld
Regarding the antiglycation supplements, is there any evidence that they reduce hba1c levels?

Most of the studies haven't measured HbA1C itself, but given that HbA1C is a measure of glycated hemoglobin one would expect them to.

Re: Carnosine
Quote: " The treatments of carnosine also significantly decreased the blood glucose levels in GTT and ITT and glycosylated hemoglobin (HbA1c), compared with the control (p less than 0.05"
http://agris.fao.org...ml;KR2010001478
Re: Benfotiamine
Quote: Thiamine derivatives, in particular the lipid.soluble prodrug benfotiamine, are effective inhibitor of intracellular formation of AGE and CML.
http://benfotiamine....nfo600Study.pdf
Re: B6
Quote: "In B6 treated group a substantial decrease was observed in HbA1c (P=0.033"
http://www.ncbi.nlm....pubmed/23392542
Quote: "Both P and PM significantly lowered lipid peroxidation and glycated hemoglobin (HbA(1)) formation in high glucose-exposed RBC" ( P being pyridoxine, PM pyridoxamine )
http://www.ncbi.nlm....pubmed/11165869
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#7 platypus

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Posted 04 March 2013 - 01:37 PM

I'm not entirely happy with my fasting blood glucose (92 mg/dL) - do you guys think that 500mg SR metformin might make a difference?

#8 Kevnzworld

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Posted 04 March 2013 - 04:46 PM

I'm not entirely happy with my fasting blood glucose (92 mg/dL) - do you guys think that 500mg SR metformin might make a difference?


It may. I would also make sure that your magnesium and chromium intake is adequate . After doing some research I've been taking 500mg SR twice a day for two years. The OP is taking twice that.
My fasting glucose levels vary, so I can't say definitively that its had an impact. You may want to get a testing meter and strips to check your post prandial glucose levels too.


#9 guitarparty

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Posted 06 March 2013 - 08:26 AM

Hello McManis and Kev,

I've read a good many posts here and just joined because I want to comment on the use of metformin (Glucophage).

I was on Glucophage XR 500 mg x 2/day for roughly five or six years. I am diabetic, and have had numerous other health issues for a good long time. My health issues fairly quickly accelerated while using Glucophage, though there was nothing apparent to make me want to get off of Glucophage shortly after starting on it. The problems crept up on me, and it took me what seems in retrospect FOREVER to figure out that everything happening to me wasn't inherent in the normal grind down that I assumed happens to every, or to most, diabetics.

My blood sugars weren't controlled at all well with Glucophage, and I'm not certain that taking this drug that fooled around with my body's own attempts at controlling blood sugar might not have in the long run made me need more and more help with controlling the problem. After four or five years on Glucophage I graduated to adding in insulin, and soon after getting started on insulin I kept creeping up the amount of that I was taking daily, and creeping it up more and more. Meanwhile, I was feeling starved all the time. Really starved, even while trying to be careful not to make things worse by taking too much insulin. And I felt awful overall--really, really tired to an extent that gradually overcame me.

Add to that the fact that with my increasing hunger on Glucophage, my weight took off at the same time. I wish I'd known to try a paleo diet at that point. I can't imagine going onto metformin in looking for a dietary aid. Paleo will work, and it won't kill your kidneys in the process.

As time went on with Glucophage, I suffered from immense swelling. I was so swollen I had a terrible time even getting up out of my chair. I looked down at my legs and it seemed I was looking at the legs of a total stranger. Scarlet from my ankles to well above my knees, and puffed up like a balloon. When your legs look like that, there's lots more to it than just looks: there's a ripping scorching pain just to put any bend into the knees at all. At the knee where you're trying to bend it, it feels just as if you had some huge tender scab over the whole thing--and you have to rip off that scab every single time you want to bend that knee to do anything at all.

I looked at myself in the mirror and a funny-looking person who couldn't open her eyelids properly looked back at me. You don't think of the eyelids as balloons, but they can easily become small balloons. They hold fluid quite easily, and then they fold over only with quite a bit of difficulty (as they have to do to some extent if you want to see out). You don't have the eyelid muscle control strength to push hard enough against those lid-balloons to come anywhere close enough to open your eyes all the way. You're peeking out at the world and can't do anything about it.

Underlying all this funny-looking stuff is an amazing tiredness that you've never experienced to this degree before.

If you have something wrong with you that's diagnosed and especially if it's something that can have so many different facets to its effects as diabetes, then don't expect your doctors to think about your drugs as a potential culprit at all; they'll just assume that your diagnosed problem is the culprit. And I would add, the probability that your doctor is going to think first of one of your self-administered supplements is close to zero when/if something goes wrong for you. And that's probably all the more so with a drug that's in such widespread use as metformin/Glucophage. It obviously has all kinds of approvals and doctors aren't trained to question its use.

I finally came to wit's end in my own condition taking Glucophage, and I came to see that as long as nothing was going to change, I wasn't going to get any better. But what to do? I managed to think about the prescriptions I was taking, and managed to find the prescribing information I'd saved on Glucophage. It was apparent in reading that information that if my age at the time had been 65, the doctor would have been warned away from prescribing it. That's because the elderly, on average, have lower kidney function, and this drug is hard on the kidneys, the prescribing information admitted.

THIS DRUG IS HARD ON THE KIDNEYS.

I wasn't even sixty years old at the time, but it occurred to me that artificial rules based on group averages on kidney function don't make much sense, even on the surface of things. How could you know for sure that a drug that's hard on the kidneys was safe at age 64, but regard it as too risky at age 65? How could you even know it was safe at 64, just because it was safe on an average person at that age? And how can you know your kidney function is fine if you're doing no testing for protein in the urine? How can you ever know that your kidneys have any capacity to spare without extensive testing or bumping up against the limit? And how much of your spare kidney capacity are you willing to give away for the supposed benefits of the drug--for instance, the "benefit" of avoiding taking/taking as much insulin?

THIS DRUG IS HARD ON THE KIDNEYS.

The next thing I did was to look up symptoms of kidney disease. Bingo. I took myself off that ____ drug.

And I got lots better fast. Not totally well, but much, much better. Very noticeably better, you could notice with just a glance in my direction. I still had diabetes to live with, of course.

Don't ask me why none of my doctors took me off that drug. What if I hadn't saved the prescribing information? What if I'd had no way to know I needed to go off the drug, or what if I were afraid to act on my own? I suppose I just would have come to my current sorry state of affairs all that much sooner. Still, my unfortunate experience with Glucophage got me well on the way to my kidney disease of today, which is fast approaching the need for dialysis.

To be clear, more drugs than Glucophage alone were involved in assaulting my kidneys. I was also on a now-discontinued drug by the name of Avandia. My doctor eventually--several years too late--suggested discontinuing Avandia. That came after the same old, same old, edema problems had resurfaced a couple of years after dropping Glucophage, and also after several months on an antibiotic daily that is supposed to be hard on the kidneys. That drug was prescribed after a (mis)diagnosis of cellulitis relative to my swollen inflammed legs that finally sent me to my doctor (on a day when someone else was taking his patients and hadn't seen the previous condition of my legs). And when the antibiotic didn't work at all on those chronically inflammed legs, the antibiotic was further prescribed to be taken chronically.

I suppose if I hadn't taken myself off that antibiotic then I'd still be taking it now (if I were still alive in spite of its effects). But since I wasn't seeing any benefit at all from the antibiotic I took myself off it after a few months. Unfortunately that was too late to save the kidneys from the damage resulting from its use. But then with the continuing of my inflammed legs problem, my doctor mentioned that Avandia might be contributing to the problem. And, sure enough, as soon as I went off Avandia, the edema problem got much, much better again. Not completely gone, as by then I was passing noticeable amounts of protein that my kidneys could no longer handle.

My edema has never disappeared altogether--not since going onto Glucophage--and it's never expected to. If anything, it's expected to get worse--not better. That's what kidney disease does.

METFORMIN/GLUCOPHAGE IS HARD ON THE KIDNEYS.

How much of your spare kidney capacity do you have to use up on this drug? Is there any drug that's worth that? Personally, I can't think of a single potential benefit that merits putting your kidneys at risk. You can't just grow a new pair of those things.

I have a book on kidney disease that was written by a kidney specialist who teaches and does research at Johns-Hopkins Medical School. He mentions in it some of the various drugs to avoid with kidney disease, and for one (Aleve, as best I can recall) he speculates it to actually *cause* kidney disease in a good many persons--people, who for various reasons, took that particular drug on a daily basis over a number of years.

Defining the word "cause" can be tricky, I suppose. But if you assume that a particular drug is one that's taken in a sizeable amount on a regular and frequent schedule, then you're certainly running a risk if that drug is one that's also hard on the kidneys.

I personally believe Metformin/Glucophage was among those factors that *caused* my kidney disease. Taking Glucophage is the #1 item I'd change if I could redo my own choices in life. I'd have a big fight with my doctor about it, if necessary. I'd never, ever take that drug again if only I could do things over. If only.

Folks, kidney disease is nothing to fool around with or take chances on. I slept for 15 hours today, and when I'm awake, I'm barely there; I can't think well any more. Don't let this happen to you.

I hope you don't misinterpret this to mean that I'm just an anti-supplements person and hang my anti-metformin feelings on that hook. I'm not. I have about a zillion dollars worth of new supplements within reach right this very minute, as a matter of fact. Though I never got around to the supplement thing in a big way until fairly recently, when I realized that going the usual medical route was aiming me toward the dialysis chair in a big hurry. So I'm looking around and hoping to bump into some things to help. I don't know that I'd say I either believe in or don't believe in supplements--I think each decision is an individual one for each supplement involved and also for each individual involved. But, at least in my circumstances, well-researched supplementing seems well worth a try. It's better to go down trying, I think.

I hope you also don't misinterpret this to mean that I'm just some naturally sickly kind of person and that nothing that has happened to me could ever happen to you. There was a time when I wasn't sickly. There was a time when I could outrun almost anyone, and when you'd have had trouble returning my serve on the tennis court too. Any one of you can become sickly, especially if you have some heavy help in that direction by taking a drug that can cause kidney damage.

Best of luck to you in all your health decisions.

Mary
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#10 s123

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Posted 06 March 2013 - 09:37 AM

Thanks for your nice review of your personal experience with metformin. I've taken metformin for 2-3 years now. My current dosage is 850mg in the morning and 425 mg in the evening. I also experienced an initial gastrointernal upset for about 3 days but then it dissapeared.

You may want to read my LongeCity article on metformin: http://www.longecity...ension-drug-r32
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#11 mikeinnaples

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Posted 06 March 2013 - 02:07 PM

I have been taking metformin for close to a decade at varying dosages. I am not diabetic and am perfectly healthy, as far as I know. No kidney problems whatsoever and I suspect this will be the case in the vast majority of the people that are actually healthy and taking this for 'off label' purposes. If you have renal deficiencies, metformin is contraindicated, but I think even this is blown a bit out of proportion for most cases. Unfortunately guitarparty, you look to be one of the rare cases. :wacko:
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#12 Kevnzworld

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Posted 06 March 2013 - 03:52 PM

I agree with Mike. I'm sorry to hear about your medical problems and bad experience with Metformin ,Guitar. It's a good reminder that medicine and supplements can contribute to kidney and liver problems in some people with underlying dysfunction.
I get a blood/ urine test twice a year, so far so good.
Metformin is the most prescribed medicine in the world and its side effect record is excellent. That doesn't mean that it isn't contraindicated for some people. S123's article is excellent. I recommend that users click on the provided link and read it.

#13 Krell

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Posted 07 March 2013 - 02:56 AM

Where can I get metformin without a prescription?

Edited by Krell, 07 March 2013 - 02:56 AM.


#14 guitarparty

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Posted 07 March 2013 - 03:43 AM

Hi s123, Mike, and Kev,

Thanks so much for your replies. I mostly want to underline my thoughts on metformin here. I don't necessarily expect to convince you to switch off taking it tomorrow, but I hope you'll be persuaded to continue to think about it from time to time. You might decide later on at some point to quit using it, and if you do, well, I'll be glad for you.

Metformin's on-label use is for treating diabetics.

I am a diabetic, along with *millions* of others. I am not a particularly odd or unusual patient. I have no reason at all to believe that prior to taking Glucophage I had any underlying kidney dysfunction. None at all.

Diabetics have a hugely increased probability over a non-diabetic of becoming a kidney disease patient. The tendency is to blame something like high blood pressure, which most diabetics also do have a problem with.

I am one of those people who used "the most prescribed medicine in the world" with its "excellent" side effect record (as far as the FDA knows/reports). And I'm one of the people whose official health record is contributing to that "excellent" record, the same as I'd guess applies to many other diabetics. In my book, the "excellent" record that I am a part of deserves a big question mark.

A side issue here is the weight given both to the FDA and the available research, from whatever quarter. First, the task of conducting research, even if you had available unlimited funding, is not an easy one, if what you want to do is to draw firm conclusions. In the dark ages back in college, I learned some things about conducting research, doing statistics, and drawing reasonably firm conclusions. It's not easy, for a multitude of reasons individualized to the particular kind of research you're involved in. As far as the FDA is concerned, the problems are multiplied by the vast amount of pushback they get from the firms attempting to develop drugs in some kind of time frame that allows for enough of a profit to make up for all the research they go with that doesn't work out at all. All this stuff gets entangled with politics and all kinds of stuff that you wish didn't happen. The FDA mostly does try to keep the patients' best interest in mind, I don't doubt. But... once a drug is rushed to approval, it's nearly impossible to get it taken off the market, and no one at all is looking for the data necessary to do that.

I had a nice chat a few years ago with a friendly hospital employee who was talking with patients all day long every day while she operated CT-scan equipment on them. I just happened to mention my experiences with Avandia, that had just been taken off the market. It took the FDA an amazingly long time to accomplish that withdrawal of approval. The CT-scan operator told me that she'd been hearing huge negatives about Avandia for *years* from that hospital's patients--but it remained on the market, year after year until just recently, however. Apparently what was obvious to so many patients had a difficult time getting to the ears of the FDA. My own problems with Avandia that I told her about also did include frightening cardiac incidents, which is the only reason I know of that Avandia was eventually removed from the market. But that drug also *caused* kidney disease, in my experience.

From time to time, articles in the New York Times detail the amazing effort the drug companies make to influence the decisions of the FDA. Because a drug is still on the market doesn't mean much to me.

One year, one of the Times' articles discussed the way a horribly dangerous heart valve made its way past FDA approval and onto the market. It stayed on the market for years, while patients kept dying later on from an infection in the device. Yes, I know about that one. My sister-in-law died from an infection in that particular device within about two years of having it implanted. As a forty-year old she had been feeling fine, absolutely fine, but a doctor at Mayo Clinic convinced her that without a valve implant, she might drop dead at any moment. My take-away from that experience is that if you're feeling fine, don't change up to use more new technology or more new drugs. Don't count on the FDA or anyone else to anticipate everything that might go wrong as a result of your new thing/drug.

No one ever sent in anything on my experiences blaming Glucophage for the kidney disease that I am very much aware was precipitated by Glucophage. At the time, my doctor didn't do any sophisticated testing to discover the earliest markers for kidney disease and wasn't interested in anything more than asking whether I needed a heavier dose of insulin to make up for the effect of dropping Glucophage (which she explicitly said sounded like a good idea on my part). That I dropped its use because it clearly *caused* kidney problems for me had zero effect on that "excellent" metformin record that includes me.

Like most diabetic patients who progress to kidney disease, the cause or one of the causes--in my case Glucophage--and the effect--kidney disease--finally officially diagnosed years later--are far too widely separated in time for doctors to make an easy connection between the two. And the drug company has scant incentive to do that kind of difficult and expensive research, given that the FDA wasn't requiring a heavy longitudinal study before approval.

Doctors really aren't well equipped (or financed) to do that kind of research either. My current doctor has never even had the time to get the story from me of what happened to me on Glucophage. By the time he got a urine sample (at my insistence after the chronic antibiotic usage fiasco), the protein numbers were in the thousands. But I am one of those people included in the wonderful record on Glucophage and no problems whatsoever show up for me with it.

My current doctor just assumes, the same as most doctors would, that my kidney problem stems from high blood pressure and diabetes--since, as you say, he knows that "the most prescribed medicine in the world and its side effect record is excellent." To whatever extent he thought about it (not very likely) he would have been choosing to assume either: 1) that commonly believed fact as to the cause--high blood pressure/diabetes, 2) that the cause was a later drug that had given me edema for *years*--Avandia--but that also he was just now noticing after I made an appointment to focus exclusively on it, and/or 3) blame it on giving me a standing endlessly refillable prescription for an antibiotic that was well-known to be hard on the kidneys. Which route do you guess a hard-working very busy doctor would have taken? To go back to Glucophage wasn't even on his radar at that point. I hadn't even been his patient when I thad taken myself off Glucophage, and I had no records to transfer when my former doctor's huge practice dissolved.

I know something quite different from "the most prescribed medicine in the world and its side effect record is excellent". And I'd bet anything that there are thousands of other diabetics out there on the road to kidney failure, thanks to Glucophage--just like me, all appearing to contribute to that "excellent" record on Glucophage, the same as I did. Blood pressure might or might not be a contributing factor, but my guess is that the longer a diabetic stays on that drug, the higher the chances that they'll find themselves in the same boat I'm in.

If it were a simple thing like taking a single dose of Glucophage/metformin and coming down with a terrible kidney effect instantly, of course the FDA would have not approved such a drug. But in the same way that Aleve isn't taken off the shelf because of its burden on the kidneys, Glucophage is still available too. It's far from obvious that taking either one inevitably or even often results in kidney failure.

Glucophage/metformin doesn't inevitably cause kidney failure in the short run, and I don't mean to claim that it does. What I want to say: taking Glucophage regularly for a long time increases the risk of causing kidney failure, and it's a significant risk. You might be lucky and still have plenty of kidney function left after years on metformin. Or not. It's your choice for whether to take the risk or not.

One other thought: you can bet that even if the prescribing information on the drug nowadays still maintains the "don't give to patients age 65 or older" advice, that doctors don't often follow it, even if they manage to find the time to read that caution. My brother-in-law died at age 72 a couple of years back, and he was still on Glucophage the day he died (not from kidney disease). His prescribing doctor practiced medicine at the Mayo Clinic, so I assume my brother-in-law was using at least as good a doctor as most people have.

One difference between Aleve and Glucophage is that Aleve isn't intended to be taken daily in significant doses for *years*. If you get a muscle sprain once in a while, you're plenty glad Aleve is still available, and the probability of having kidney disease from an occasional use is remote. No such stricture applies to Glucophage, however: it's *intended* to be used *daily* for *years*.

I don't recall for certain, but I believe I read that kidney disease is on the rise nowadays, accompanying the rise in numbers of diabetics. My bet: that the percentage of aging diabetics who progress to kidney disease greatly increased after the point in time when Glucophage was introduced and approved by the FDA for thousands/millions of dibetic patients.

In my view, in a better world, metformin would never have reared its head. I think it ought not to be used at all. And in that better world, I believe we'd see the numbers of new kidney patients dropping, high blood pressure notwithstanding.

I'd not advise anyone to experiment with this drug. People are always free to make their own decisions, of course. And I know I've made plenty of mistakes in my time. Still, I think as long as you remain on this particular drug, I'll keep my fingers especially crossed for you, wishing you the best of luck.

Mary

#15 Kevnzworld

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Posted 07 March 2013 - 04:00 AM

Mary, I appreciate your concern. Remember that one of the most common afflictions from diabetes is renal impairment. Your anecdotal experience is sad, but it it has to be weighed against the other millions that didn't have a side effect. Remember, we don't know what other drugs you were taking simultaneously, or what your kidney health was prior to taking Metformin.
The reason that non diabetic people like me take metformin is for longevity purposes. Did you read some of the the other posts?
Here is a synopsis of why a healthy non diabetic would take Metformin
http://www.lef.org/m...h&key=Metformin
I wish you well, and as I said before, be careful with what you take, and get your hepatic/ renal functions tested...semi annually.

Edited by Kevnzworld, 07 March 2013 - 04:01 AM.

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#16 mikeinnaples

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Posted 07 March 2013 - 04:48 PM

You may want to read my LongeCity article on metformin: http://www.longecity...ension-drug-r32


Mary, please read this as well. It is well put together and written.

Where can I get metformin without a prescription?


That is always a good question, especially for people in the US. I would be interesting in a trusted source even though I *do* have a valid prescription. I would rather not be limited to what my current physician feels comfortable prescribing for off label use. I like him and would rather not switch to another just for that reason. It would be nice to get back to my old dosage though.

#17 niner

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Posted 07 March 2013 - 08:58 PM

Mary, I'm sorry to hear of your kidney problems. In diabetic nephropathy, the cause is usually Advanced Glycation Endproducts; crosslinks between structural proteins that are caused by excessive blood glucose concentration. Even if metformin contributed to your kidney disease, the crosslinks are probably a big factor. There is a compound called Alagebrium (sometimes known as ALT-711) that was designed to be a crosslink breaker. I've heard that people have had pretty decent luck with it in diabetic nephropathy. It's possible to get it via the internet, if you're interested in reading up on it and running an experiment. I'd also consider trying c60-olive oil. It is a potent antioxidant that may also be able to increase the fraction of successful stem cell differentiations.

I think that metformin is unlikely to cause a problem in healthy young people, but it wouldn't be a bad idea for people to monitor basic metabolic markers, including kidney function, during any drug or supplement regimen.

#18 Methos000

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Posted 07 March 2013 - 10:48 PM

Where can I get metformin without a prescription?



Google 'bmpharmacy'.

#19 guitarparty

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Posted 11 March 2013 - 12:30 AM

In diabetic nephropathy, the cause is usually Advanced Glycation Endproducts; crosslinks between structural proteins that are caused by excessive blood glucose concentration. Even if metformin contributed to your kidney disease, the crosslinks are probably a big factor. There is a compound called Alagebrium (sometimes known as ALT-711) that was designed to be a crosslink breaker. I've heard that people have had pretty decent luck with it in diabetic nephropathy. It's possible to get it via the internet, if you're interested in reading up on it and running an experiment. I'd also consider trying c60-olive oil. It is a potent antioxidant that may also be able to increase the fraction of successful stem cell differentiations.


Hi Niner,

Thanks so much! I'm very much interested in the ALT-711, but will postpone adding anything else in beyond what I'm doing right now to give some more time to evaluate all that I'm doing in term of the GRF reading next time. The main reason I'm content to wait a bit is that my diabetes is in better control right now than it has been in approximately a decade. Some of the ton of supplements I'm on specifically are geared toward evening out the blood glucose. Along with a diet change, they're definitely having an effect: I've gradually cut my insulin usage by more than half since January. I was for many years hitting highs and lows unpredictably, even though I gave it good attention. Anyway, I feel as if I'm on a roll right now, but won't wait long before trying ALT-711 if the kidney disease doesn't at least stabilize under this new regime.

I really appreciate your tip! Thanks!

Mary

#20 Michael

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Posted 31 July 2013 - 08:03 PM

It's flunked again. I'd suggest that you (and all) drop it.
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#21 joelcairo

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Posted 01 August 2013 - 07:48 AM

Don't have any opinion about its ability to extend max lifespan, but Metformin does have well-documented effects against cancer. Specifically it seems to target cancer stem cells, the subpopulation of cells within a tumor which are required for it to grow indefinitely.
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#22 Michael

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Posted 01 August 2013 - 03:31 PM

Don't have any opinion about its ability to extend max lifespan, but Metformin does have well-documented effects against cancer.


It has well-documented effects against cancer in people and mice with diabetes, where the control group is hyperinsulinemic and/or treated with insulin or sulfonylureas. It's not surprising that avoiding massive insulin overexposure reduces the risk of cancer; that doesn't mean it's beneficial in normoglycemic folk.

It's also been found beneficial in some strains of cancer-prone rats and mice. Again, that doesn't necessarily mean it has any benefits in people with a normal genetic roll of the dice.

As already noted, the new studies in healthy, normal, nonobese, nondiabetic mice found no changes in cause of death between treated and untreated animals.

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#23 joelcairo

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Posted 01 August 2013 - 05:21 PM

Well here's a study showing that diabetic patients had a significantly higher risk of ovarian cancer progression than non-diabetic patients, whereas diabetic patients using Metformin had a significantly lower risk than non-diabetic patients. That certainly suggests that something interesting is going on beyond the treatment of diabetes.


Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity

"The progression-free survival at 5 years was 51% for diabetic patients who used metformin compared with 23% for the nondiabetic patients and 8% for the diabetic patients who did not use metformin (P=.03)."

http://www.ncbi.nlm....pubmed/22183212
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#24 blood

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Posted 02 August 2013 - 07:03 AM

I began taking Metformin around 3 months ago at 2 gm/ day.

It's been somewhat of a revelation... my appetite is obliterated... the kgs are falling off.

I've lost around 8 kgs over the past 2 months.

Edited by blood, 02 August 2013 - 07:48 AM.

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#25 Andey

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Posted 02 August 2013 - 08:00 AM

I began taking Metformin around 3 months ago at 2 gm/ day. It's been somewhat of a revelation... my appetite is obliterated, and the kgs are falling off. I've lost around 8 kgs over the past 2 months. Metformin makes aggressive reduction of food intake feasible. I wonder what weight I will stabilize at? Looking forward to finding out. I feel great. Hooray for metformin!


Starting 2 gm a day is rather extreme approach )
I use 850mg time release and after 3 month could say that after some adaptation period my appetite stabilized at the same level as before. Only major difference I noticed is that it became hard to gain some weight both by overeating or excercise+proteins. I didnt solve this problem so far and if first is beneficial the latter is a problem.
May be its a placebo effect but I noticed some loss of libido and have added DAA to compensate it - so far its rather overcompensate it but I really like such outcome )

#26 blood

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Posted 06 August 2013 - 06:35 AM

I began taking Metformin around 3 months ago at 2 gm/ day. It's been somewhat of a revelation... my appetite is obliterated, and the kgs are falling off. I've lost around 8 kgs over the past 2 months. Metformin makes aggressive reduction of food intake feasible. I wonder what weight I will stabilize at? Looking forward to finding out. I feel great. Hooray for metformin!


Starting 2 gm a day is rather extreme approach )


I am about 175 cm, so my supposedly ideal weight would be around 55-65 kg. For most of my life I've been at 55 to 60 kg. Over the past few years my weight crept up to 76 kg. (I think the increase in weight was partly a consequence of getting older, and partly due to stressful work conditions). The situation was emergency - I faced having to throw out a wardrobe of beautiful slim fitting shirts - something had to be done. I couldn't "feel" the effects of 500-1000 mg metformin. But at 2 gm/ day of metformin produces a strong reduction in appetite for me. It also reduces the amount of food that can be consumed without producing a gross feeling of fullness/ being stuffed to the gills. I now eat two meals a day. Breakfast consists of a small piece of fruit, and 40 grams whey protein. An evening meal contains some carbs, some fat (olive oil, eggs, cheese), some vegetables. I have no cravings. I take a broad spectrum of polyphenols, and also a bunch of stuff to eliminate insulin resistance/ improve sugar metabolism. And of course some vitamins, some trace minerals, etc. I'm down to around 68 kg. I don't seem to be losing muscle around my arms, chest. So far the weight seems to be melting away from the right places - my waist, my gut, my neck.



I use 850mg time release and after 3 month could say that after some adaptation period my appetite stabilized at the same level as before. Only major difference I noticed is that it became hard to gain some weight both by overeating or excercise+proteins. I didnt solve this problem so far and if first is beneficial the latter is a problem. May be its a placebo effect but I noticed some loss of libido and have added DAA to compensate it - so far its rather overcompensate it but I really like such outcome )


I think I've noticed a small reduction in libido. Not enough that I feel it is problematic.

#27 mikeinnaples

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Posted 06 August 2013 - 02:34 PM

As already noted, the new studies in healthy, normal, nonobese, nondiabetic mice found no changes in cause of death between treated and untreated animals.


Too bad the majority of the North American population doesn't fit that healthy, normal, non-obese group.
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#28 albedo

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Posted 11 August 2013 - 09:34 AM

As per 23andme I am TT on rs4585 (0.75 times the odds of having a positive response to metformin). Are you sharing the same and still have positive response to metformin? I am considering it too but did not make the step yet.

#29 jack black

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Posted 07 February 2017 - 11:12 PM

I know this is old, but i wanted to say to the OP: thank you very much for starting this topic.

 

I've been prescribed metformin for "metabolic syndrome" by 2 different docs at different points with no effects whatsoever, but they used low dose 500-1000mg/day.

This info encouraged me to look and sure enough drugs.com clearly states that 2000mg is the target dose and anything below 1700mg is ineffective. I even talked to a few clinicians I know that prescribe this for diabetes and they were not aware of this either. They thought 2000mg was the "maximal" dose and not the "optimal" one.

 

I went ahead and increased the dose and even with 1500mg I felt less hungry and started losing weight all previous week. Now, I'm doing 2x1000mg this week and the effects are striking. Now i can skip dinner/supper and go to bed hungry (a healthy thing), something i was not able to do my entire life (i even considered i had a night eating syndrome). I even feel better psychologically. It could be a placebo, but as we know, metformin goes to brain and has effects there too.

 

I agree with slight libido change.


Edited by jack black, 07 February 2017 - 11:14 PM.

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#30 Mind_Paralysis

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Posted 12 February 2017 - 01:33 PM

I know this is old, but i wanted to say to the OP: thank you very much for starting this topic.

 

I've been prescribed metformin for "metabolic syndrome" by 2 different docs at different points with no effects whatsoever, but they used low dose 500-1000mg/day.

This info encouraged me to look and sure enough drugs.com clearly states that 2000mg is the target dose and anything below 1700mg is ineffective. I even talked to a few clinicians I know that prescribe this for diabetes and they were not aware of this either. They thought 2000mg was the "maximal" dose and not the "optimal" one.

 

I went ahead and increased the dose and even with 1500mg I felt less hungry and started losing weight all previous week. Now, I'm doing 2x1000mg this week and the effects are striking. Now i can skip dinner/supper and go to bed hungry (a healthy thing), something i was not able to do my entire life (i even considered i had a night eating syndrome). I even feel better psychologically. It could be a placebo, but as we know, metformin goes to brain and has effects there too.

 

I agree with slight libido change.

 

What sort of change?

 

I'm guessing lowered libido? Since this seems to lower cravings, in a way.
 







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