Talk:Metformin/Archive 2

Archive 1

Archive 2

Use in Pregnancy

Here's a recent study: http://www.ncbi.nlm.nih.gov/pubmed/26117686

(On a different issue: Metformin is considered unlikely to cause hypoglycaemia when used as monotherapy. It may occasionally do so, but it's uncommon).

— Preceding unsigned comment added by 121.211.73.2 (talk • contribs) 13:27, 23 July 2015 (UTC)

Who does this?

"There is no evidence that metformin affects the risk of cancer"

I read the articles linked with the above quote. Is it a fair summary of:

"The remarkable efficiency of metformin to inhibit cancer cell growth in vitro and tumor proliferation in animals, and its low toxicity, favor the potential use of this agent in the treatment of cancer. However, depending on cell lines, the mechanism of action of metformin and its sensitivity toward this agent are different. Therefore, it is important to determine the cellular and molecular action of metformin in order to optimize its use in cancer therapy [...] As a result, we believe that trials of metformin as an adjuvant treatment in breast cancer and more generally in other cancers should move forward in nondiabetic patients." http://mct.aacrjournals.org/content/9/5/1092

"The available evidence from basic science, clinical, and population-based research supports the anticancer effect of metformin. However, randomized controlled clinical trials do not provide enough evidence for a strong protective effect of metformin on cancer incidence or mortality. One of the most important limitations of these trials is the short duration of the followup. Further long-term randomized controlled clinical trials specifically designed to determine metformin effect on cancer risk are needed to provide the best answer to this challenge." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800579/

So.. there is no evidence that metformin affects the risk of cancer? At most one could say that, at the present moment, the evidence is inconclusive. But it's likely that it does have an anti-cancer effect.

It also contradicts this sentence from the 1st paragraph "Limited evidence suggests metformin may prevent the cardiovascular disease and cancer complications of diabetes.", which also cites one of the above articles. — Preceding unsigned comment added by Adrian1616 (talk • contribs) 07:43, 30 June 2016 (UTC)

Hi -- I just replaced the "no evidence" sentence with what I think is a better summary of what the two articles it cited say. As Adrian1616 cites above, "The available evidence ... *supports* the anticancer effect of metformin". Previous randomized clinical trials haven't shown enough effect, probably because follow-up was short; so long-term controlled studies are needed. Howie Goodell (talk) 18:48, 8 July 2016 (UTC)

Thank you! — Preceding unsigned comment added by Adrian1616 (talk • contribs) 20:45, 11 July 2016 (UTC)

Mechanism of action

There's quite a lot of primary sources in the section discussing the mechanism of action. I would suggest that doi:10.1038/nrendo.2016.86 could be used to replace quite a lot of them. JFW | T@lk 12:14, 28 December 2016 (UTC)

Review

Use of metformin if renal, liver or cardiac function is not all that doi:10.7326/M16-1901 JFW | T@lk 11:18, 3 January 2017 (UTC)

Request for consensus on inclusion or deletion of information on combination treatment of metformin and syrosingopine

I had added the information below, which may be the most important development in cancer therapy in the last few decades, but it was deleted. While treatment sections generally rely on reviews and meta-analyses, is not correct that research sections include only information from reviews. If that were the case, we should never include Research sections, because Wikipedia would be a history book, not an encyclopedia. I find it odd that information about possible life extension, which may or may not have any practical use this century is included, but this highly relevant information is excluded. Since both drugs are already approved, this may become an approved treatment long before reviews and meta-analyses materialize. Please post thoughts on relevance below. Here's what I had included: A combination of metformin and the antihypertensive drug syrosingopine killed tumor cells in blood samples (in vitro) from leukemia patients, while it did not damage blood cells in samples from healthy patients. The combination of metformin and syrosingopine also reduced or eliminated tumors in mice with malignant liver cancer. The drugs interfere with the cancer cells' glucose (i.e. energy) supply and utilization. Cancer cells have much higher energy requirements than normal cells, making them vulnerable when there is a reduction in the available energy supply.

References

-- Tetsuo (talk) 05:29, 19 January 2017 (UTC)

Thanks for bringing this to talk! The sources here are popular news article and a primary source. This scenario is specifically described in WP:MEDREV, which is part of WP:MEDRS. Please do read and follow MEDRS; if you don't understand why the community created and implements MEDRS consistently across articles about health, the essay WP:Why MEDRS? may help you.

For sections about research, we also look for secondary sources, that provide trends in research. If research sections became open to primary sources they would soon become a huge catalog of pubmed abstracts, with no sense or order about what is important in the field, what is maybe interesting in the field, what is pretty meaningless, and what even gets retracted! Jytdog (talk) 05:39, 19 January 2017 (UTC)

Yup please use high quality secondary sources per MEDRS Best Doc James (talk · contribs · email) 16:46, 19 January 2017 (UTC)

use in pregnancy

we need to harmonize what we say. at one point "The use of metformin during all parts of pregnancy is controversial". At another point "Metformin is safe in pregnancy" and the lead says "While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.".

don't have time to fix right now. Jytdog (talk) 21:01, 2 June 2017 (UTC)

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Aging

There are some claims that metformin may be an anti-aging wonder drug, e.g. Wired coverage. These likely need to be mentioned in the article, but I lack the medical expertise to evaluate them well & either add links to better sources or add appropriate cautions. Can someone do that? Pashley (talk) 14:00, 5 July 2017 (UTC)

Discussed in a more encyclopedic tone already here Metformin#Research :-) Doc James (talk · contribs · email) 14:38, 5 July 2017 (UTC)

I think this deserves mention in the opening paragraph of the article. Elohim (talk) 03:35, 29 December 2017 (UTC)

We are not part of the anti-aging hype machine. If this ever becomes medicine, that will indeed be a very big deal and of course would be added to the lead. Jytdog (talk) 04:16, 29 December 2017 (UTC)

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Edits

User:Jessperrone your edits are not OK; you are using a bunch of primary sources and removing secondary sources and overplaying the evidence. Please respond. Jytdog (talk) 02:02, 3 June 2018 (UTC)

I have gone through and trimmed the primary sources.

A bunch of the rest was already covered using newer sources.

And some other bits were off topic. Doc James (talk · contribs · email) 07:06, 3 June 2018 (UTC)

Evidence Please!

Why is this article so terrible? Metformin is not a minor drug. It is widely used around the world, and gets a lot of page hits. This article requires a thorough rewriting to remove opinions and replace with strong secondary or tertiary sources and add additional info. There is a disconnect between the current state of the evidence and information presented in this article. There is also a lot of missing information. I've done this for the fertility subsection and corrected a few other glaring flaws. More needs to be done. — Preceding unsigned comment added by Sbelknap (talk • contribs) 20:31, 18 November 2018 (UTC)

Have restored some of the reviews that were removed.

You changed the article to say a whole bunch of things the refs did not support. In fact the refs said the opposite... Doc James (talk · contribs · email) 05:31, 19 November 2018 (UTC)

Examples, please? So far, you have not provided any examples of this. Sbelknap (talk) 14:29, 19 November 2018 (UTC)

Evidence

1

In this edit you changed "tentative" to "equivocal" https://en.wikipedia.org/w/index.php?title=Metformin&curid=253720&diff=869587694&oldid=869532416&diffmode=source

Ref says "Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low." https://www.ncbi.nlm.nih.gov/pubmed/29183107

The results section of the abstract states "Metformin versus placebo or no treatment: The evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low-quality evidence)" An OR of 1.59 is a very weak effect and the confidence interval includes 1, indicating that "no effect" is within the confidence interval.

2

In these edits https://en.wikipedia.org/w/index.php?title=Metformin&type=revision&diff=869530342&oldid=868417644&diffmode=source

You added "The available scientific evidence does not support metformin use during pregnancy for improving maternal and infant outcomes in obese women."

While the first ref supports the second ref is about PCOS and says "Use of metformin throughout pregnancy in women with polycystic ovary syndrome (PCOS) has shown to reduce the rates of early pregnancy loss, preterm labor, and prevention of fetal growth restriction."

The relevant outcome is live births (or healthy 18 year olds, if one takes an economic perspective). These other outcomes are irrelevant. Sbelknap (talk) 20:47, 19 November 2018 (UTC)

3

You than added "Use of metformin treatment increases the rate of pregnancy but does not increase the likelihood of successful pregnancy or live births in women with polycystic ovarian syndrome undergoing in vitro fertilization."

The first ref supports but the second ref is not even about in vitro fertilization.

References

Doc James (talk · contribs · email) 17:41, 19 November 2018 (UTC)

Treatment of infertility does not necessarily require in vitro fertilization. Anything that lowers androgens potentially works. Sbelknap (talk) 20:47, 19 November 2018 (UTC)

Evidence and practice

Sbelknap thanks for putting time into this page. It has been subject to a ton of advocacy editing about a few different things, as is clear if you review the history.

Importantly, this is a topic where we have to keep in mind that "medical use" describes actual clinical practice, as well as guidelines, as well as evidence. Your editing here (as it has a few times in the past) swept away everything other than evidence. This is not OK in Wikipedia. Where evidence and guidelines and practice don't align or even contradict each other (including among guidelines), we need to represent that lack of alignment here in a away that honors the spirit and letter of NPOV. As an example, the NIH Office of Womens health says " Metformin is often used to treat type 2 diabetes and may help some women with PCOS symptoms. It is not approved by the FDA to treat PCOS symptoms. Metformin improves insulin's ability to lower your blood sugar and can lower both insulin and androgen levels. After a few months of use, metformin may help restart ovulation, but it usually has little effect on acne and extra hair on the face or body. Recent research shows that metformin may have other positive effects, including lowering body mass and improving cholesterol levels." Tha page was last updated October 22, 2018. Important, uptodate refs like that cannot be left out. Things go much more smoothly and importantly, less time is lost in disputes or edits that get reverted, when we all aim at the same thing. Jytdog (talk) 19:55, 19 November 2018 (UTC)

Here you are citing general info on treatment of polycystic ovary syndrome, not specifically info on improving fertility of women with polycystic ovary syndrome. My suggestion (which I stated) is that this general info should be in the main article but not in the lede.

w/r/t the information specifically about fertility/pregnancy in women with polycystic ovary syndrome, you have the wrong link. The correct link, which does not mention metformin, is here: https://www.nichd.nih.gov/health/topics/infertility/conditioninfo/treatments/treatments-women Sbelknap (talk) 20:37, 19 November 2018 (UTC)

NICE Guidelines

The NICE guidelines for use of metformin during pregnancy have not been updated in several years. It would appear that they contain statements that do not reflect the current secondary or tertiary medical literature. Metformin is not labelled for use in pregnancy in the US nor in the UK. Here is a relevant statement from NICE: "Although metformin is commonly used in UK clinical practice in the management of diabetes in pregnancy and lactation, and there is strong evidence for its effectiveness and safety (presented in the full version of the guideline), at the time of publication (February 2015) metformin did not have a UK marketing authorisation for this indication. The summary of product characteristics advises that when a patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information."

References

--— Preceding unsigned comment added by Sbelknap (talk • contribs) 14:40, 19 November 2018 (UTC)

Okay? The companies have not bothered to request marketing approval? And why would they? Metformin is a generic. This is marketing strategies of companies and not medicine. Doc James (talk · contribs · email) 17:43, 19 November 2018 (UTC)

Absence of evidence supporting this indication from the Full Prescribing Information is certainly relevant. Current guidelines do not recommend using metformin as an adjunct for assistive fertility treatments *AND* there is no evidence from full prescribing information in support of such use. Sbelknap (talk) 18:52, 19 November 2018 (UTC)

Please see the Canadian guidelines on diabetes and pregnancy. The Canadian guidelines are current and are excellent. There are multiple separate topics in the Canadian guidelines. By my read, the section on fertility in the current version of the metformin article is out-of-step with these Canadian guidelines.

References

-Sbelknap (talk) 18:55, 19 November 2018 (UTC)

Sure the Canadian guidelines can be used. They say "First-line therapy consists of diet and physical activity. If glycemic targets are not met, insulin or metformin can then be used."

Here, you are quoting from the abstract of the Canadian guidelines on gestational diabetes mellitus. There is more info in the article on GDM and metformin on page S269. The important issue to also address for the wikipedia article is regarding long-term follow-up.

It is not about PCOS. Doc James (talk · contribs · email) 19:27, 19 November 2018 (UTC)

Sure it is. The Canadian guidelines are about many things that are relevant to metformin and fertility. w/r/t PCOS, the Canadian guidelines state, "Studies looking at metformin use for GDM reduction in women with obesity (231) and with PCOS (232) have not shown benefit."Sbelknap (talk) 20:12, 19 November 2018 (UTC)

Yes metformin does not decrease the risk of GDM in women with obesity or PCOS. That is not what it is used for though. It is not a statement on the utility of metformin for infertility due to PCOS. Doc James (talk · contribs · email) 21:56, 19 November 2018 (UTC)

These Canadian guidelines also give recommendations regarding metformin use women with irregular menses/PCOS on page S271. (low quality data, expert consensus only).

Lazarus Study

I note that Doc James has removed the Lazarus et al citation from the discussion of adverse effects of metformin. This study analyzed data from a ommunity-based cohort of 75 413 patients with diabetes in Geisinger Health System, with time-dependent assessment of eGFR stage from January 2004 until January 2017. Results were replicated in 67 578 new metformin users and 14 439 new sulfonylurea users from 2010 to 2015, source from a separate dataset. There are two problems here. First, Doc James did not acknowledge that he was deleting this citation and it's conclusions. Second, Doc James continues to misapply the wikipedia guidelines for medical articles by removing many high-quality primary sources. This is not what these guidelines state. Primary sources vary in quality, and are worthy of citation, particularly on issues where clinical trials and resulting meta-analyses do not adequately study adverse drug effects. Doc James (and others) are asked to be explicit in their edits when they are removing citations. Also, Doc James is asked to reread and reconsider the intent of the medical wikipedia guidelines w/r/t primary sources.Sbelknap (talk) 13:54, 19 December 2018 (UTC)

References

Per WP:MEDPRI, "If material can be supported by either primary or secondary sources – the secondary sources should be used." Rather than quote a cohort study, why not simply quote the FDA's guidance on the matter? ―Biochemistry🙴❤ 14:00, 21 December 2018 (UTC)

Better to use a secondary source on the topic. Doc James (talk · contribs · email) 07:52, 11 January 2020 (UTC)

Text

"Metformin increases circulating levels of GDF15, which reduces food intake and lowers body weight through a brain stem-restricted receptor.""

Would belong under mechanism of action if anywhere. Doc James (talk · contribs · email) 07:52, 11 January 2020 (UTC)

Note authors think the relevance is to obesity: [1] Ratel (talk) 10:58, 11 January 2020 (UTC)

References

Pharmacokinetics

The pharmacokinetics section seems not to be up to date with the latest literature. Rather than edit this myself, I would prefer if an author of this article would look over the newer literature and make changes as necessary. I would, in particular, suggest that the metformin tail is asymptotically a power function. There are some drugs (e.g., amiodarone) for which this is known to be important, and the new information is that it is important for metformin as well. For example, with a terminal power function, there is no terminal half-life per sey. This explains why the literature includes wildly divergent half-life values for metformin; for a power function the half-life depends on when the last sample was collected, and the longer one samples, the longer the apparent terminal half-life seems to be. This can be explained as follows: 1) Only monoexponentials have a constant half-life. 2) When a monoexponential is plotted tangent to a negative power function of time at any particular time, its half-life is that of the monoexponential at that particular time. However, 3) negative power functions of time have more shallow curvature than monoexponentials such that the later in time one constructs the tangent, the longer the monoexponential's half-life appears to be. Those are the most basic concepts for metformin pharmacokinetics. For a much more elaborate treatment please see.

For an independent evaluation of that work please see, , and for an executive summary, please read. CarlWesolowski (talk) 21:26, 4 July 2020 (UTC)

Not done, this is too soon. The article hasn't been independently reviewed yet the second source appears to be a collaborator. If you can provide independent reviews in a scientific journal of this work we can add it. We don't cite primary sources so it won't be your article that is cited, therefore if you can find an independent source to add the detail you want there won't be a conflict in you directly editing this article. It doesn't really work like normal science writing so it is necessarily behind in the times sorry I couldn't be of more help to you! PainProf (talk) 23:58, 4 July 2020 (UTC)

First of all, Prof. Tucker wrote the review when he was not a collaborator and was so impressed with the work that he contacted the first author to write an executive summary. As for being too soon, the results are very solid and if you wish to dispute them a lack of argument is not in itself a discussion point. Put in the obverse, the evidence in the paper for not using sums of exponential terms and not assuming exponential conditions is solid. Furthermore, 100 years of repetition of bad models without testing of assumptions is too long, and it is none too soon to question them. Seen from that POV, what is written in the PK section herein is very misleading. I strongly suggest that you read the article in the first reference, which includes such niceties as reviewing the scattered values that have been provided for metformin half-life, their lack of coherence and the alternative explanation for them. There will never be any scientific progress if the evidence is not even considered, and familiarity with models that are not explanatory is not an excuse for ignoring explanatory models that are unfamiliar. CarlWesolowski (talk) 00:26, 5 July 2020 (UTC)

Hi sorry the main point is fact it hasn't been cited. It would be original research to cite it at the moment. It needs to be reviewed as it is a primary source. I must confess to not being up to date on pharmacokinetics. I am wary to include this because; the explanation is unclear and dense, it isn't accepted or debated by the field at large. Either way it won't be included as it is a primary source. Probably the best is to wait a few hears once the field have had time to read it and debate it. Wikipedia isn't the place for the latest and greatest research. It gets updated mainly when there are significant new reviews or synthesis on the topic. If you can point to one I'd be delighted to help you add it. PainProf (talk) 00:50, 5 July 2020 (UTC)

Could you show a testable hypothesis that is best explained by your model?

I was not suggesting, nor did I suggest that the articles I cited should be included in the text. All I did was to point to articles that show how poorly the text is written. In particular the half-life data cited in the article is ridiculous and does not represent any consensus on that topic, and this is reviewed in the articles I cited on this talk page. I do not care what you do but if you disagree with me you should follow protocol on that. Harassment for things for which you have no particular training is not proper. If you disagree with me for example, seeking out variable volume pharmacokinetics, which admittedly could have a dozen more citations and going to war over it is not appropriate behaviour. Appropriate behaviour is as follows:

References

Follow the normal protocol

When you find a passage in an article that is biased, inaccurate, or unsourced the best practice is to improve it if you can rather than deleting salvageable text. For example, if an article appears biased, add balancing material or make the wording more neutral. Include citations for any material you add. If you do not know how to fix a problem, ask for help on the talk page.

Any more harassment will be reported. CarlWesolowski (talk) 02:52, 5 July 2020 (UTC)

Hi the only reason this was drawn to my attention is that I noticed it already had a Wikipedia link on the publication when I read it. I found that surprising as there are no literature citations. It says that you included the link which may be wp:citespam but also suggests you may not have an entirely neutral point of view. I notice that this theory isn't the accepted model for pharmacology, you claim to have invented it but there are no independent citations as yet. The prose is needlessly dense, honestly I should not find it difficult to understand. None of this is harrassment rather it is due diligence when potential citation spam is found. Please just include a few independent references and I won't propose the article for deletion. PainProf (talk) 03:19, 5 July 2020 (UTC)

I did not invent variable volume PK, I added variable half-life to it. That is not something that is up for debate, the only thing having constant half-life is the monoexponential; all the others have variable half-life. That is elementary mathematics, and the fact that it has been blithely ignored we can speculate on all we want, but it is here to stay. As for citations, there are 4, two mine, two not. There need to be more, and when I have time, if no one else does, I will include them. You really need to read the papers before you jump to conclusions. CarlWesolowski (talk) 03:52, 5 July 2020 (UTC)

Several points: Pure mathematics as a matter of formal proof does not accrue validity, it is axiomatic, is not hypothetical and is unchanged by citation, unless that citation is a counter proof. Second, either one can read the proof or not. Its validity stands irrespective of the readers ability to understand it. Third, to copy a proof verbatim without citation would be plagiarism. Fourth, proofs are not "invented" they are shown. Fifth, the article included review and was itself was both reviewed and cited. The issue at hand is as follows:

"Two time-sample exponential $t_{1/2}$,

$\xi =-\ln(2){\dfrac {t_{i+1}-t_{i}}{\ln(C_{i+1})-\ln(C_{i})}}\qquad (5)$

Instantaneous half-life (definition),

$t_{1/2};f(t)=-\ln(2){\dfrac {f(t)}{f'(t)}}\qquad \qquad (6)$

...Equation (5) is common knowledge for any two time-samples, $\{t_{i},C_{i}\}$ and $\{t_{i+1},C_{i+1}\}$...However, Eq. (5) only applies for monoexponential conditions or in the limit if we substitute $f(t)\approx C_{i}$, and $t_{i+i}=t_{i}+\Delta t$ and let $\Delta t\to 0^{+}$, where $f(t)$ is ${\textit {any}}$ continuously differentiable function. That yields Eq. (6), which is of classical mechanical type, and applies equally well to the evolution of half-life of satellite orbital decay as to variable half-life of concentration of any drug. Half-lives can be both positive and negative. For an $f(t)$ that increases in time, the $t_{1/2}$ is negative. For example, this occurs when concentration is increasing in time in a peripheral vein shortly after intravenous injection. It easier to understand a negative half-life of an increasing function of time when some maximum total value of a measurement is being approached in time by subtracting the measured values from that maximum and viewing the result as a positive half-life of a decreasing function in time, as is done, for example, using total dosage administered for a urinary drug recovery $t_{1/2}$ calculation. However, growth of any function in time, including drug mass accumulating in urine, actually has a negative half-life."

The only thing that is "hypothetical" is that sums of exponential terms can form good models of metformin. That hypothesis was tested and found wanting. I will continue this later. CarlWesolowski (talk) 19:30, 6 July 2020 (UTC)

Any model in biology requires experimental proof and a testable hypothesis, I'm unclear as to why a mathematical proof is being discussed here. This may all be true of mathematical models but you have entered the world of biology, where a model requires significant experimental evidence before being accepted. As a note, I actually think the concentration of a drug after intravenous injection would rather rapidly be the same in the blood probably negligible with respect to total half life (in the blood at least since it rapidly mixes). I assumed your situation was more where there is a difference in the cell or tissue such as the physical properties within it that makes it accumalate differently or enter at a slower rate or a SC injection where there is more limited distribution. For instance the non-solid phase components of a cell will have a different rate of accumulation due to density. Either way, the model hasn't gained widespread use or acceptance at this stage. That would be shown by synthesis reviews of many papers discussing approaches to pharmacokinetics using the method. As an aside none of this is relevant to this metformin article, it wouldn't help the reader to include a mathematical proof PainProf (talk) 20:43, 6 July 2020 (UTC)

You are fighting me rather than asking, there is a point here: I wish to weigh in on the points of discussion here that I consider dangerous to patient health. From the Comparison... paper "bolus intravenous metformin plasma half-life was 1.5 h as last sampled at 8 h \cite{Sirtori1978}, 4.5 h as last sampled at 12 h \cite{tucker1981metformin}, and 20.4 h, as last sampled at 72 h (dogs) \cite{johnston2017pharmacokinetics}, such that there is good evidence that metformin plasma half-lives increase with elapsing time." What this let us say "potentially" if I am "correct" leads to is overdosing patients with reduced renal function. I consider it my duty to warn people rather than let potentially dangerous information go unquestioned. Now, are you suggesting that I should keep quite because it takes a long time to explain things, or, do you want me to continue? CarlWesolowski (talk) 21:05, 6 July 2020 (UTC)

Now, to continue, if I did not show that half-life is in general variable, the alternative hypothesis that metformin half-life is poorly characterized would be given some credence: "rather than just accept that metformin plasma concentration half-lives are poorly characterised \cite{Graham2011}" This is what physicists would call hand waving. Nowhere in the metformin article here does anyone even note that there is any difficulty determining a metformin half-life. Continuing the quote "we note that Xie et al. \cite{xie2015metformin} as well as Sambol et al. \cite{sambol1996pharmacokinetics}, the latter for oral multidosing, have commented that metformin half-life increased with elapsing time." It is because of this increase in half-life with elapsing time that metformin build-up could proceed to dangerous drug levels in renal failure. Finally, I don't care if anyone ever duplicates the model, or it comes into general usage. I am not wearing my ego on my sleeve, this is not about me. Some of my colleagues cannot read a model like this:

${\text{GPC}}(a,b,\alpha ,\beta ;t)=\theta (t-\beta ){\frac {\alpha b^{a}\beta ^{\alpha }}{\Gamma (a)}}\sum _{n=0}^{\infty }{\frac {1}{n!}}(-1)^{n}b^{n}t^{a-\alpha +n-1}B_{1-{\frac {\beta }{t}}}(a+n,-\alpha )$

Such that requiring them to learn what a unit step function, $\theta (x)$, is, or an incomplete Beta function, $B_{x}(g,h)$, is, could take a long time. Concerning half-life, if I rewrote half-life for PK, I dare say it would meet with much more resistance than if I rewrote it for physics on this same website. I can go on to include more evidence, but, at this point, consider yourself warned, be wary of dosing metformin in renal failure, build up to toxic levels could take a very long time and have an apparently erratic appearance, so much so that cause and effect may be hard to piece together. — Preceding unsigned comment added by CarlWesolowski (talk • contribs) 22:30, 6 July 2020 (UTC)

That those patients are overdosed needs a medical citation (it would need to be in a clinical guideline to override any information on the use in renal impaired patients), Metformin is contraindicated in patients with renal failure due to the known risk of lactic acidosis, this is mentioned on the box of metformin, on this article and in National guidelines for the treatment of diabetes. Extreme caution is warranted in renal impairment, this is well known, any clinician prescribing this drug would be aware of the potential contraindication. PainProf (talk) 23:24, 6 July 2020 (UTC)

There are two sides to that argument in this talk section, I have weighed in on one of them. Missing from this article is any indication of difficulty in measuring half-life. I do not need to cause lactic acidosis to raise theoretical objections and I feel duty bound to do so. CarlWesolowski (talk) 23:47, 6 July 2020 (UTC)

References

Liver and kidneys

"Lactic acidosis rare but potentially fatal. Increased risk of lactic acidosis in patients with renal impairment and advanced age"

"Generally avoid use in patients with clinical or laboratory evidence of hepatic disease."

"Do not use in patients with severe renal disease or dysfunction"

https://www.drugs.com/monograph/metformin-hydrochloride.html

Doc James (talk · contribs · email) 00:03, 22 April 2020 (UTC)

The text in the lead is not accurate, because there is strong evidence that it is safe to use metformin in patients with renal failure. Please review the text and citation in the main body of the article, which present high-quality evidence that metformin is OK to use in patients with renal failure. The lead, as it stands is wrong. Also, see Sbelknap (talk) 17:08, 22 April 2020 (UTC)

References

The AHFS citation does not advise against use of metformin in patients with renal failure or liver disease. This topic is covered in more detail in the main body of the article. I've corrected the lead to reflect the cited information.Sbelknap (talk) 20:03, 23 April 2020 (UTC)

With respect to the above those are exact quotes. What do you think "Do not use in patients with severe renal disease or dysfunction" means? I guess the kidney issue is controversial. Doc James (talk · contribs · email) 00:08, 24 April 2020 (UTC)

The current statement in the lead states: "High blood lactic acid level is a concern if the medication is used in overly large doses or prescribed inappropriately, such as those with kidney problems." This is overly broad, as most of the population aged > 60 has some sort of kidney problem. The statement in the lead does not reflect the statement in the cited reference, "Do not use in patients with severe renal disease or dysfunction." The statement in the lead does not mention severity and the term "kidney problems" is so vague as to be almost meaningless. It is specifically diminished renal clearance that is a problem, and not other sorts of kidney disease. It is not controversial to use metformin in patients with eGFR>45 ml/min. Please review the FDA-approved FPI. This current statement in the lead is incorrect and has potential to do harm. It is also inconsistent with more detailed information in the main article. Sbelknap (talk) 04:23, 24 April 2020 (UTC)

Renal failure is indeed problematic for metformin as distribution into tissue is, even in the normal kidney function case, numerically much larger than clearance, but metformin is only renal cleared. Thus, tissue concentration (but not plasma concentration) is problematic in renal failure. This metformin Wikipedia article has been cited, for better or worse, in "Metformin disposition—A 40‐year‐old mystery", which is mercifully short and which I would suggest reading. I cannot cite this myself in the main text as I am the second author, and Wikipedia excludes primary researchers, for better or worse, from citing themselves, as this has the "potential" of being "spam." Personally, I think that allowing people who have never done metformin research to say anything they feel like is the greater risk, and so, I am relegated to leaving it to the reader (as a self-selected peer; good grief!) to determine what should be done with the misleading introductory material. CarlWesolowski (talk) 18:32, 22 July 2020 (UTC)

Hi Carl I wouldn't include this but you can ask for edits using this template with instructions here to get visibility for your request. Or if you find a secondary source that isn't from you you could already include it. It is best to make the exact text you want clear best wishes,Wikipedia:Edit_requests PainProf (talk) 12:15, 24 July 2020 (UTC)

As I've said before, there has been a review see https://europepmc.org/article/med/31865474 and at the bottom click on reviews to find the link to the F1000 article, namely https://facultyopinions.com/prime/737178685#eval793569420. Concerning that author, he was so impressed with the work, that AFTER he wrote the review, he contacted me to publish a clarification with me of the mysterious nature of metformin, the 40 year mystery paper. Once one leaves the comfortable arena of 100 y/o models, things can get quite complicated, and there are relatively few PK experts who know mathematics to a graduate level. Writing new material, no matter how explanatory, that involves hitherto undocumented mathematics, and then getting it published, is not for the faint of heart. I do not wish on you to discover the properties of an entirely new mathematical function. Consider how long it took people to understand sin(x), for example, and how much work was involved. However, for metformin, there is little choice. I am going to have to follow up, with lots more math, and the properties of the gamma Pareto type I convolution are only now becoming apparent, how to calculate it in milliseconds out to infinite time is only now becoming apparent, as are the simplest form for its multiple integrals; the integral, the integral of the integral, and so forth, its derivative, the derivative of the derivative and so forth. I pity the poor reviewers of such material, it spans numerical methods, higher math, physics, pharmacology, biology, medicine, and pharmacokinetics, AND YET such people exist, it's just that percentage wise, there aren't a lot of them. My job here is just to issue a warning, you don't have to believe me any more than you have to believe in general relativity, or anything else complicated. However, I wanted to issue a caution on this talk page as a public service which boils down to this: giving metformin when renal function is low may cause a delayed overdose. More information will become available in the fullness of time as this is a topic of general interest.CarlWesolowski (talk) 05:39, 5 August 2020 (UTC)

Here from issue highlights is the editorial commentary from the British Journal of Clinical Pharmacology, (https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.14477) regarding the review of metformin: Metformin disposition—A 40‐year‐old mystery

“I know that I know nothing”, ascribed to Socrates is most certainly applicable to the pharmacokinetics of metformin. Investigated for decades we still do not fully understand the pharmacokinetics of this small, yet oh so important, molecule. Our current knowledge base, and the apparent gaps in it, are summarized in a nice commentary by philosophers of metformin kinetics, Geoff Tucker and Carl Wesolowski."

So that makes for editorial commentary on a review of an article, and it is the first, thus most prominent editorial opinion of those issue highlights. I'm not sure how derivative you want to get before you accept something as at least having an authoritative chain of opinion of its being interesting work.CarlWesolowski (talk) 06:26, 6 August 2020 (UTC)

References

PCOS symptoms other than infertility

The subsection on PCOS itself was removed and there is only a section on infertility (which is all about infertility from PCOS). Metformin is used to treat other symptoms of PCOS per the office of womens health ref and others. I think we should rename this section to PCOS and discuss other symptoms as well. Thoughts? Jytdog (talk) 21:29, 19 November 2018 (UTC)

Sure. Its use for infertility outside of PCOS is poor. Doc James (talk · contribs · email) 21:55, 19 November 2018 (UTC)

OK by me to have a PCOS section, although that compels other adjustments. Many obese patients with GDM or DM2 but without PCOS are treated with metformin during pregnancy, although this is not supported by the Dodd meta-analysis. How about a "metformin during pregnancy" section and a separate "metformin for enhancing female fertility section?" That would seem to be more intuitive for the reader. No strong feelings on this, though.Sbelknap (talk) 22:35, 19 November 2018 (UTC)

That's still focusing on fertility. Metformin can also help with symptoms of PCOS that are completely unrelated to reproduction, such as weight, hirsutism, thin hair, acne, etc. Having a section simply on PCOS in general makes a lot more sense than looking at women as nothing but walking wombs. Critterkeeper (talk) 21:57, 24 January 2021 (UTC)

References

Multiple sclerosis

• • Non-Diabetic Application**

I haven't edited Wiki in a LONG time, unaccustomed to the new format I find daunting, I don't want to screw things up. I DO want to add multiple sclerosis to the list of other ailments treated. Here are some citations:

https://pubmed.ncbi.nlm.nih.gov/32877653/#:~:text=In%20summary%2C%20we%20identify%20that,promoting%20oligodendrocyte%20regeneration%20and%20remyelination.

https://cdmrp.army.mil/msrp/research_highlights/21colognato_highlight

https://www.mssociety.org.uk/research/latest-research/latest-research-news-and-blogs/trial-shows-myelin-repair-humans-possible

2603:7080:A501:B92B:B84F:E80D:9CFF:7702 (talk) 10:29, 26 March 2022 (UTC)

So far as I can see there's just been some animal research done, with the usual attendant hype. PMID:35269466, a not-great review article, mentions it. I'd be inclined to to include unless there are better sources. Alexbrn (talk) 10:47, 26 March 2022 (UTC)

Study: Metformin use may increase risk of birth defects

Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring

Annals of Internal Medicine

Background:

Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.

Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]).

Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).

https://www.acpjournals.org/doi/full/10.7326/M21-4389

https://doi.org/10.7326/M21-4389

- 2804:14D:5C59:8693:B005:9FA7:5D5D:9FB8 (talk) 02:58, 29 March 2022 (UTC)

2021 review

This 2021 review which looked at both observational and controlled trials of Metformin and health effects found that most of the evidence is of low quality. Although used to treat Type 2 diabetes there is no strong evidence that metformin has any other health benefit. The evidence for Metformin lowering mortality risk of CVD is only a weak association [2]. Much of the content in the "medical uses" section is outdated and fails WP:MEDRS. Psychologist Guy (talk) 19:39, 5 September 2022 (UTC)