Talk:Metformin

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).

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)

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

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)

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 of 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) 07:20, 4 July 2020 (UTC)