[16] High blood lactic acid level (acidosis) is a concern if the medication is used in overly large doses or prescribed in people with severe kidney problems.

[52][53] In an updated Cochrane (2020) review on metformin versus placebo/no treatment before or during IVF/ICSI in women with PCOS no conclusive evidence of improved live birth rates was found.

[55] The United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin for anovulation and infertility when other therapies fail to produce results.

Metformin treatment decreases the risk of developing type 2 diabetes in women with PCOS who exhibited impaired glucose tolerance at baseline.

[61] Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes.

This pattern of initial low birth weight followed by catch-up growth that surpasses comparative children has been associated with long-term cardiometabolic disease.

[89] Although more research is needed to understand the mechanisms of this association, it is suggested that people who take metformin monitor their vitamin B12 levels and if low, begin supplementation.

In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs.

[45] Given severely impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup.

[96] The clinical significance of this is unknown, though, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.

[100] Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a forensic death investigation.

Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving therapeutic doses, 40–120 mg/L in victims of acute overdosage, and 80–200 mg/L in fatalities.

[9] A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism;[105] theoretically, other cationic medications may produce the same effect.

[59][35] The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.

[112] AMPK is an enzyme that plays an important role in insulin signaling, whole-body energy balance, and the metabolism of glucose and fats.

[117] Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice, and this may contribute to its mode of action possibly through an effect on glucagon-like peptide-1 secretion.

[122] Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms, however, AMPK likely has a modest overall effect and its activity is not likely to directly decrease gluconeogenesis in the liver.

It is cleared from the body by tubular secretion and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose.

In December 2019, the US Food and Drug Administration (FDA) announced that it learned that some metformin medicines manufactured outside the United States might contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen, at low levels.

[155] In July 2020, Lupin Pharmaceuticals pulled all lots (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.

[162] That year, Filipino physician Eusebio Y. Garcia[163] used metformin (he named it Fluamine) to treat influenza; he noted the medication "lowered the blood sugar to minimum physiological limit" and was not toxic.

[164] In a series of articles in 1954, Polish pharmacologist Janusz Supniewski[165] was unable to confirm most of these effects, including lowered blood sugar.

[166][167] French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from G. officinalis, which is related in structure to metformin, and had seen brief use as an antidiabetic before the synthalins were developed.

[168] Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate the blood sugar-lowering activity of metformin and several biguanide analogs.

[174] Metformin and its major transformation product guanylurea [de] are present in wastewater treatment plant effluents and regularly detected in surface waters.

Guanylurea concentrations above 200 μg/L have been measured in the German river Erpe, which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.

[186] However, following a meta-analysis in 2007, that linked the medication's use to an increased risk of heart attack,[187] concerns were raised over the safety of medicines containing rosiglitazone.

[213] As a result, they have a shorter duration of action compared to sulfonylureas and require higher blood glucose levels to begin to secrete insulin.

[citation needed] Despite that, metformin has received substantial interest as an agent that delays aging; it has been shown to increase longevity in some animal models (e.g., C. elegans and crickets).

[233][235] Whether metformin may help extend life, even in otherwise healthy people, remains unknown; a 2021 review of the literature found it is likely to improve healthspan, i.e., the number of years spent in good health, rather than lifespan overall.