The United Kingdom Prospective Diabetes Study, a large clinical trial performed in 1980-90s, provided evidence that metformin reduced the rate of adverse cardiovascular outcomes in overweight patients with type 2 diabetes relative to other antihyperglycemic agents. Accumulated evidence from other and more recent trials, though, reduced confidence in the efficacy of metformin for cardiovascular disease prevention. Outcomes are improved even in those with some degree of kidney disease, heart failure, or chronic liver disease.
In 2017, the American College of Physicians's guidelines were updated to recognize metformin as the first-line treatment for type 2 diabetes. These guidelines supersede earlier reviews. For example, a 2014 review found tentative evidence that people treated with sulfonylureas had a higher risk of severe low blood sugar events (RR 5.64), though their risk of nonfatal cardiovascular events was lower than the risk of those treated with metformin (RR 0.67). Not enough data were available at that time to determine the relative risk of death or of death from heart disease.
The use of metformin reduces body weight in persons with type 2 diabetes mellitus in contrast to sulfonylureas, which are associated with weight gain. Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes. Metformin has a lower risk of hypoglycemia than the sulfonylureas, although hypoglycemia has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose. Metformin modestly reduces low density lipoprotein and triglyceride levels.
Polycystic ovarian syndrome
In those with polycystic ovarian syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births. This includes in those who have not been able to get pregnant with clomiphene. Metformin does not appear to change the risk of miscarriage. A number of other benefits have also been found both during pregnancy and in nonpregnant women with PCOS. 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. In long GnRH-agonist protocols there was uncertainty in the evidence of improved live birth rates but there could be increases in clinical pregnancy rate. In short GnRH-antagonist protocols metformin may reduce live birth rates with uncertainty on its effect on clinical pregnancy rate. Metformin may result in a reduction of OHSS but could come with a greater frequency of side effects. There was uncertainty as to metformin's impact on miscarriage. The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women.
A total review of metformin use during pregnancy compared to insulin alone found good short-term safety for both the mother and baby, but unclear long-term safety. Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes. Nonetheless, several concerns have been raised and evidence on the long-term safety of metformin for both mother and child is lacking. Compared with insulin, women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre-eclampsia during pregnancy. Babies born to women treated with metformin have less visceral fat, and this may make them less prone to insulin resistance in later life. The use of metformin for gestational diabetes resulted in smaller babies compared to treatment with insulin. However, despite initially lower birth weight, children exposed to metformin during pregnancy had accelerated growth after birth, and were heavier by mid-childhood than those exposed to insulin during pregnancy. This pattern of initial low birth weight followed by catch-up growth that surpasses comparative children has been associated with long-term cardiometabolic disease.
Metformin use is typically associated with weight loss. It appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine. Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more valuable.
Use with insulin
Metformin may reduce the insulin requirement in type 1 diabetes, albeit with an increased risk of hypoglycemia.
Metformin is recommended to be temporarily discontinued before any procedure involving use of iodinated contrast agents, (such as a contrast-enhanced CT scan or angiogram) due to the increased risk of lactic acidosis resulting from impaired kidney function; metformin can be resumed after two days after contrast administration, if renal function is adequate and stable.
The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence; metformin is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications. The most serious potential adverse effect of metformin is lactic acidosis; this complication is rare, and the vast majority of these cases seem to be related to conditions such as impaired liver or kidney function, rather than to the metformin itself. Metformin is not approved for use in those with severe kidney disease, but may still be used at lower doses in those with kidney problems.
Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7 g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate metformin. Use of slow or extended-release preparations may improve tolerability.
Lactic acidosis almost never occurs with metformin exposure during routine medical care. Rates of metformin-associated lactic acidosis are about nine per 100,000 persons/year, which is similar to the background rate of lactic acidosis in the general population. A systematic review concluded no data exists to definitively link metformin to lactic acidosis.
Metformin is generally safe in people with mild to moderate chronic kidney disease, with proportional reduction of metformin dose according to severity of estimated glomerular filtration rate (eGFR) and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement). The FDA recommends avoiding the use of metformin in more severe chronic kidney disease, below the eGFR cutoff of 30 ml/minute/1.73 m2. Lactate uptake by the liver is diminished with metformin use because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. 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. Given severely impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.
Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. 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.
The risk of metformin-associated lactic acidosis is also increased by a massive overdose of metformin, although even quite large doses are often not fatal.
Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or to 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. Chromatographic techniques are commonly employed.
Metformin also interacts with anticholinergic medications, due to their effect on gastric motility. Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the gastrointestinal tract. This impairment may lead to more metformin being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of metformin in the plasma and increasing the risk for adverse effects.
Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signalling, whole-body energy balance, and the metabolism of glucose and fats. AMPK activation was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, metformin increases the concentration of cytosolicadenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate). Metformin inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels. 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.
In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. The increase in insulin binding after metformin treatment has also been demonstrated in patients with diabetes mellitus type 2.
AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms.
Metformin also has significant effects on the gut microbiome, such as its effect on increasing agmatine production by gut bacteria, but the relative importance of this mechanism compared to other mechanisms is uncertain.
Metformin has acid dissociation constant values (pKa) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pKa values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the lipid solubility of the nonionized species is slight as shown by its low logP value (log(10) of the distribution coefficient of the nonionized form between octanol and water) of -1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely. As a result of its low lipid solubility it requires the transporterSLC22A1 in order for it to enter cells. The logP of metformin is less than that of phenformin (-0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in phenformin. More lipophilic derivatives of metformin are presently under investigation with the aim of producing prodrugs with superior oral absorption than metformin.
Metformin is not metabolized. 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. The average elimination half-life in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).
Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration.
Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pKa of metformin is 12.4. The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylaminehydrochloride and 2-cyanoguanidine over heat.
According to the procedure described in the 1975 Aron patent, and the Pharmaceutical Manufacturing Encyclopedia,equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield.[medical ]
Galega officinalis is a natural source of galegine.
The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries.G. officinalis itself does not contain any of these medications, but isoamylene guanidine; phenformin, buformin, and metformin are chemically synthesized compounds composed of two guanidine molecules, and are more lipophilic than the plant-derived parent compound.
Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of N,N-dimethylguanidine. In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied. This result was completely forgotten, as other guanidine analogs such as the synthalins, took over and were themselves soon overshadowed by insulin.
Interest in metformin resumed at the end of the 1940s. In 1950, metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals. That year, Filipino physician Eusebio Y. Garcia 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. Garcia believed metformin to have bacteriostatic, antiviral, antimalarial, antipyretic, and analgesic actions. In a series of articles in 1954, Polish pharmacologist Janusz Supniewski was unable to confirm most of these effects, including lowered blood sugar. Instead he observed antiviral effects in humans.
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. 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. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the medication and published his results in 1957.
Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972, but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994. Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the U.S., beginning on March 3, 1995.Generic formulations are now available in several countries, and metformin is believed to have become the world's most widely prescribed antidiabetic medication.
Society and culture
Metformin and its major transformation product guanylurea are present in wastewater treatment plant effluents and regularly detected in surface waters. Guanylurea concentrations above 200 ?g/l have been measured in a German river, which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.
Generic metformin 500-mg tablets, as sold in the United Kingdom.
The name "Metformin" is the BAN, USAN, and INN for this medication, and is sold under several trade names. Common brand names include Glucophage, Riomet, Fortamet, and Glumetza in the US. In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor. There are several formulations of Metformin available to the market, and all but the liquid form have generic equivalents. Metformin IR (immediate release) is available in 500-, 850-, and 1000-mg tablets, while Metformin XR (extended release) is available in 500-, 750-, and 1000-mg strengths (also sold as Fortamet, Glumetza, and Glucophage XR in the US). The use of an extended release formulation is to counteract common gastrointestinal adverse effects, as well as to increase compliance by reducing pill burden and therefore can improve adherence, at the expense of the pill's larger size. Also available is liquid metformin (sold only as Riomet in the US), where 5 mL of solution contains the same amount of drug as a 500-mg tablet. The use of a liquid form can be beneficial in helping those with physical or psychological swallowing problems take the medication, or to potentially reduce the number of steps needed to take the medication.
Combination with other medications
When used for type 2 diabetes, metformin is often prescribed in combination with other medications.
A combination of metformin and rosiglitazone was released in 2002, and sold as Avandamet by GlaxoSmithKline, or as a generic medication. Formulations are 500/1, 500/2, 500/4, 1000/2, and 1000 mg/4 mg of metformin/rosiglitazone.
By 2009, it had become the most popular metformin combination.
In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices. The medication pair continued to be prescribed separately, and Avandamet was again available by the end of that year. A generic formulation of metformin/rosiglitazone from Teva received tentative approval from the FDA and reached the market in early 2012.
However, following a meta-analysis in 2007 that linked the medication's use to an increased risk of heart attack, concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the European Medicines Agency recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.
It was withdrawn from the market in the UK and India in 2010, and in New Zealand and South Africa in 2011. From November 2011 until November 2013 the FDA did not allow rosiglitazone or metformin/rosiglitazone to be sold without a prescription; moreover, makers were required to notify patients of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.
In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial (a six-year, open-label randomized control trial), which failed to show elevated risk of heart attack or death associated with the medication.
Sulfonylureas act by increasing insulin release from the beta cells in the pancreas. They often can be used as secondary therapy if metformin alone is not sufficiently effective at reaching normal blood glucose levels.
Metformin is available combined with the sulfonylureas glipizide (Metaglip) and glibenclamide (US: glyburide) (Glucovance). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter is more popular).
Meglitinides are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs' affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas, and require higher blood glucose levels to begin to secrete insulin. Both meglitinides, known as nateglinide and repanglinide, is sold in formulations combined with metformin. A repaglinide/metformin combination is sold as Prandimet, or as its generic equivalent.
The combination of metformin with dapagliflozen and saxagliptin is available in the United States as Qternmet XR.
The combination of metformin with pioglitazone and glibenclamide is available in India as Accuglim-MP, Adglim MP, and Alnamet-GP, along with the Philippines as Tri-Senza.
The combination of metformin with pioglitazone and lipoic acid is available in Turkey as Pional.
In December 2019, the U.S. 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. Health Canada announced that it was assessing NDMA levels in metformin.
In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.
In February 2020, Health Canada announced a recall of Apotex immediate-release metformin, followed in March by recalls of Ranbaxy metformin and in March by Jamp metformin.
On 29 May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products. The five companies were not named, but they were revealed to be Amneal Pharmaceuticals, Actavis Pharma, Apotex Corp, Lupin Pharma, and Marksans Pharma Limited in a letter sent to Valisure, the pharmacy that had first alerted the FDA to this contaminant in metformin via a Citizen Petition.
In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested. It found NDMA in certain lots of ER metformin, and is recommending companies recall lots with levels of NDMA above the acceptable intake limit of 96 nanograms per day. The FDA is also collaborating with international regulators to share testing results for metformin.
In July 2020, Lupin Pharmaceuticals pulled all lots (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.
In August 2020, Bayshore Pharmaceuticals recalled two lots of tablets.
Metformin has been studied for its effects on multiple other conditions, including:
While metformin may reduce body weight in persons with fragile X syndrome, whether it improves neurological or psychiatric symptoms is uncertain. Metformin has been studied in vivo (C. elegans and crickets) for effects on aging. A 2017 review found that people with diabetes who were taking metformin had lower all-cause mortality. They also had reduced cancer and cardiovascular disease compared with those on other therapies.
^Sirtori CR, Franceschini G, Galli-Kienle M, Cighetti G, Galli G, Bondioli A, Conti F (December 1978). "Disposition of metformin (N,N-dimethylbiguanide) in man". Clinical Pharmacology and Therapeutics. 24 (6): 683-93. doi:10.1002/cpt1978246683. PMID710026. S2CID24531910.
^Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. (June 2016). "Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 164 (11): 740-51. doi:10.7326/M15-2650. PMID27088241. S2CID32016657.
^"Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects". Prescrire International. 23 (154): 269-72. November 2014. PMID25954799.
^ abTriggle CR, Ding H (January 2017). "Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium". Acta Physiologica. 219 (1): 138-151. doi:10.1111/apha.12644. PMID26680745. S2CID312517.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ abcdeTso LO, Costello MF, Albuquerque LE, Andriolo RB, Macedo CR (December 2020). "Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome". The Cochrane Database of Systematic Reviews. 2020 (12): CD006105. doi:10.1002/14651858.CD006105.pub4. PMC 8171384. PMID33347618.
^Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L (January 2017). "Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis". Diabetic Medicine. 34 (1): 27-36. doi:10.1111/dme.13150. PMID27150509. S2CID3418227.
^Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E (January 2009). "Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review". Obstetrics and Gynecology. 113 (1): 193-205. doi:10.1097/AOG.0b013e318190a459. PMID19104375. S2CID28115952.
^Kitwitee P, Limwattananon S, Limwattananon C, Waleekachonlert O, Ratanachotpanich T, Phimphilai M, et al. (September 2015). "Metformin for the treatment of gestational diabetes: An updated meta-analysis". Diabetes Research and Clinical Practice. 109 (3): 521-32. doi:10.1016/j.diabres.2015.05.017. PMID26117686.
^Thomsen HS, Morcos SK (August 2003). "Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines". The British Journal of Radiology. 76 (908): 513-8. doi:10.1259/bjr/26964464. PMID12893691.
^ abShu AD, Myers MG, Shoelson SE (2005). "Chapter 29: Pharmacology of the Endocrine Pancreas". In Golan ED, Tashjian AH, Armstrong EJ, Galanter JM, Armstrong AW, Arnaout RA, Rose HS (eds.). Principles of pharmacology: the pathophysiologic basis of drug therapy. Philadelphia: Lippincott, Williams & Wilkins. pp. 540-41. ISBN978-0-7817-4678-6.
^ abCalello DP, Liu KD, Wiegand TJ, Roberts DM, Lavergne V, Gosselin S, et al. (August 2015). "Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup". Critical Care Medicine. 43 (8): 1716-30. doi:10.1097/CCM.0000000000001002. PMID25860205. S2CID13861731.
^Liu A, Coleman SP (November 2009). "Determination of metformin in human plasma using hydrophilic interaction liquid chromatography-tandem mass spectrometry". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 877 (29): 3695-700. doi:10.1016/j.jchromb.2009.09.020. PMID19783231.
^R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 939-940.
^Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y (2002). "Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers". Drug Metabolism and Drug Interactions. 19 (1): 41-8. doi:10.1515/dmdi.2002.19.1.41. PMID12222753. S2CID26919498.
^Zhang L, He H, Balschi JA (July 2007). "Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration". American Journal of Physiology. Heart and Circulatory Physiology. 293 (1): H457-66. doi:10.1152/ajpheart.00002.2007. PMID17369473.
^Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ (July 2006). "Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle". American Journal of Physiology. Endocrinology and Metabolism. 291 (1): E182-9. doi:10.1152/ajpendo.00272.2005. PMID16478780.
^Fantus IG, Brosseau R (October 1986). "Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo". The Journal of Clinical Endocrinology and Metabolism. 63 (4): 898-905. doi:10.1210/jcem-63-4-898. PMID3745404.
^ abNikolakis G, Kyrgidis A, Zouboulis CC (August 2019). "Is There a Role for Antiandrogen Therapy for Hidradenitis Suppurativa? A Systematic Review of Published Data". American Journal of Clinical Dermatology. 20 (4): 503-513. doi:10.1007/s40257-019-00442-w. PMID31073704. S2CID149443722.
^See Chemical Abstracts, v.23, 42772 (1929) Slotta KH, Tschesche R (1929). "Über Biguanide, II.: Die blutzucker-senkende Wirkung der Biguanide". Berichte der Deutschen Chemischen Gesellschaft (A and B Series). 62 (6): 1398-1405. doi:10.1002/cber.19290620605.
^ abCampbell IW, ed. (September 2007). "Metformin - life begins at 50: A symposium held on the occasion of the 43rd Annual Meeting of the European Association for the Study of Diabetes, Amsterdam, The Netherlands, September 2007". The British Journal of Diabetes & Vascular Disease. 7 (5): 247-52. doi:10.1177/14746514070070051001.
^Quoted from Chemical Abstracts, v.45, 24828 (1951) Garcia EY (July 1950). "Flumamine, a new synthetic analgesic and anti-flu drug". Journal of the Philippine Medical Association. 26 (7): 287-93. PMID14779282.
^See Chemical Abstracts, v. 52, 22272 (1958) Supniewski J, Chrusciel T (1954). "[N-dimethyl-di-guanide and its biological properties]". Archivum Immunologiae et Therapiae Experimentalis (in Polish). 2: 1-15. PMID13269290.
^Quoted from Chemical Abstracts, v.49, 74699 (1955) Supniewski J, Krupinska J (1954). "[Effect of biguanide derivatives on experimental cowpox in rabbits]". Bulletin de l'Académie Polonaise des Sciences, Classe 3: Mathématique, Astronomie, Physique, Chimie, Géologie et Géographie (in French). 2(Classe II): 161-65.
^Nissen SE, Wolski K (June 2007). "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes". The New England Journal of Medicine. 356 (24): 2457-71. doi:10.1056/NEJMoa072761. PMID17517853.
^"Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Archived from the original on 21 February 2015. Retrieved 2013.
^Panikar V, Chandalia HB, Joshi SR, Fafadia A, Santvana C (November 2003). "Beneficial effects of triple drug combination of pioglitazone with glibenclamide and metformin in type 2 diabetes mellitus patients on insulin therapy". The Journal of the Association of Physicians of India. 51: 1061-4. PMID15260389.
^ abCampbell JM, Bellman SM, Stephenson MD, Lisy K (November 2017). "Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis". Ageing Research Reviews. 40: 31-44. doi:10.1016/j.arr.2017.08.003. PMID28802803. S2CID20334490.
Markowicz-Piasecka M, Huttunen KM, Mateusiak L, Mikiciuk-Olasik E, Sikora J (2017). "Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics". Current Pharmaceutical Design. 23 (17): 2532-2550. doi:10.2174/1381612822666161201152941. PMID27908266.
Zhou T, Xu X, Du M, Zhao T, Wang J (October 2018). "A preclinical overview of metformin for the treatment of type 2 diabetes". Biomedicine & Pharmacotherapy. 106: 1227-1235. doi:10.1016/j.biopha.2018.07.085. PMID30119191.
"Metformin". Drug Information Portal. U.S. National Library of Medicine.