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Wikipedia

Metformin

April 10, 2024

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes,[12][13][14][15] particularly in people who are overweight.[13] It is also used in the treatment of polycystic ovary syndrome.[14] It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics.[16] Metformin is not associated with weight gain[17] and is taken by mouth.[14]

Metformin
Clinical data
Pronunciation/mɛtˈfɔːrmɪn/, met-FOR-min
Trade namesFortamet, Glucophage, Glumetza, others
Other namesN,N-dimethylbiguanide[1]
AHFS/Drugs.comMonograph
MedlinePlusa696005
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50–60%[9][10]
Protein bindingMinimal[9]
MetabolismNot by liver[9]
Elimination half-life4–8.7 hours[9]
ExcretionUrine (90%)[9]
Identifiers
  • N,N-Dimethylimidodicarbonimidic diamide
CAS Number
  • 657-24-9
  • as HCl: 1115-70-4
PubChem CID
  • 4091
IUPHAR/BPS
  • 4779
DrugBank
  • DB00331
ChemSpider
  • 3949
UNII
  • 9100L32L2N
  • as HCl: 786Z46389E
KEGG
  • D04966
  • as HCl: C07151
ChEBI
  • CHEBI:6801
  • as HCl: CHEBI:6802
ChEMBL
  • ChEMBL1431
CompTox Dashboard (EPA)
  • DTXSID2023270
ECHA InfoCard100.010.472
Chemical and physical data
FormulaC4H11N5
Molar mass129.167 g·mol−1
3D model (JSmol)
  • Interactive image
Density1.3±0.1[11] g/cm3
  • CN(C)C(=N)N=C(N)N
  • InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
  • Key:XZWYZXLIPXDOLR-UHFFFAOYSA-N Y

Metformin is generally well tolerated.[18] Common adverse effects include diarrhea, nausea, and abdominal pain.[14] It has a small risk of causing low blood sugar.[14] 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.[19][20]

Metformin is a biguanide anti-hyperglycemic agent.[14] It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues,[14] and increasing GDF15 secretion, which reduces appetite and caloric intake.[21][22][23][24]

Metformin was first described in scientific literature in 1922 by Emil Werner and James Bell.[25] French physician Jean Sterne began the study in humans in the 1950s.[25] It was introduced as a medication in France in 1957 and the United States in 1995.[14][26] Metformin is on the World Health Organization's List of Essential Medicines,[27] and is the most widely used medication for diabetes taken by mouth.[25] It is available as a generic medication.[14] In 2021, it was the second most commonly prescribed medication in the United States, with more than 91 million prescriptions.[28][29]

Medical uses edit

Metformin is used to lower the blood glucose in those with type 2 diabetes.[14] It is also used as a second-line agent for infertility in those with polycystic ovary syndrome.[14][30]

Type 2 diabetes edit

The American Diabetes Association and the American College of Physicians both recommend metformin as a first-line agent to treat type 2 diabetes.[31][32][33] It is as effective as repaglinide and more effective than all other oral drugs for type 2 diabetes.[34]

Efficacy edit

Treatment guidelines for major professional associations, including the European Association for the Study of Diabetes, the European Society for Cardiology, and the American Diabetes Association, describe evidence for the cardiovascular benefits of metformin as equivocal.[32][35] A 2020 Cochrane systematic review did not find enough evidence of reduction of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke when comparing metformin monotherapy to other glucose-lowering drugs, behavior change interventions, placebo or no intervention.[36]

The use of metformin reduces body weight in people with type 2 diabetes[21][37] in contrast to sulfonylureas, which are associated with weight gain.[37] Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes.[38][39] Metformin has a lower risk of hypoglycemia than the sulfonylureas,[40][41] although hypoglycemia has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose.[42][43] Metformin modestly reduces low density lipoprotein and triglyceride levels.[40][41]

In individuals with prediabetes, a 2019 systematic review comparing the effects of metformin with other interventions in the reduction of risk of developing type 2 diabetes[44] found moderate-quality evidence that metformin reduced the risk of developing type 2 diabetes when compared to diet and exercise or a placebo.[44] However, when comparing metformin to intensive diet or exercise, moderate-quality evidence was found that metformin did not reduce risk of developing type 2 diabetes and very low-quality evidence was found that adding metformin to intensive diet or exercise did not show any advantage or disadvantage in reducing risk of type 2 diabetes when compared to intensive exercise and diet alone.[44] The same review also found one suitable trial comparing the effects of metformin and sulfonylurea in reducing risk of developing type 2 diabetes in prediabetic individuals, however this trial did not report any patient relevant outcomes.[44]

Polycystic ovarian syndrome edit

In those with polycystic ovarian syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births.[45] This includes in those who have not been able to get pregnant with clomiphene.[46] Metformin does not appear to change the risk of miscarriage.[45] A number of other benefits have also been found both during pregnancy and in nonpregnant women with PCOS.[47][48] 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.[49] 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.[49] In short GnRH-antagonist protocols metformin may reduce live birth rates with uncertainty on its effect on clinical pregnancy rate.[49] Metformin may result in a reduction of OHSS but could come with a greater frequency of side effects.[49] There was uncertainty as to metformin's impact on miscarriage.[49] The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women.[50]

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.[51] UK and international clinical practice guidelines do not recommend metformin as a first-line treatment[52] or do not recommend it at all, except for women with glucose intolerance.[53] The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from medical treatment. Metformin treatment decreases the risk of developing type 2 diabetes in women with PCOS who exhibited impaired glucose tolerance at baseline.[54][55]

Gastric Cancer edit

Gastric cancer (GC) stands as a major global health concern due to its high prevalence and mortality rate. Amidst various treatment avenues, metformin, a common medication for type-2 diabetes mellitus (T2DM), has garnered attention for its potential anti-cancer properties. While its effectiveness in combating GC has been a subject of debate, recent clinical studies predominantly support metformin's protective impact on reducing the risk and improving the survival rates of GC patients.[56] The drug's anti-cancer effects are believed to be mediated through multiple pathways, particularly involving AMPK activation and IGF-1R modulation. Despite promising findings, the consensus on metformin's application in GC prevention and treatment necessitates further clinical and mechanistic studies to confirm its therapeutic role.[57]

Diabetes and pregnancy edit

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.[58] Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes.[59][60] Nonetheless, several concerns have been raised and evidence on the long-term safety of metformin for both mother and child is lacking.[61] Compared with insulin, women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre‐eclampsia during pregnancy.[61][62] Babies born to women treated with metformin have less visceral fat, and this may make them less prone to insulin resistance in later life.[63] 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.[64]

Weight change edit

Metformin use is typically associated with weight loss.[65] It appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine.[66][67] Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more valuable.[68]

Use with insulin edit

Metformin may reduce the insulin requirement in type 1 diabetes, albeit with an increased risk of hypoglycemia.[69]

Life extension edit

There is some evidence metformin may be helpful in extending lifespan, even in otherwise healthy people. It has received substantial interest as an agent that delays aging, possibly through similar mechanisms as its treatment of diabetes (insulin and carbohydrate regulation).[70][71]

Alzheimer's disease edit

Preliminary studies have examined whether metformin can reduce the risk of Alzheimer's disease, and whether there is a correlation between type 2 diabetes and risk of Alzheimer's disease.[72][73]

Contraindications edit

Metformin is contraindicated in people with:

Adverse effects edit

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.[41] The most serious potential adverse effect of metformin is lactic acidosis; this complication is rare, and seems to be related to impaired liver or kidney function.[76] 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.[77]

Gastrointestinal edit

Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased.[75] 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.[75][78] Use of slow or extended-release preparations may improve tolerability.[78]

Long-term use of metformin has been associated with increased homocysteine levels[79] and malabsorption of vitamin B12.[75][80][81] Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency,[82] and some researchers recommend screening or prevention strategies.[83]

Lactic acidosis edit

Lactic acidosis almost never occurs with metformin exposure during routine medical care.[84] 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.[85] A systematic review concluded no data exists to definitively link metformin to lactic acidosis.[86]

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).[87] The US Food and Drug Administration (FDA) recommends avoiding the use of metformin in more severe chronic kidney disease, below the eGFR cutoff of 30 mL/minute/1.73 m2.[88] 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.[40] 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.[89]

Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors.[90] 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.[40][89][91]

Overdose edit

The most common symptoms following an overdose include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and rarely, hypoglycemia or hyperglycemia.[92][93] Treatment of metformin overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses.[94] Due to metformin's low molecular weight and lack of plasma protein binding, these techniques have the benefit of removing metformin from the blood plasma, preventing further lactate overproduction.[94]

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.[95][96]

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.[97]

Interactions edit

The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys;[98] both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism.[8] A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism;[99] theoretically, other cationic medications may produce the same effect.[8]

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.[100]

Pharmacology edit

Mechanism of action edit

The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on gut microbiota.[24][101][102][103]

Metformin exerts an anorexiant effect in most people, decreasing caloric intake.[23] Metformin decreases gluconeogenesis (glucose production) in the liver.[90][18] Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin,[104] which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries.[54][30] The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.[105]

Activation of AMPK was required for metformin's inhibitory effect on liver glucose production.[106] AMPK is an enzyme that plays an important role in insulin signaling, whole-body energy balance, and the metabolism of glucose and fats.[107] AMPK activation is 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.[108] 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: metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate) which could activate AMPK allosterically at high levels;[109] a newer theory involves binding to PEN-2.[110] Metformin inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels.[111] 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.[102]

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,[112] 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.[113] The increase in insulin binding after metformin treatment has also been demonstrated in patients with type 2 diabetes.[114]

AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle.[115] AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake.[116] 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.[117]

Metformin has indirect antiandrogenic effects in women with insulin resistance, such as those with PCOS, due to its beneficial effects on insulin sensitivity.[118] It may reduce testosterone levels in such women by as much as 50%.[118] A Cochrane review, though, found that metformin was only slightly effective for decreasing androgen levels in women with PCOS.[119]

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.[120][121][122]

Due to its effect on GLUT4 and AMPK, metformin has been described as an exercise mimetic.[123][124]

Pharmacokinetics edit

Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.[8][125] Peak plasma concentrations (Cmax) are reached within 1–3 hours of taking immediate-release metformin and 4–8 hours with extended-release formulations.[8][125] The plasma protein binding of metformin is negligible, as reflected by its very high apparent volume of distribution (300–1000 L after a single dose). Steady state is usually reached in 1–2 days.[8]

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 transporter SLC22A1 in order for it to enter cells.[126][127] 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.[128]

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.[8][129] The average elimination half-life in plasma is 6.2 hours.[8] Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours[8] (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).[129]

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.[117]

Chemistry edit

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.[130] The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat.[131][132]

 

According to the procedure described in the 1975 Aron patent,[133] and the Pharmaceutical Manufacturing Encyclopedia,[134] 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 citation needed]

Derivatives edit

A new derivative HL156A, also known as IM156, is a potential new drug for medical use.[135][136][137][138][139][140]

History edit

 
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.[141] 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.[141]

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.[131] In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied.[142] This result was ignored, as other guanidine analogs such as the synthalins, took over and were themselves soon overshadowed by insulin.[143]

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.[144] That year, Filipino physician Eusebio Y. Garcia[145] 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.[146] In a series of articles in 1954, Polish pharmacologist Janusz Supniewski[147] was unable to confirm most of these effects, including lowered blood sugar. Instead he observed antiviral effects in humans.[148][149]

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.[150] 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.[143][150]

Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona.[151]

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s.[5] Metformin was approved in Canada in 1972,[5] but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994.[152] Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the U.S., beginning on 3 March 1995.[153] Generic formulations are available in several countries, and metformin is believed to have become the world's most widely prescribed antidiabetic medication.[150]

Society and culture edit

Environmental edit

Metformin and its major transformation product guanylurea 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.[154]

Formulations edit

 
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.[155] In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor.[156][157] There are several formulations of Metformin available to the market, and all but the liquid form have generic equivalents.[155] 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). Also available is liquid metformin (sold as Riomet in the US), where 5 mL of solution contains the same amount of drug as a 500-mg tablet.

Combination with other medications edit

When used for type 2 diabetes, metformin is often prescribed in combination with other medications.

Several are available as fixed-dose combinations, with the potential to reduce pill burden, decrease cost, and simplify administration.[158][159]

Thiazolidinediones (glitazones) edit

Rosiglitazone edit

A combination of metformin and rosiglitazone was released in 2002, and sold as Avandamet by GlaxoSmithKline,[160] or as a generic medication.[161] 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.[162]

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.[163] 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.[164]

However, following a meta-analysis in 2007 that linked the medication's use to an increased risk of heart attack,[165] 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.[166][167]

It was withdrawn from the market in the UK and India in 2010,[168] and in New Zealand and South Africa in 2011.[169] From November 2011 until November 2013 the FDA[170] 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.[171][172]

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.[173][174][175]

Pioglitazone edit

The combination of metformin and pioglitazone (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union.[176][177][178][179][180]

DPP-4 inhibitors edit

Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels.

DPP-4 inhibitors combined with metformin include a sitagliptin/metformin combination (Janumet),[181][182] a saxagliptin/metformin combination (Kombiglyze XR, Komboglyze),[183][184] and an alogliptin/metformin combination (Kazano, Vipdomet).[185][186]

Linagliptin combined with metformin hydrochloride is sold under the brand name Jentadueto.[187][188][189] As of August 2021, linagliptin/metformin is available as a generic medicine in the US.[190]

SGLT-2 inhibitors edit

There are combinations of metformin with the SGLT-2 inhibitors dapagliflozin, empagliflozin, and canagliflozin.

Sulfonylureas edit

Sulfonylureas act by increasing insulin release from the beta cells in the pancreas.[191]

A 2019 systematic review suggested that there is limited evidence if the combined used of metformin with sulfonylurea compared to the combination of metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events, macrovascular and microvascular complications.[192] Combined metformin and sulfonylurea therapy did appear to lead to higher risk of hypoglicaemia.[192]

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).[193]

Meglitinide edit

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.[191] 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.[194][195]

Triple combination edit

The combination of metformin with dapagliflozen and saxagliptin is available in the United States as Qternmet XR.[196][197]

The combination of metformin with pioglitazone and glibenclamide[198] is available in India as Accuglim-MP, Adglim MP, and Alnamet-GP, along with the Philippines as Tri-Senza.[157]

The combination of metformin with pioglitazone and lipoic acid is available in Turkey as Pional.[157]

Impurities edit

See also: Ranitidine § impurities

In December 2019, the US 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.[199] Health Canada announced that it was assessing NDMA levels in metformin.[200]

In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.[201][202]

In February 2020, Health Canada announced a recall of Apotex immediate-release metformin,[203] followed in March by recalls of Ranbaxy metformin[204] and in March by Jamp metformin.[205]

In May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products.[206][207][208][209][210][211] 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.[212]

In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested.[213] 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.[213] The FDA is also collaborating with international regulators to share testing results for metformin.[213]

In July 2020, Lupin Pharmaceuticals pulled all lots (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.[214]

In August 2020, Bayshore Pharmaceuticals recalled two lots of tablets.[215]

Research edit

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.[226] Metformin has been studied in vivo (C. elegans and crickets) for effects on aging.[127][227] 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.[224]

There is also some research suggesting that although metformin prevents diabetes, it does not reduce the risk of cancer and cardiovascular disease and thus does not extend lifespan in non-diabetic individuals.[228] Furthermore, some studies suggest that long-term chronic use of metformin by healthy individuals may develop vitamin B12 deficiency.[229]

References edit

  1. ^ Sirtori CR, Franceschini G, Galli-Kienle M, Cighetti G, Galli G, Bondioli A, et al. (December 1978). "Disposition of metformin (N,N-dimethylbiguanide) in man". Clinical Pharmacology and Therapeutics. 24 (6): 683–93. doi:10.1002/cpt1978246683. PMID 710026. S2CID 24531910.
  2. ^ "Metformin Use During Pregnancy". Drugs.com. 10 September 2019. from the original on 16 April 2020. Retrieved 4 February 2020.
  3. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  4. ^ "Metformin SANDOZ metformin hydrochloride 850mg tablet bottle (148270)". Therapeutic Goods Administration (TGA). 27 May 2022. Retrieved 29 April 2023.
  5. ^ a b c Lucis OJ (January 1983). "The status of metformin in Canada". Canadian Medical Association Journal. 128 (1): 24–6. PMC 1874707. PMID 6847752.
  6. ^ "Metformin Hydrochloride". Health Canada. from the original on 6 March 2023. Retrieved 6 March 2023.
  7. ^ "Glucophage 500 mg film coated tablets - Summary of Product Characteristics (SmPC)". (emc). 25 October 2022. from the original on 20 June 2022. Retrieved 5 March 2023.
  8. ^ a b c d e f g h i "Glucophage (metformin hydrochloride) tablets, for oral use; Glucophage XR (metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval:1995". DailyMed. from the original on 6 March 2023. Retrieved 5 March 2023.
  9. ^ a b c d e Dunn CJ, Peters DH (May 1995). "Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus". Drugs. 49 (5): 721–49. doi:10.2165/00003495-199549050-00007. PMID 7601013.
  10. ^ Hundal RS, Inzucchi SE (2003). "Metformin: new understandings, new uses". Drugs. 63 (18): 1879–94. doi:10.2165/00003495-200363180-00001. PMID 12930161.
  11. ^ "Metformin". www.chemsrc.com. from the original on 12 June 2017. Retrieved 10 May 2018.
  12. ^ Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, et al. (January 2022). "9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022". Diabetes Care. 45 (Suppl 1): S125–S143. doi:10.2337/dc22-s009. PMID 34964831. S2CID 245538347.
  13. ^ a b Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. (January 2020). "2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD". European Heart Journal. 41 (2): 255–323. doi:10.1093/eurheartj/ehz486. PMID 31497854.
  14. ^ a b c d e f g h i j k "Metformin Hydrochloride". The American Society of Health-System Pharmacists. from the original on 24 December 2016. Retrieved 2 January 2017.
  15. ^ 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): 740–751. doi:10.7326/M15-2650. PMID 27088241. S2CID 32016657.
  16. ^ de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R (October 2016). "Metformin in prevention and treatment of antipsychotic-induced weight gain: a systematic review and meta-analysis". BMC Psychiatry. 16 (1): 341. doi:10.1186/s12888-016-1049-5. PMC 5048618. PMID 27716110.
  17. ^ "Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects". Prescrire International. 23 (154): 269–272. November 2014. PMID 25954799.
  18. ^ a b Triggle 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. PMID 26680745. S2CID 312517.
  19. ^ Blumenberg A, Benabbas R, Sinert R, Jeng A, Wiener SW (April 2020). "Do Patients Die with or from Metformin-Associated Lactic Acidosis (MALA)? Systematic Review and Meta-analysis of pH and Lactate as Predictors of Mortality in MALA". Journal of Medical Toxicology. 16 (2): 222–229. doi:10.1007/s13181-019-00755-6. PMC 7099117. PMID 31907741.
  20. ^ Lipska KJ, Bailey CJ, Inzucchi SE (June 2011). "Use of metformin in the setting of mild-to-moderate renal insufficiency". Diabetes Care. 34 (6): 1431–7. doi:10.2337/dc10-2361. PMC 3114336. PMID 21617112.
  21. ^ a b Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, et al. (February 2020). "GDF15 mediates the effects of metformin on body weight and energy balance". Nature. 578 (7795): 444–448. doi:10.1038/s41586-019-1911-y. PMC 7234839. PMID 31875646.
  22. ^ Day EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR, Gutgesell RM, et al. (December 2019). "Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss". Nature Metabolism. 1 (12): 1202–1208. doi:10.1038/s42255-019-0146-4. PMID 32694673. S2CID 213199603.
  23. ^ a b Pappachan JM, Viswanath AK (January 2017). "Medical Management of Diabesity: Do We Have Realistic Targets?". Current Diabetes Reports. 17 (1): 4. doi:10.1007/s11892-017-0828-9. PMID 28101792. S2CID 10289148.
  24. ^ a b LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, et al. (March 2022). "Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis". Proceedings of the National Academy of Sciences of the United States of America. 119 (10): e2122287119. Bibcode:2022PNAS..11922287L. doi:10.1073/pnas.2122287119. PMC 8916010. PMID 35238637.
  25. ^ a b c Fischer J (2010). Analogue-based Drug Discovery II. John Wiley & Sons. p. 49. ISBN 978-3-527-63212-1. from the original on 8 September 2017.
  26. ^ Stargrove MB, Treasure J, McKee DL (2008). Herb, nutrient, and drug interactions : clinical implications and therapeutic strategies. St. Louis, Mo.: Mosby/Elsevier. p. 217. ISBN 978-0-323-02964-3. from the original on 8 September 2017.
  27. ^ 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.
  28. ^ "The Top 300 of 2021". ClinCalc. from the original on 15 January 2024. Retrieved 14 January 2024.
  29. ^ "Metformin - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  30. ^ a b Lord JM, Flight IH, Norman RJ (October 2003). "Metformin in polycystic ovary syndrome: systematic review and meta-analysis". BMJ. 327 (7421): 951–3. doi:10.1136/bmj.327.7421.951. PMC 259161. PMID 14576245.
  31. ^ Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. (May 2011). "Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations". Annals of Internal Medicine. 154 (9): 602–13. doi:10.7326/0003-4819-154-9-201105030-00336. PMC 3733115. PMID 21403054.
  32. ^ a b Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. (June 2012). "Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)". Diabetes Care. 35 (6): 1364–79. doi:10.2337/dc12-0413. PMC 3357214. PMID 22517736.
  33. ^ Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P (February 2012). "Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Annals of Internal Medicine. 156 (3): 218–31. doi:10.7326/0003-4819-156-3-201202070-00011. PMID 22312141.
  34. ^ Jia Y, Lao Y, Zhu H, Li N, Leung SW (January 2019). "Is metformin still the most efficacious first-line oral hypoglycaemic drug in treating type 2 diabetes? A network meta-analysis of randomized controlled trials". Obesity Reviews. 20 (1): 1–12. doi:10.1111/obr.12753. PMID 30230172.
  35. ^ Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. (May 2014). "ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary". Diabetes & Vascular Disease Research. 11 (3): 133–73. doi:10.1177/1479164114525548. PMID 24800783.
  36. ^ Gnesin F, Thuesen AC, Kähler LK, Madsbad S, Hemmingsen B, et al. (Cochrane Metabolic and Endocrine Disorders Group) (June 2020). "Metformin monotherapy for adults with type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 2020 (6): CD012906. doi:10.1002/14651858.CD012906.pub2. PMC 7386876. PMID 32501595.
  37. ^ a b Johansen K (January 1999). "Efficacy of metformin in the treatment of NIDDM. Meta-analysis". Diabetes Care. 22 (1): 33–7. doi:10.2337/diacare.22.1.33. PMID 10333900.
  38. ^ Golay A (January 2008). "Metformin and body weight". International Journal of Obesity. 32 (1): 61–72. doi:10.1038/sj.ijo.0803695. PMID 17653063.
  39. ^ Mead E, Atkinson G, Richter B, Metzendorf MI, Baur L, Finer N, et al. (November 2016). "Drug interventions for the treatment of obesity in children and adolescents". The Cochrane Database of Systematic Reviews. 11 (11): CD012436. doi:10.1002/14651858.CD012436. hdl:10149/620651. PMC 6472619. PMID 27899001.
  40. ^ a b c d Maharani U (2009). "Chapter 27: Diabetes Mellitus & Hypoglycemia". In Papadakis MA, McPhee SJ (eds.). Current Medical Diagnosis and Treatment 2010 (49th ed.). McGraw-Hill Medical. pp. 1092–93. ISBN 978-0-07-162444-2.
  41. ^ a b c Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al. (September 2007). "Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus". Annals of Internal Medicine. 147 (6): 386–99. doi:10.7326/0003-4819-147-6-200709180-00178. PMID 17638715.
  42. ^ DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM (2005). Pharmacotherapy: a pathophysiologic approach. New York: McGraw-Hill. ISBN 978-0-07-141613-9.
  43. ^ . Princeton, NJ: Bristol-Myers Squibb Company. 2009. Archived from the original on 29 August 2021 – via DailyMed.
  44. ^ a b c d Madsen KS, Chi Y, Metzendorf MI, Richter B, Hemmingsen B, et al. (Cochrane Metabolic and Endocrine Disorders Group) (December 2019). "Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 2019 (12): CD008558. doi:10.1002/14651858.CD008558.pub2. PMC 6889926. PMID 31794067.
  45. ^ a b Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH (November 2017). "Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility". The Cochrane Database of Systematic Reviews. 11 (2): CD003053. doi:10.1002/14651858.CD003053.pub6. PMC 6486196. PMID 29183107. Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low.
  46. ^ Ghazeeri GS, Nassar AH, Younes Z, Awwad JT (June 2012). "Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview". Acta Obstetricia et Gynecologica Scandinavica. 91 (6): 658–78. doi:10.1111/j.1600-0412.2012.01385.x. PMID 22375613. S2CID 41145972.
  47. ^ Kumar P, Khan K (May 2012). "Effects of metformin use in pregnant patients with polycystic ovary syndrome". Journal of Human Reproductive Sciences. 5 (2): 166–9. doi:10.4103/0974-1208.101012. PMC 3493830. PMID 23162354.
  48. ^ Tay CT, Joham AE, Hiam DS, Gadalla MA, Pundir J, Thangaratinam S, et al. (November 2018). "Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews". Clinical Endocrinology. 89 (5): 535–553. doi:10.1111/cen.13753. hdl:10536/DRO/DU:30151483. PMID 29846959.
  49. ^ a b c d e Tso 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. PMID 33347618.
  50. ^ Dodd JM, Grivell RM, Deussen AR, Hague WM (July 2018). "Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes". The Cochrane Database of Systematic Reviews. 2018 (7): CD010564. doi:10.1002/14651858.CD010564.pub2. PMC 6513233. PMID 30039871.
  51. ^ National Collaborating Centre for Women's and Children's Health (2004). Fertility: assessment and treatment for people with fertility problems (PDF). London: Royal College of Obstetricians and Gynaecologists. pp. 58–59. ISBN 978-1-900364-97-3. (PDF) from the original on 11 July 2009.
  52. ^ Balen A (December 2008). "Metformin therapy for the management of infertility in women with polycystic ovary syndrome" (PDF). Scientific Advisory Committee Opinion Paper 13. Royal College of Obstetricians and Gynaecologists. Archived from the original (PDF) on 18 December 2009. Retrieved 13 December 2009.
  53. ^ The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (March 2008). "Consensus on infertility treatment related to polycystic ovary syndrome". Human Reproduction. 23 (3): 462–77. doi:10.1093/humrep/dem426. PMID 18308833.
  54. ^ a b Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C (September 2010). "Metformin in polycystic ovary syndrome". Annals of the New York Academy of Sciences. 1205 (1): 192–8. Bibcode:2010NYASA1205..192D. doi:10.1111/j.1749-6632.2010.05679.x. PMID 20840272. S2CID 44203632.
  55. ^ Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN (February 2010). "Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome". European Journal of Endocrinology. 162 (2): 193–212. doi:10.1530/EJE-09-0733. PMID 19841045.
  56. ^ Zhang J, Wen L, Zhou Q, He K, Teng L (16 September 2020). "Preventative and Therapeutic Effects of Metformin in Gastric Cancer: A New Contribution of an Old Friend". Cancer Management and Research. 12: 8545–8554. doi:10.2147/CMAR.S264032. PMC 7505710. PMID 32982447.
  57. ^ Sharma A (29 October 2023). "The Role of Metformin in Gastric Cancer Treatment". Witfire. Retrieved 3 November 2023.
  58. ^ 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. PMID 27150509. S2CID 3418227.
  59. ^ 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. PMID 19104375. S2CID 28115952.
  60. ^ 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. PMID 26117686.
  61. ^ a b Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R (January 2015). "Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis". BMJ (Systematic Review & Meta-Analysis). 350: h102. doi:10.1136/bmj.h102. PMC 4301599. PMID 25609400.
  62. ^ Alqudah A, McKinley MC, McNally R, Graham U, Watson CJ, Lyons TJ, et al. (February 2018). "Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis". Diabetic Medicine. 35 (2): 160–172. doi:10.1111/dme.13523. hdl:10453/130987. PMID 29044702. S2CID 40045912. from the original on 29 April 2023. Retrieved 7 April 2023.
  63. ^ Sivalingam VN, Myers J, Nicholas S, Balen AH, Crosbie EJ (2014). "Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications". Human Reproduction Update. 20 (6): 853–68. doi:10.1093/humupd/dmu037. PMID 25013215.
  64. ^ Tarry-Adkins JL, Aiken CE, Ozanne SE (August 2019). "Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis". PLOS Medicine. 16 (8): e1002848. doi:10.1371/journal.pmed.1002848. PMC 6684046. PMID 31386659.
  65. ^ Yerevanian A, Soukas AA (June 2019). "Metformin: Mechanisms in Human Obesity and Weight Loss". Current Obesity Reports. 8 (2): 156–164. doi:10.1007/s13679-019-00335-3. PMC 6520185. PMID 30874963.
  66. ^ Choi YJ (2015). "Efficacy of adjunctive treatments added to olanzapine or clozapine for weight control in patients with schizophrenia: a systematic review and meta-analysis". TheScientificWorldJournal. 2015: 970730. doi:10.1155/2015/970730. PMC 4310265. PMID 25664341.
  67. ^ Praharaj SK, Jana AK, Goyal N, Sinha VK (March 2011). "Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis". British Journal of Clinical Pharmacology. 71 (3): 377–82. doi:10.1111/j.1365-2125.2010.03783.x. PMC 3045546. PMID 21284696.
  68. ^ Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S (2016). "Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis". PLOS ONE. 11 (6): e0156208. Bibcode:2016PLoSO..1156208S. doi:10.1371/journal.pone.0156208. PMC 4909277. PMID 27304831.
  69. ^ Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR (May 2010). "The use of metformin in type 1 diabetes: a systematic review of efficacy". Diabetologia. 53 (5): 809–20. doi:10.1007/s00125-009-1636-9. PMID 20057994.
  70. ^ a b Novelle MG, Ali A, Diéguez C, Bernier M, de Cabo R (March 2016). "Metformin: A Hopeful Promise in Aging Research". Cold Spring Harbor Perspectives in Medicine. 6 (3): a025932. doi:10.1101/cshperspect.a025932. PMC 4772077. PMID 26931809.
  71. ^ Kulkarni AS, Gubbi S, Barzilai N (July 2020). "Benefits of Metformin in Attenuating the Hallmarks of Aging". Cell Metabolism. 32 (1): 15–30. doi:10.1016/j.cmet.2020.04.001. PMC 7347426. PMID 32333835.
  72. ^ Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E (2018). "Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis". Journal of Alzheimer's Disease. 65 (4): 1225–1236. doi:10.3233/jad-180263. PMC 6218120. PMID 30149446.
  73. ^ Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E (August 2017). "Metformin and Alzheimer's disease, dementia and cognitive impairment: a systematic review protocol". JBI Database of Systematic Reviews and Implementation Reports. 15 (8): 2055–2059. doi:10.11124/JBISRIR-2017-003380. PMID 28800055.
  74. ^ a b c "Metformin: medicine to treat type 2 diabetes". National Health Service. 25 February 2019. from the original on 11 March 2021. Retrieved 15 October 2020.
  75. ^ a b c d "METFORMIN HYDROCHLORIDE". NICE. from the original on 10 June 2021. Retrieved 15 October 2020.
  76. ^ Khurana R, Malik IS (January 2010). "Metformin: safety in cardiac patients". Heart. 96 (2): 99–102. doi:10.1136/hrt.2009.173773. PMID 19564648. S2CID 9746741.
  77. ^ Heaf J (June 2014). "Metformin in chronic kidney disease: time for a rethink". Peritoneal Dialysis International. 34 (4): 353–7. doi:10.3747/pdi.2013.00344. PMC 4079480. PMID 24711640.
  78. ^ a b Fujita Y, Inagaki N (January 2017). "Metformin: New Preparations and Nonglycemic Benefits". Current Diabetes Reports. 17 (1): 5. doi:10.1007/s11892-017-0829-8. PMID 28116648. S2CID 9277684.
  79. ^ Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al. (November 2003). "Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial". Journal of Internal Medicine. 254 (5): 455–63. doi:10.1046/j.1365-2796.2003.01213.x. PMID 14535967. S2CID 12507226.
  80. ^ Andrès E, Noel E, Goichot B (October 2002). "Metformin-associated vitamin B12 deficiency". Archives of Internal Medicine. 162 (19): 2251–2. PMID 12390080.
  81. ^ Gilligan MA (February 2002). "Metformin and vitamin B12 deficiency". Archives of Internal Medicine. 162 (4): 484–5. PMID 11863489.
  82. ^ de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, et al. (May 2010). "Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial". BMJ. 340: c2181. doi:10.1136/bmj.c2181. PMC 2874129. PMID 20488910.
  83. ^ Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM (October 2006). "Risk factors of vitamin B(12) deficiency in patients receiving metformin". Archives of Internal Medicine. 166 (18): 1975–9. doi:10.1001/archinte.166.18.1975. PMID 17030830.
  84. ^ Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. (January 2009). "Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes". Diabetologia. 52 (1): 17–30. doi:10.1007/s00125-008-1157-y. PMID 18941734.
  85. ^ Stang M, Wysowski DK, Butler-Jones D (June 1999). "Incidence of lactic acidosis in metformin users". Diabetes Care. 22 (6): 925–7. doi:10.2337/diacare.22.6.925. PMID 10372243.
  86. ^ Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (November 2003). "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis". Archives of Internal Medicine. 163 (21): 2594–602. doi:10.1001/archinte.163.21.2594. PMID 14638559.
  87. ^ Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK (2014). "Metformin in patients with type 2 diabetes and kidney disease: a systematic review". JAMA. 312 (24): 2668–75. doi:10.1001/jama.2014.15298. PMC 4427053. PMID 25536258.
  88. ^ "FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function". U.S. Food and Drug Administration (FDA). 14 November 2017. from the original on 25 May 2021. Retrieved 21 December 2018.
  89. ^ a b Shu 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. ISBN 978-0-7817-4678-6.
  90. ^ a b Kirpichnikov D, McFarlane SI, Sowers JR (July 2002). "Metformin: an update". Annals of Internal Medicine. 137 (1): 25–33. doi:10.7326/0003-4819-137-1-200207020-00009. PMID 12093242. S2CID 9140541.
  91. ^ Davis SN (2006). "Chapter 60: Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas". In Brunton L, Lazo J, Parker K (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. ISBN 978-0-07-142280-2.
  92. ^ Forrester MB (July 2008). "Adult metformin ingestions reported to Texas poison control centers, 2000-2006". Human & Experimental Toxicology. 27 (7): 575–83. Bibcode:2008HETox..27..575F. CiteSeerX 10.1.1.1031.9486. doi:10.1177/0960327108090589. PMID 18829734. S2CID 5413561.
  93. ^ Suchard JR, Grotsky TA (August 2008). "Fatal metformin overdose presenting with progressive hyperglycemia". The Western Journal of Emergency Medicine. 9 (3): 160–4. PMC 2672258. PMID 19561734.
  94. ^ a b Calello 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. PMID 25860205. S2CID 13861731.
  95. ^ 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. PMID 19783231.
  96. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 939–940.
  97. ^ Teale KF, Devine A, Stewart H, Harper NJ (July 1998). "The management of metformin overdose". Anaesthesia. 53 (7): 698–701. doi:10.1046/j.1365-2044.1998.436-az0549.x. PMID 9771180. S2CID 45218798.
  98. ^ Somogyi A, Stockley C, Keal J, Rolan P, Bochner F (May 1987). "Reduction of metformin renal tubular secretion by cimetidine in man". British Journal of Clinical Pharmacology. 23 (5): 545–51. doi:10.1111/j.1365-2125.1987.tb03090.x. PMC 1386190. PMID 3593625.
  99. ^ 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. PMID 12222753. S2CID 26919498.
  100. ^ May M, Schindler C (April 2016). "Clinically and pharmacologically relevant interactions of antidiabetic drugs". Therapeutic Advances in Endocrinology and Metabolism. 7 (2): 69–83. doi:10.1177/2042018816638050. PMC 4821002. PMID 27092232.
  101. ^ Rena G, Pearson ER, Sakamoto K (September 2013). "Molecular mechanism of action of metformin: old or new insights?". Diabetologia. 56 (9): 1898–906. doi:10.1007/s00125-013-2991-0. PMC 3737434. PMID 23835523.
  102. ^ a b Burcelin R (May 2014). "The antidiabetic gutsy role of metformin uncovered?". Gut. 63 (5): 706–7. doi:10.1136/gutjnl-2013-305370. PMID 23840042. S2CID 42142919.
  103. ^ Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. (June 2014). "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase". Nature. 510 (7506): 542–6. Bibcode:2014Natur.510..542M. doi:10.1038/nature13270. PMC 4074244. PMID 24847880.
  104. ^ Vázquez-Borrego MC, Fuentes-Fayos AC, Gahete MD, Castaño JP, Kineman RD, Luque RM (2018). "The Pituitary Gland is a Novel Major Site of Action of Metformin in Non-Human Primates: a Potential Path to Expand and Integrate Its Metabolic Actions". Cellular Physiology and Biochemistry. 49 (4): 1444–1459. doi:10.1159/000493448. PMID 30205369.
  105. ^ Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. (December 2000). "Mechanism by which metformin reduces glucose production in type 2 diabetes". Diabetes. 49 (12): 2063–9. doi:10.2337/diabetes.49.12.2063. PMC 2995498. PMID 11118008.
  106. ^ Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. (October 2001). "Role of AMP-activated protein kinase in mechanism of metformin action". The Journal of Clinical Investigation. 108 (8): 1167–74. doi:10.1172/JCI13505. PMC 209533. PMID 11602624.
  107. ^ Towler MC, Hardie DG (February 2007). "AMP-activated protein kinase in metabolic control and insulin signaling". Circulation Research. 100 (3): 328–41. doi:10.1161/01.RES.0000256090.42690.05. PMID 17307971.
  108. ^ Kim YD, Park KG, Lee YS, Park YY, Kim DK, Nedumaran B, et al. (February 2008). "Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP". Diabetes. 57 (2): 306–14. doi:10.2337/db07-0381. PMID 17909097.
  109. ^ 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. PMID 17369473.
  110. ^ Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, et al. (March 2022). "Low-dose metformin targets the lysosomal AMPK pathway through PEN2". Nature. 603 (7899): 159–165. Bibcode:2022Natur.603..159M. doi:10.1038/s41586-022-04431-8. PMC 8891018. PMID 35197629.
  111. ^ Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ (February 2013). "Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP". Nature. 494 (7436): 256–60. Bibcode:2013Natur.494..256M. doi:10.1038/nature11808. PMC 3573218. PMID 23292513.
  112. ^ 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. PMID 16478780.
  113. ^ Bailey CJ, Turner RC (February 1996). "Metformin". The New England Journal of Medicine. 334 (9): 574–9. doi:10.1056/NEJM199602293340906. PMID 8569826.
  114. ^ 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. PMID 3745404.
  115. ^ Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, et al. (July 2002). "Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes". Diabetes. 51 (7): 2074–2081. doi:10.2337/diabetes.51.7.2074. PMID 12086935.
  116. ^ Hardie DG, Ross FA, Hawley SA (March 2012). "AMPK: a nutrient and energy sensor that maintains energy homeostasis". Nature Reviews. Molecular Cell Biology. 13 (4): 251–262. doi:10.1038/nrm3311. PMC 5726489. PMID 22436748.
  117. ^ a b LaMoia TE, Shulman GI (January 2021). "Cellular and Molecular Mechanisms of Metformin Action". Endocrine Reviews. 42 (1): 77–96. doi:10.1210/endrev/bnaa023. PMC 7846086. PMID 32897388.
  118. ^ a b Nikolakis 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. PMID 31073704. S2CID 149443722.
  119. ^ Luque-Ramírez M, Nattero-Chávez L, Ortiz Flores AE, Escobar-Morreale HF (March 2018). "Combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome: a systematic review and meta-analysis". Human Reproduction Update. 24 (2): 225–241. doi:10.1093/humupd/dmx039. PMID 29293982.
  120. ^ Weersma RK, Zhernakova A, Fu J (August 2020). "Interaction between drugs and the gut microbiome". Gut. 69 (8): 1510–1519. doi:10.1136/gutjnl-2019-320204. PMC 7398478. PMID 32409589.
  121. ^ MacNeil LT, Schertzer JD, Steinberg GR (January 2020). "Bacteria transmit metformin-associated lifespan extension". Nature Reviews. Endocrinology. 16 (1): 9–10. doi:10.1038/s41574-019-0278-3. PMID 31645681. S2CID 204836737.
  122. ^ Jones GR, Molloy MP (June 2020). "Metformin, Microbiome and Protection Against Colorectal Cancer". Digestive Diseases and Sciences. 66 (5): 1409–1414. doi:10.1007/s10620-020-06390-4. PMID 32533543. S2CID 219607625.
  123. ^ Guerrieri D, Moon HY, van Praag H (March 2017). "Exercise in a Pill: The Latest on Exercise-Mimetics". Brain Plasticity. 2 (2): 153–169. doi:10.3233/BPL-160043. PMC 5928571. PMID 29765854.
  124. ^ Boulé NG, Robert C, Bell GJ, Johnson ST, Bell RC, Lewanczuk RZ, et al. (July 2011). "Metformin and exercise in type 2 diabetes: examining treatment modality interactions". Diabetes Care. 34 (7): 1469–1474. doi:10.2337/dc10-2207. PMC 3120188. PMID 21602430.
  125. ^ a b Heller JB (2007). (PDF). Veterinary Medicine (April): 231–33. Archived from the original (PDF) on 23 October 2007.
  126. ^ Rosilio C, Ben-Sahra I, Bost F, Peyron JF (May 2014). "Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia". Cancer Letters. 346 (2): 188–96. doi:10.1016/j.canlet.2014.01.006. PMID 24462823.
  127. ^ a b Pryor R, Cabreiro F (November 2015). "Repurposing metformin: an old drug with new tricks in its binding pockets". The Biochemical Journal. 471 (3): 307–22. doi:10.1042/bj20150497. PMC 4613459. PMID 26475449.
  128. ^ Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. (February 2011). "Clinical pharmacokinetics of metformin". Clinical Pharmacokinetics. 50 (2): 81–98. doi:10.2165/11534750-000000000-00000. PMID 21241070. S2CID 1440441.
  129. ^ a b Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau JD (June 2003). "Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects". Diabetes & Metabolism. 29 (3): 279–83. doi:10.1016/s1262-3636(07)70037-x. PMID 12909816.
  130. ^ Tilley J, Grimsby J, Erickson S, Berthel S (2010). "Diabetes Drugs: Present and Emerging". Burger's Medicinal Chemistry and Drug Discovery. pp. 1–38. doi:10.1002/0471266949.bmc198. ISBN 978-0471266945.
  131. ^ a b Werner E, Bell J (1922). "The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively". J. Chem. Soc., Trans. 121: 1790–95. doi:10.1039/CT9222101790. from the original on 8 June 2021. Retrieved 4 September 2020.
  132. ^ Shapiro SL, Parrino VA, Freedman L (1959). "Hypoglycemic Agents. I Chemical Properties of β-Phenethylbiguanide. A New Hypoglycemic Agent". J Am Chem Soc. 81 (9): 2220–25. doi:10.1021/ja01518a052.
  133. ^ "Procédé de préparation de chlorhydrate de diméthylbiguanide". Patent FR 2322860 (in French). 1975.
  134. ^ Pharmaceutical Manufacturing Encyclopedia (Sittig's Pharmaceutical Manufacturing Encyclopedia). Vol. 3 (3rd ed.). Norwich, NY: William Andrew. 2007. p. 2208. ISBN 978-0-8155-1526-5.
  135. ^ Lam TG, Jeong YS, Kim SA, Ahn SG (March 2018). "New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways". Cancer Science. 109 (3): 699–709. doi:10.1111/cas.13482. PMC 5834796. PMID 29285837.
  136. ^ Tsogbadrakh B, Ju KD, Lee J, Han M, Koh J, Yu Y, et al. (2018). "HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model". PLOS ONE. 13 (8): e0201692. Bibcode:2018PLoSO..1301692T. doi:10.1371/journal.pone.0201692. PMC 6116936. PMID 30161162.
  137. ^ Jeong YS, Lam TG, Jeong S, Ahn SG (August 2020). "Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells". Pharmaceuticals. 13 (9): 218. doi:10.3390/ph13090218. PMC 7560051. PMID 32872293.
  138. ^ Kim SA, Lam TG, Yook JI, Ahn SG (September 2018). "Antioxidant modifications induced by the new metformin derivative HL156A regulate metabolic reprogramming in SAMP1/kl (-/-) mice". Aging. 10 (9): 2338–2355. doi:10.18632/aging.101549. PMC 6188477. PMID 30222592.
  139. ^ Choi J, Lee JH, Koh I, Shim JK, Park J, Jeon JY, et al. (October 2016). "Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A)". Oncotarget. 7 (40): 65643–65659. doi:10.18632/oncotarget.11595. PMC 5323181. PMID 27582539.
  140. ^ Ju KD, Kim HJ, Tsogbadrakh B, Lee J, Ryu H, Cho EJ, et al. (March 2016). "HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis". American Journal of Physiology. Renal Physiology. 310 (5): F342-50. doi:10.1152/ajprenal.00204.2015. PMID 26661649.
  141. ^ a b Witters LA (October 2001). "The blooming of the French lilac". The Journal of Clinical Investigation. 108 (8): 1105–7. doi:10.1172/JCI14178. PMC 209536. PMID 11602616.
  142. ^ 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.
  143. ^ a b Campbell 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.
  144. ^ Dawes GS, Mott JC (March 1950). "Circulatory and respiratory reflexes caused by aromatic guanidines". British Journal of Pharmacology and Chemotherapy. 5 (1): 65–76. doi:10.1111/j.1476-5381.1950.tb00578.x. PMC 1509951. PMID 15405470.
  145. ^ About Eusebio Y. Garcia, see: Carteciano J (2005). . Philippines Department of Science and Technology. Archived from the original on 24 October 2009. Retrieved 5 December 2009.
  146. ^ 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. PMID 14779282.
  147. ^ About Janusz Supniewski, see: Wołkow PP, Korbut R (April 2006). (PDF). Journal of Physiology and Pharmacology. 57 (Suppl 1): 119–136. PMID 16766803. Archived from the original (PDF) on 24 October 2009. Retrieved 22 December 2009.
  148. ^ 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. PMID 13269290.
  149. ^ 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.
  150. ^ a b c Bailey CJ, Day C (2004). "Metformin: its botanical background". Practical Diabetes International. 21 (3): 115–17. doi:10.1002/pdi.606. S2CID 208203689. Archived from the original on 17 December 2012.
  151. ^ Hadden DR (October 2005). "Goat's rue - French lilac - Italian fitch - Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection" (PDF). The Journal of the Royal College of Physicians of Edinburgh. 35 (3): 258–60. PMID 16402501. (PDF) from the original on 25 October 2020. Retrieved 21 December 2009.
  152. ^ (Press release). U.S. Food and Drug Administration (FDA). 30 December 1994. Archived from the original on 29 September 2007. Retrieved 6 January 2007.
  153. ^ "Drug Approval Package: Glucophage (metformin)" (PDF). U.S. Food and Drug Administration (FDA). (PDF) from the original on 5 February 2020. Retrieved 8 January 2007.
  154. ^ Posselt M, Jaeger A, Schaper JL, Radke M, Benskin JP (December 2018). "Determination of polar organic micropollutants in surface and pore water by high-resolution sampling-direct injection-ultra high performance liquid chromatography-tandem mass spectrometry". Environmental Science: Processes & Impacts. 20 (12): 1716–1727. doi:10.1039/C8EM00390D. PMID 30350841.
  155. ^ a b Christofides EA (July 2019). "Practical Insights Into Improving Adherence to Metformin Therapy in Patients With Type 2 Diabetes". Clinical Diabetes. 37 (3): 234–241. doi:10.2337/cd18-0063. PMC 6640881. PMID 31371854.
  156. ^ a b Kaushik D, Karnes RJ, Eisenberg MS, Rangel LJ, Carlson RE, Bergstralh EJ (January 2014). "Effect of metformin on prostate cancer outcomes after radical prostatectomy". Urologic Oncology. 32 (1): 43.e1–7. doi:10.1016/j.urolonc.2013.05.005. PMC 4006350. PMID 23810664. Metformin use at time of RP was extracted from the Mayo Clinic electronic medical record (EMR) by searching in the 3 months prior to the RP for the terms- metformin, Glucophage, Glumetza, Riomet, Fortamet, Obimet, Gluformin, Dianben, Diabex, Diaformin or Metsol.
  157. ^ a b c "Metformin". Drugs.com. from the original on 28 November 2020. Retrieved 17 July 2020.
  158. ^ Bailey CJ, Day C (June 2009). "Fixed-dose single tablet antidiabetic combinations". Diabetes, Obesity & Metabolism. 11 (6): 527–33. doi:10.1111/j.1463-1326.2008.00993.x. PMID 19175373. S2CID 6569131.
  159. ^ Sheehan MT (July 2003). "Current therapeutic options in type 2 diabetes mellitus: a practical approach". Clinical Medicine & Research. 1 (3): 189–200. doi:10.3121/cmr.1.3.189. PMC 1069045. PMID 15931309.
  160. ^ "FDA Approves GlaxoSmithKline's Avandamet (rosiglitazone maleate and metformin HCl), The Latest Advancement in the Treatment of Type 2 Diabetes" (Press release). GlaxoSmithKline. 12 October 2002. from the original on 21 January 2007. Retrieved 27 December 2006.
  161. ^ "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). from the original on 21 March 2021. Retrieved 21 July 2020.
  162. ^ (PDF). Archived from the original (PDF) on 14 July 2011. (96.5 KB). Drug Topics (17 June 2010). Retrieved 2 September 2010.
  163. ^ (Press release). U.S. Food and Drug Administration (FDA). 4 March 2005. Archived from the original on 14 October 2007. Retrieved 27 December 2006.
  164. ^ "Teva Pharm announces settlement of generic Avandia, Avandamet, and Avandaryl litigation with GlaxoSmithKline" (Press release). Reuters. 27 September 2007. from the original on 3 May 2021. Retrieved 17 February 2009.
  165. ^ 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. PMID 17517853.
  166. ^ "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim". European Medicines Agency (EMA). 23 September 2010. from the original on 24 September 2015.
  167. ^ "Call to 'suspend' diabetes drug". BBC News Online. 23 September 2010. from the original on 24 September 2010.
  168. ^ . 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 17 September 2013.
  169. ^ . Stuff.co.nz. NZPA. 17 February 2011. Archived from the original on 13 October 2013. Retrieved 5 November 2011.
  170. ^ Harris G (19 February 2010). "Controversial Diabetes Drug Harms Heart, U.S. Concludes". The New York Times. from the original on 19 March 2017.
  171. ^ "Updated Risk Evaluation and Mitigation Strategy (REMS)". U.S. Food and Drug Administration (FDA). 1 July 2021. Retrieved 6 March 2023.
  172. ^ "FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines". U.S. Food and Drug Administration (FDA). 21 June 2019. from the original on 4 September 2022. Retrieved 6 March 2023.
  173. ^ "Glaxo's Avandia Cleared From Sales Restrictions by FDA". Bloomberg. from the original on 9 November 2014.
  174. ^ . U.S. Food and Drug Administration (FDA) (Press release). 25 November 2013. Archived from the original on 4 May 2015.
  175. ^ "US agency reverses stance on controversial diabetes drug". from the original on 11 December 2015.
  176. ^ "Glubrava EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 9 June 2021. Retrieved 31 March 2020.
  177. ^ "Competact EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 9 June 2021. Retrieved 31 March 2020.
  178. ^ "Pioglitazone (marketed as Actos, Actoplus Met, Duetact, and Oseni) Information". U.S. Food and Drug Administration (FDA). 11 January 2017. from the original on 17 January 2021. Retrieved 31 March 2020.
  179. ^ "FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function". U.S. Food and Drug Administration (FDA). 3 April 2013. from the original on 25 May 2021. Retrieved 31 March 2020.
  180. ^ "FDA Drug Safety Communication: Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer". U.S. Food and Drug Administration (FDA). 4 August 2011. from the original on 26 January 2021. Retrieved 31 March 2020.
  181. ^ "Janumet- sitagliptin and metformin hydrochloride tablet, film coated". DailyMed. 12 August 2019. from the original on 9 June 2021. Retrieved 15 May 2020.
  182. ^ "Janumet EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 9 June 2021. Retrieved 15 May 2020.
  183. ^ "Kombiglyze XR- saxagliptin and metformin hydrochloride tablet, film coated, extended release". DailyMed. 24 October 2019. from the original on 25 September 2020. Retrieved 15 May 2020.
  184. ^ "Komboglyze EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 30 October 2020. Retrieved 15 May 2020.
  185. ^ "Kazano- alogliptin and metformin hydrochloride tablet, film coated". DailyMed. 14 June 2019. from the original on 9 June 2021. Retrieved 15 May 2020.
  186. ^ "Vipdomet EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 9 June 2021. Retrieved 15 May 2020.
  187. ^ "Jentadueto EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 9 June 2021. Retrieved 31 March 2020.
  188. ^ "Jentadueto- linagliptin and metformin hydrochloride tablet, film coated". DailyMed. 18 July 2019. from the original on 9 June 2021. Retrieved 31 March 2020.
  189. ^ "Jentadueto XR- linagliptin and metformin hydrochloride tablet, film coated, extended release". DailyMed. from the original on 5 October 2021. Retrieved 4 October 2021.
  190. ^ "Linagliptin and Metformin Hydrochloride: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). from the original on 25 September 2021. Retrieved 24 September 2021.
  191. ^ a b Grant JS, Graven LJ (September 2016). "Progressing From Metformin to Sulfonylureas or Meglitinides". Workplace Health & Safety. 64 (9): 433–9. doi:10.1177/2165079916644263. PMID 27621259.
  192. ^ a b Madsen KS, Kähler P, Kähler LK, Madsbad S, Gnesin F, Metzendorf MI, et al. (Cochrane Metabolic and Endocrine Disorders Group) (April 2019). "Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 4 (4): CD012368. doi:10.1002/14651858.CD012368.pub2. PMC 6472662. PMID 30998259.
  193. ^ "The Use of Medicines in the United States: Review of 2010" (PDF). (PDF) from the original on 22 April 2011. (1.79 MB). IMS Institute for Healthcare Informatics (April 2011). Retrieved 28 April 2011.
  194. ^ "Drug Approval Package: PrandiMet (repaglinide/metformin HCI fixed-dose combination) NDA 22386". U.S. Food and Drug Administration (FDA). from the original on 21 July 2020. Retrieved 21 July 2020.
  195. ^ "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). from the original on 22 July 2020. Retrieved 21 July 2020.
  196. ^ "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). from the original on 22 March 2021. Retrieved 21 July 2020.
  197. ^ "Qternmet XR (dapagliflozin, saxagliptin, and metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval: 2019". DailyMed. from the original on 6 March 2023. Retrieved 5 March 2023.
  198. ^ 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. PMID 15260389.
  199. ^ "Statement from Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research, on impurities found in diabetes drugs outside the U.S." U.S. Food and Drug Administration (FDA). 5 December 2019. from the original on 18 January 2021. Retrieved 4 February 2020.   This article incorporates text from this source, which is in the public domain.
  200. ^ "Recalls and safety alerts". Health Canada evaluating NDMA in metformin drugs. 5 December 2019. from the original on 17 April 2020. Retrieved 4 February 2020.
  201. ^ "Laboratory Tests - Metformin". U.S. Food and Drug Administration (FDA). 3 February 2020. from the original on 25 February 2020. Retrieved 4 February 2020.
  202. ^ "FDA Updates and Press Announcements on NDMA in Metformin". U.S. Food and Drug Administration (FDA). 4 February 2020. from the original on 25 February 2020. Retrieved 4 February 2020.
  203. ^ "APO-Metformin (2020-02-04)". Health Canada. 4 February 2020. from the original on 27 December 2020. Retrieved 2 June 2020.
  204. ^ "Ranbaxy Metformin Product Recall (2020-02-26)". Health Canada. 26 February 2020. from the original on 26 November 2020. Retrieved 2 June 2020.
  205. ^ "Jamp-Metformin Product Recall (2020-03-10)". Health Canada. 10 March 2020. from the original on 26 November 2020. Retrieved 2 June 2020.
  206. ^ "FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products" (Press release). U.S. Food and Drug Administration (FDA). 28 May 2020. from the original on 22 March 2021. Retrieved 2 June 2020.
  207. ^ "Questions and Answers: NDMA impurities in metformin products". U.S. Food and Drug Administration (FDA). 28 May 2020. from the original on 2 March 2021. Retrieved 5 June 2020.
  208. ^ "Amneal Pharmaceuticals LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets, USP, 500 mg and 750 mg, Due to Detection of N-Nitrosodimethylamine (NDMA) Impurity". U.S. Food and Drug Administration (FDA). 29 May 2020. from the original on 16 January 2021. Retrieved 2 June 2020.
  209. ^ "Apotex Corp. Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets 500mg Due to the Detection of N-nitrosodimethylamine (NDMA)". U.S. Food and Drug Administration (FDA). 27 May 2020. from the original on 4 March 2021. Retrieved 2 June 2020.
  210. ^ "Teva Pharmaceuticals USA, Inc. Initiates Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP 500 mg and 750 mg Due to Detection of N-Nitrosodimethylamine (NDMA)". U.S. Food and Drug Administration (FDA). 2 June 2020. from the original on 21 January 2021. Retrieved 5 June 2020.
  211. ^ "Marksans Pharma Limited Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, USP 500mg, Due to the Detection of N-Nitrosodimethylamine (NDMA)". U.S. Food and Drug Administration (FDA). 2 June 2020. from the original on 23 January 2021. Retrieved 5 June 2020.
  212. ^ Cavazzoni P (28 May 2020). "Re: Docket No. FDA-2020-P-0978" (PDF). U.S. Food and Drug Administration (FDA). (PDF) from the original on 8 February 2021. Retrieved 2 June 2020.
  213. ^ a b c "Laboratory Tests - Metformin". U.S. Food and Drug Administration (FDA). 5 June 2020. from the original on 22 April 2021. Retrieved 5 June 2020.   This article incorporates text from this source, which is in the public domain.
  214. ^ "Lupin Pharmaceuticals, Inc. Issues Voluntarily Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, 500mg and 1000mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity" (Press release). Lupin Pharmaceuticals Inc. from the original on 9 June 2021. Retrieved 9 July 2020 – via PR Newswire.
  215. ^ "Bayshore Pharmaceuticals, LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP, 500 mg and 750 mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity". U.S. Food and Drug Administration (FDA). 19 August 2020. from the original on 19 December 2020. Retrieved 25 August 2020.
  216. ^ Jalali M, Rahimlou M, Mahmoodi M, Moosavian SP, Symonds ME, Jalali R, et al. (September 2020). "The effects of metformin administration on liver enzymes and body composition in non-diabetic patients with non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis: An up-to date systematic review and meta-analysis of randomized controlled trials". Pharmacological Research. 159: 104799. doi:10.1016/j.phrs.2020.104799. PMID 32278041. S2CID 215741792.
  217. ^ Blazina I, Selph S (November 2019). "Diabetes drugs for nonalcoholic fatty liver disease: a systematic review". Systematic Reviews. 8 (1): 295. doi:10.1186/s13643-019-1200-8. PMC 6884753. PMID 31783920.
  218. ^ Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L (August 2018). "Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis". World Journal of Gastroenterology. 24 (30): 3361–3373. doi:10.3748/wjg.v24.i30.3361. PMC 6092580. PMID 30122876.
  219. ^ Ibáñez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F (August 2006). "Metformin treatment to prevent early puberty in girls with precocious pubarche". The Journal of Clinical Endocrinology and Metabolism. 91 (8): 2888–91. doi:10.1210/jc.2006-0336. PMID 16684823.
  220. ^ Ibáñez L, López-Bermejo A, Díaz M, Marcos MV, de Zegher F (August 2011). "Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence". The Journal of Clinical Endocrinology and Metabolism. 96 (8): E1262-7. doi:10.1210/jc.2011-0555. PMID 21632811.
  221. ^ Ibáñez L, Díaz R, López-Bermejo A, Marcos MV (March 2009). "Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism". Reviews in Endocrine & Metabolic Disorders. 10 (1): 63–76. doi:10.1007/s11154-008-9096-y. PMID 18726694. S2CID 9129907.
  222. ^ Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F (May 2010). "Metformin in cancer therapy: a new perspective for an old antidiabetic drug?". Molecular Cancer Therapeutics. 9 (5): 1092–9. doi:10.1158/1535-7163.MCT-09-1186. PMID 20442309.
  223. ^ Malek M, Aghili R, Emami Z, Khamseh ME (September 2013). "Risk of cancer in diabetes: the effect of metformin". ISRN Endocrinology. 2013: 636927. doi:10.1155/2013/636927. PMC 3800579. PMID 24224094.
  224. ^ a b Campbell 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. PMID 28802803. S2CID 20334490.
  225. ^ Soukas AA, Hao H, Wu L (October 2019). "Metformin as Anti-Aging Therapy: Is It for Everyone?". Trends in Endocrinology and Metabolism. 30 (10): 745–755. doi:10.1016/j.tem.2019.07.015. PMC 6779524. PMID 31405774.
  226. ^ Gantois I, Popic J, Khoutorsky A, Sonenberg N (January 2019). "Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders". Annual Review of Medicine. 70: 167–181. doi:10.1146/annurev-med-081117-041238. PMID 30365357. S2CID 53093694. from the original on 6 March 2023. Retrieved 9 October 2022.
  227. ^ Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (June 2016). "Metformin as a Tool to Target Aging". Cell Metabolism. 23 (6): 1060–1065. doi:10.1016/j.cmet.2016.05.011. PMC 5943638. PMID 27304507.
  228. ^ Lee CG, Heckman-Stoddard B, Dabelea D, et al. Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Care. 2021;44(12):2775-2782. doi:10.2337/dc21-1046
  229. ^ Mohammed I, Hollenberg MD, Ding H, Triggle CR (2021). "A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan". Frontiers in Endocrinology. 12: 718942. doi:10.3389/fendo.2021.718942. PMC 8374068. PMID 34421827.

Further reading edit

  • 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. PMID 27908266.
  • McCreight LJ, Bailey CJ, Pearson ER (March 2016). "Metformin and the gastrointestinal tract". Diabetologia. 59 (3): 426–35. doi:10.1007/s00125-015-3844-9. PMC 4742508. PMID 26780750.
  • Moin T, Schmittdiel JA, Flory JH, Yeh J, Karter AJ, Kruge LE, et al. (October 2018). "Review of Metformin Use for Type 2 Diabetes Prevention". American Journal of Preventive Medicine. 55 (4): 565–574. doi:10.1016/j.amepre.2018.04.038. PMC 6613947. PMID 30126667.
  • Rena G, Hardie DG, Pearson ER (September 2017). "The mechanisms of action of metformin". Diabetologia. 60 (9): 1577–1585. doi:10.1007/s00125-017-4342-z. PMC 5552828. PMID 28776086.
  • Sanchez-Rangel E, Inzucchi SE (September 2017). "Metformin: clinical use in type 2 diabetes". Diabetologia. 60 (9): 1586–1593. doi:10.1007/s00125-017-4336-x. PMID 28770321.
  • Zhou J, Massey S, Story D, Li L (September 2018). "Metformin: An Old Drug with New Applications". International Journal of Molecular Sciences. 19 (10): 2863. doi:10.3390/ijms19102863. PMC 6213209. PMID 30241400.
  • 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. PMID 30119191. S2CID 52031602.

External links edit

 
Wikimedia Commons has media related to Metformin.
  • "Nitrosamine impurities in medications: Guidance". Health Canada. 4 April 2022.

April 10, 2024
metformin, sold, under, brand, name, glucophage, among, others, main, first, line, medication, treatment, type, diabetes, particularly, people, overweight, also, used, treatment, polycystic, ovary, syndrome, sometimes, used, label, adjunct, lessen, risk, metab. Metformin sold under the brand name Glucophage among others is the main first line medication for the treatment of type 2 diabetes 12 13 14 15 particularly in people who are overweight 13 It is also used in the treatment of polycystic ovary syndrome 14 It is sometimes used as an off label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics 16 Metformin is not associated with weight gain 17 and is taken by mouth 14 MetforminClinical dataPronunciation m ɛ t ˈ f ɔːr m ɪ n met FOR minTrade namesFortamet Glucophage Glumetza othersOther namesN N dimethylbiguanide 1 AHFS Drugs comMonographMedlinePlusa696005License dataUS DailyMed MetforminPregnancycategoryAU C 2 Routes ofadministrationBy mouthATC codeA10BA02 WHO A10BD23 WHO A10BD02 WHO A10BD18 WHO A10BD11 WHO A10BD25 WHO A10BD22 WHO A10BD14 WHO A10BD16 WHO A10BD17 WHO A10BD05 WHO A10BD15 WHO A10BD07 WHO A10BD10 WHO A10BD13 WHO A10BD20 WHO A10BD08 WHO A10BD03 WHO Legal statusLegal statusAU S4 Prescription only 4 CA only 5 6 UK POM Prescription only 7 US WARNING 3 Rx only 8 EU Rx onlyPharmacokinetic dataBioavailability50 60 9 10 Protein bindingMinimal 9 MetabolismNot by liver 9 Elimination half life4 8 7 hours 9 ExcretionUrine 90 9 IdentifiersIUPAC name N N Dimethylimidodicarbonimidic diamideCAS Number657 24 9as HCl 1115 70 4PubChem CID4091IUPHAR BPS4779DrugBankDB00331ChemSpider3949UNII9100L32L2Nas HCl 786Z46389EKEGGD04966as HCl C07151ChEBICHEBI 6801as HCl CHEBI 6802ChEMBLChEMBL1431CompTox Dashboard EPA DTXSID2023270ECHA InfoCard100 010 472Chemical and physical dataFormulaC 4H 11N 5Molar mass129 167 g mol 13D model JSmol Interactive imageDensity1 3 0 1 11 g cm3SMILES CN C C N N C N NInChI InChI 1S C4H11N5 c1 9 2 4 7 8 3 5 6 h1 2H3 H5 5 6 7 8 Key XZWYZXLIPXDOLR UHFFFAOYSA N YMetformin is generally well tolerated 18 Common adverse effects include diarrhea nausea and abdominal pain 14 It has a small risk of causing low blood sugar 14 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 19 20 Metformin is a biguanide anti hyperglycemic agent 14 It works by decreasing glucose production in the liver increasing the insulin sensitivity of body tissues 14 and increasing GDF15 secretion which reduces appetite and caloric intake 21 22 23 24 Metformin was first described in scientific literature in 1922 by Emil Werner and James Bell 25 French physician Jean Sterne began the study in humans in the 1950s 25 It was introduced as a medication in France in 1957 and the United States in 1995 14 26 Metformin is on the World Health Organization s List of Essential Medicines 27 and is the most widely used medication for diabetes taken by mouth 25 It is available as a generic medication 14 In 2021 it was the second most commonly prescribed medication in the United States with more than 91 million prescriptions 28 29 Contents 1 Medical uses 1 1 Type 2 diabetes 1 1 1 Efficacy 1 2 Polycystic ovarian syndrome 1 3 Gastric Cancer 1 4 Diabetes and pregnancy 1 5 Weight change 1 6 Use with insulin 1 7 Life extension 1 8 Alzheimer s disease 2 Contraindications 3 Adverse effects 3 1 Gastrointestinal 3 2 Lactic acidosis 3 3 Overdose 3 4 Interactions 4 Pharmacology 4 1 Mechanism of action 4 2 Pharmacokinetics 5 Chemistry 5 1 Derivatives 6 History 7 Society and culture 7 1 Environmental 7 2 Formulations 7 2 1 Combination with other medications 7 2 1 1 Thiazolidinediones glitazones 7 2 1 1 1 Rosiglitazone 7 2 1 1 2 Pioglitazone 7 2 1 2 DPP 4 inhibitors 7 2 1 3 SGLT 2 inhibitors 7 2 1 4 Sulfonylureas 7 2 1 5 Meglitinide 7 2 1 6 Triple combination 7 3 Impurities 8 Research 9 References 10 Further reading 11 External linksMedical uses editMetformin is used to lower the blood glucose in those with type 2 diabetes 14 It is also used as a second line agent for infertility in those with polycystic ovary syndrome 14 30 Type 2 diabetes edit The American Diabetes Association and the American College of Physicians both recommend metformin as a first line agent to treat type 2 diabetes 31 32 33 It is as effective as repaglinide and more effective than all other oral drugs for type 2 diabetes 34 Efficacy edit Treatment guidelines for major professional associations including the European Association for the Study of Diabetes the European Society for Cardiology and the American Diabetes Association describe evidence for the cardiovascular benefits of metformin as equivocal 32 35 A 2020 Cochrane systematic review did not find enough evidence of reduction of cardiovascular mortality non fatal myocardial infarction or non fatal stroke when comparing metformin monotherapy to other glucose lowering drugs behavior change interventions placebo or no intervention 36 The use of metformin reduces body weight in people with type 2 diabetes 21 37 in contrast to sulfonylureas which are associated with weight gain 37 Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes 38 39 Metformin has a lower risk of hypoglycemia than the sulfonylureas 40 41 although hypoglycemia has uncommonly occurred during intense exercise calorie deficit or when used with other agents to lower blood glucose 42 43 Metformin modestly reduces low density lipoprotein and triglyceride levels 40 41 In individuals with prediabetes a 2019 systematic review comparing the effects of metformin with other interventions in the reduction of risk of developing type 2 diabetes 44 found moderate quality evidence that metformin reduced the risk of developing type 2 diabetes when compared to diet and exercise or a placebo 44 However when comparing metformin to intensive diet or exercise moderate quality evidence was found that metformin did not reduce risk of developing type 2 diabetes and very low quality evidence was found that adding metformin to intensive diet or exercise did not show any advantage or disadvantage in reducing risk of type 2 diabetes when compared to intensive exercise and diet alone 44 The same review also found one suitable trial comparing the effects of metformin and sulfonylurea in reducing risk of developing type 2 diabetes in prediabetic individuals however this trial did not report any patient relevant outcomes 44 Polycystic ovarian syndrome edit In those with polycystic ovarian syndrome PCOS tentative evidence shows that metformin use increases the rate of live births 45 This includes in those who have not been able to get pregnant with clomiphene 46 Metformin does not appear to change the risk of miscarriage 45 A number of other benefits have also been found both during pregnancy and in nonpregnant women with PCOS 47 48 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 49 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 49 In short GnRH antagonist protocols metformin may reduce live birth rates with uncertainty on its effect on clinical pregnancy rate 49 Metformin may result in a reduction of OHSS but could come with a greater frequency of side effects 49 There was uncertainty as to metformin s impact on miscarriage 49 The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women 50 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 51 UK and international clinical practice guidelines do not recommend metformin as a first line treatment 52 or do not recommend it at all except for women with glucose intolerance 53 The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from medical treatment Metformin treatment decreases the risk of developing type 2 diabetes in women with PCOS who exhibited impaired glucose tolerance at baseline 54 55 Gastric Cancer edit Gastric cancer GC stands as a major global health concern due to its high prevalence and mortality rate Amidst various treatment avenues metformin a common medication for type 2 diabetes mellitus T2DM has garnered attention for its potential anti cancer properties While its effectiveness in combating GC has been a subject of debate recent clinical studies predominantly support metformin s protective impact on reducing the risk and improving the survival rates of GC patients 56 The drug s anti cancer effects are believed to be mediated through multiple pathways particularly involving AMPK activation and IGF 1R modulation Despite promising findings the consensus on metformin s application in GC prevention and treatment necessitates further clinical and mechanistic studies to confirm its therapeutic role 57 Diabetes and pregnancy edit 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 58 Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes 59 60 Nonetheless several concerns have been raised and evidence on the long term safety of metformin for both mother and child is lacking 61 Compared with insulin women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre eclampsia during pregnancy 61 62 Babies born to women treated with metformin have less visceral fat and this may make them less prone to insulin resistance in later life 63 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 64 Weight change edit Metformin use is typically associated with weight loss 65 It appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine 66 67 Although modest reversal of clozapine associated weight gain is found with metformin primary prevention of weight gain is more valuable 68 Use with insulin edit Metformin may reduce the insulin requirement in type 1 diabetes albeit with an increased risk of hypoglycemia 69 Life extension edit There is some evidence metformin may be helpful in extending lifespan even in otherwise healthy people It has received substantial interest as an agent that delays aging possibly through similar mechanisms as its treatment of diabetes insulin and carbohydrate regulation 70 71 Alzheimer s disease edit Preliminary studies have examined whether metformin can reduce the risk of Alzheimer s disease and whether there is a correlation between type 2 diabetes and risk of Alzheimer s disease 72 73 Contraindications editMetformin is contraindicated in people with Severe renal impairment estimated glomerular filtration rate eGFR below 30 mL min 1 73 m2 74 Known hypersensitivity to metformin 74 Acute or chronic metabolic acidosis including diabetic ketoacidosis from uncontrolled diabetes 74 with or without coma 75 Adverse effects editThe 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 41 The most serious potential adverse effect of metformin is lactic acidosis this complication is rare and seems to be related to impaired liver or kidney function 76 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 77 Gastrointestinal edit Gastrointestinal upset can cause severe discomfort it is most common when metformin is first administered or when the dose is increased 75 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 75 78 Use of slow or extended release preparations may improve tolerability 78 Long term use of metformin has been associated with increased homocysteine levels 79 and malabsorption of vitamin B12 75 80 81 Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency 82 and some researchers recommend screening or prevention strategies 83 Lactic acidosis edit Lactic acidosis almost never occurs with metformin exposure during routine medical care 84 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 85 A systematic review concluded no data exists to definitively link metformin to lactic acidosis 86 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 87 The US Food and Drug Administration FDA recommends avoiding the use of metformin in more severe chronic kidney disease below the eGFR cutoff of 30 mL minute 1 73 m2 88 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 40 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 89 Metformin associated lactate production may also take place in the large intestine which could potentially contribute to lactic acidosis in those with risk factors 90 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 40 89 91 Overdose edit The most common symptoms following an overdose include vomiting diarrhea abdominal pain tachycardia drowsiness and rarely hypoglycemia or hyperglycemia 92 93 Treatment of metformin overdose is generally supportive as no specific antidote is known Extracorporeal treatments are recommended in severe overdoses 94 Due to metformin s low molecular weight and lack of plasma protein binding these techniques have the benefit of removing metformin from the blood plasma preventing further lactate overproduction 94 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 95 96 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 97 Interactions edit The H2 receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys 98 both metformin and cimetidine are cleared from the body by tubular secretion and both particularly the cationic positively charged form of cimetidine may compete for the same transport mechanism 8 A small double blind randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism 99 theoretically other cationic medications may produce the same effect 8 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 100 Pharmacology editMechanism of action edit The molecular mechanism of metformin is not completely understood Multiple potential mechanisms of action have been proposed inhibition of the mitochondrial respiratory chain complex I activation of AMP activated protein kinase AMPK inhibition of glucagon induced elevation of cyclic adenosine monophosphate cAMP with reduced activation of protein kinase A PKA complex IV mediated inhibition of the GPD2 variant of mitochondrial glycerol 3 phosphate dehydrogenase thereby reducing glycerol derived hepatic gluconeogenesis and an effect on gut microbiota 24 101 102 103 Metformin exerts an anorexiant effect in most people decreasing caloric intake 23 Metformin decreases gluconeogenesis glucose production in the liver 90 18 Metformin inhibits basal secretion from the pituitary gland of growth hormone adrenocorticotropic hormone follicle stimulating hormone and expression of proopiomelanocortin 104 which in part accounts for its insulin sensitizing effect with multiple actions on tissues including the liver skeletal muscle endothelium adipose tissue and the ovaries 54 30 The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis metformin treatment reduces this by over one third 105 Activation of AMPK was required for metformin s inhibitory effect on liver glucose production 106 AMPK is an enzyme that plays an important role in insulin signaling whole body energy balance and the metabolism of glucose and fats 107 AMPK activation is 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 108 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 metformin increases the concentration of cytosolic adenosine monophosphate AMP as opposed to a change in total AMP or total AMP adenosine triphosphate which could activate AMPK allosterically at high levels 109 a newer theory involves binding to PEN 2 110 Metformin inhibits cyclic AMP production blocking the action of glucagon and thereby reducing fasting glucose levels 111 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 102 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 112 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 113 The increase in insulin binding after metformin treatment has also been demonstrated in patients with type 2 diabetes 114 AMPK probably also plays a role in increased peripheral insulin sensitivity as metformin administration increases AMPK activity in skeletal muscle 115 AMPK is known to cause GLUT4 deployment to the plasma membrane resulting in insulin independent glucose uptake 116 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 117 Metformin has indirect antiandrogenic effects in women with insulin resistance such as those with PCOS due to its beneficial effects on insulin sensitivity 118 It may reduce testosterone levels in such women by as much as 50 118 A Cochrane review though found that metformin was only slightly effective for decreasing androgen levels in women with PCOS 119 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 120 121 122 Due to its effect on GLUT4 and AMPK metformin has been described as an exercise mimetic 123 124 Pharmacokinetics edit Metformin has an oral bioavailability of 50 60 under fasting conditions and is absorbed slowly 8 125 Peak plasma concentrations Cmax are reached within 1 3 hours of taking immediate release metformin and 4 8 hours with extended release formulations 8 125 The plasma protein binding of metformin is negligible as reflected by its very high apparent volume of distribution 300 1000 L after a single dose Steady state is usually reached in 1 2 days 8 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 transporter SLC22A1 in order for it to enter cells 126 127 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 128 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 8 129 The average elimination half life in plasma is 6 2 hours 8 Metformin is distributed to and appears to accumulate in red blood cells with a much longer elimination half life 17 6 hours 8 reported as ranging from 18 5 to 31 5 hours in a single dose study of nondiabetics 129 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 117 Chemistry editMetformin 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 4 130 The usual synthesis of metformin originally described in 1922 involves the one pot reaction of dimethylamine hydrochloride and 2 cyanoguanidine over heat 131 132 nbsp According to the procedure described in the 1975 Aron patent 133 and the Pharmaceutical Manufacturing Encyclopedia 134 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 citation needed Derivatives edit A new derivative HL156A also known as IM156 is a potential new drug for medical use 135 136 137 138 139 140 History edit nbsp 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 141 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 141 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 131 In 1929 Slotta and Tschesche discovered its sugar lowering action in rabbits finding it the most potent biguanide analog they studied 142 This result was ignored as other guanidine analogs such as the synthalins took over and were themselves soon overshadowed by insulin 143 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 144 That year Filipino physician Eusebio Y Garcia 145 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 146 In a series of articles in 1954 Polish pharmacologist Janusz Supniewski 147 was unable to confirm most of these effects including lowered blood sugar Instead he observed antiviral effects in humans 148 149 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 150 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 143 150 Metformin became available in the British National Formulary in 1958 It was sold in the UK by a small Aron subsidiary called Rona 151 Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s 5 Metformin was approved in Canada in 1972 5 but did not receive approval by the U S Food and Drug Administration FDA for type 2 diabetes until 1994 152 Produced under license by Bristol Myers Squibb Glucophage was the first branded formulation of metformin to be marketed in the U S beginning on 3 March 1995 153 Generic formulations are available in several countries and metformin is believed to have become the world s most widely prescribed antidiabetic medication 150 Society and culture editEnvironmental edit Metformin and its major transformation product guanylurea are present in wastewater treatment plant effluents and regularly detected in surface waters Guanylurea concentrations above 200 mg L have been measured in the German river Erpe which are amongst the highest reported for pharmaceutical transformation products in aquatic environments 154 Formulations edit nbsp Generic metformin 500 mg tablets as sold in the United KingdomThe 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 155 In other areas of the world there is also Obimet Gluformin Dianben Diabex Diaformin Metsol Siofor Metfogamma and Glifor 156 157 There are several formulations of Metformin available to the market and all but the liquid form have generic equivalents 155 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 Also available is liquid metformin sold as Riomet in the US where 5 mL of solution contains the same amount of drug as a 500 mg tablet Combination with other medications edit When used for type 2 diabetes metformin is often prescribed in combination with other medications Several are available as fixed dose combinations with the potential to reduce pill burden decrease cost and simplify administration 158 159 Thiazolidinediones glitazones edit Rosiglitazone edit A combination of metformin and rosiglitazone was released in 2002 and sold as Avandamet by GlaxoSmithKline 160 or as a generic medication 161 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 162 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 163 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 164 However following a meta analysis in 2007 that linked the medication s use to an increased risk of heart attack 165 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 166 167 It was withdrawn from the market in the UK and India in 2010 168 and in New Zealand and South Africa in 2011 169 From November 2011 until November 2013 the FDA 170 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 171 172 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 173 174 175 Pioglitazone edit The combination of metformin and pioglitazone Actoplus Met Piomet Politor Glubrava is available in the US and the European Union 176 177 178 179 180 DPP 4 inhibitors edit Dipeptidyl peptidase 4 inhibitors inhibit dipeptidyl peptidase 4 and thus reduce glucagon and blood glucose levels DPP 4 inhibitors combined with metformin include a sitagliptin metformin combination Janumet 181 182 a saxagliptin metformin combination Kombiglyze XR Komboglyze 183 184 and an alogliptin metformin combination Kazano Vipdomet 185 186 Linagliptin combined with metformin hydrochloride is sold under the brand name Jentadueto 187 188 189 As of August 2021 linagliptin metformin is available as a generic medicine in the US 190 SGLT 2 inhibitors edit There are combinations of metformin with the SGLT 2 inhibitors dapagliflozin empagliflozin and canagliflozin Sulfonylureas edit Sulfonylureas act by increasing insulin release from the beta cells in the pancreas 191 A 2019 systematic review suggested that there is limited evidence if the combined used of metformin with sulfonylurea compared to the combination of metformin plus another glucose lowering intervention provides benefit or harm in mortality severe adverse events macrovascular and microvascular complications 192 Combined metformin and sulfonylurea therapy did appear to lead to higher risk of hypoglicaemia 192 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 193 Meglitinide edit 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 191 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 194 195 Triple combination edit The combination of metformin with dapagliflozen and saxagliptin is available in the United States as Qternmet XR 196 197 The combination of metformin with pioglitazone and glibenclamide 198 is available in India as Accuglim MP Adglim MP and Alnamet GP along with the Philippines as Tri Senza 157 The combination of metformin with pioglitazone and lipoic acid is available in Turkey as Pional 157 Impurities edit See also Ranitidine impurities In December 2019 the US 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 199 Health Canada announced that it was assessing NDMA levels in metformin 200 In February 2020 the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake 201 202 In February 2020 Health Canada announced a recall of Apotex immediate release metformin 203 followed in March by recalls of Ranbaxy metformin 204 and in March by Jamp metformin 205 In May 2020 the FDA asked five companies to voluntarily recall their sustained release metformin products 206 207 208 209 210 211 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 212 In June 2020 the FDA posted its laboratory results showing NDMA amounts in metformin products it tested 213 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 213 The FDA is also collaborating with international regulators to share testing results for metformin 213 In July 2020 Lupin Pharmaceuticals pulled all lots batches of metformin after discovering unacceptably high levels of NDMA in tested samples 214 In August 2020 Bayshore Pharmaceuticals recalled two lots of tablets 215 Research editMetformin has been studied for its effects on multiple other conditions including Non alcoholic fatty liver disease 216 217 218 Premature puberty 219 220 221 Cancer 156 222 223 Cardiovascular disease in people with diabetes 224 Aging 225 70 While metformin may reduce body weight in persons with fragile X syndrome whether it improves neurological or psychiatric symptoms is uncertain 226 Metformin has been studied in vivo C elegans and crickets for effects on aging 127 227 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 224 There is also some research suggesting that although metformin prevents diabetes it does not reduce the risk of cancer and cardiovascular disease and thus does not extend lifespan in non diabetic individuals 228 Furthermore some studies suggest that long term chronic use of metformin by healthy individuals may develop vitamin B12 deficiency 229 References edit Sirtori CR Franceschini G Galli Kienle M Cighetti G Galli G Bondioli A et al December 1978 Disposition of metformin N N dimethylbiguanide in man Clinical Pharmacology and Therapeutics 24 6 683 93 doi 10 1002 cpt1978246683 PMID 710026 S2CID 24531910 Metformin Use During Pregnancy Drugs com 10 September 2019 Archived from the original on 16 April 2020 Retrieved 4 February 2020 FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 October 2023 Metformin SANDOZ metformin hydrochloride 850mg tablet bottle 148270 Therapeutic Goods Administration TGA 27 May 2022 Retrieved 29 April 2023 a b c Lucis OJ January 1983 The status of metformin in Canada Canadian Medical Association Journal 128 1 24 6 PMC 1874707 PMID 6847752 Metformin Hydrochloride Health Canada Archived from the original on 6 March 2023 Retrieved 6 March 2023 Glucophage 500 mg film coated tablets Summary of Product Characteristics SmPC emc 25 October 2022 Archived from the original on 20 June 2022 Retrieved 5 March 2023 a b c d e f g h i Glucophage metformin hydrochloride tablets for oral use Glucophage XR metformin hydrochloride extended release tablets for oral use Initial U S Approval 1995 DailyMed Archived from the original on 6 March 2023 Retrieved 5 March 2023 a b c d e Dunn CJ Peters DH May 1995 Metformin A review of its pharmacological properties and therapeutic use in non insulin dependent diabetes mellitus Drugs 49 5 721 49 doi 10 2165 00003495 199549050 00007 PMID 7601013 Hundal RS Inzucchi SE 2003 Metformin new understandings new uses Drugs 63 18 1879 94 doi 10 2165 00003495 200363180 00001 PMID 12930161 Metformin www chemsrc com Archived from the original on 12 June 2017 Retrieved 10 May 2018 Draznin B Aroda VR Bakris G Benson G Brown FM Freeman R et al January 2022 9 Pharmacologic Approaches to Glycemic Treatment Standards of Medical Care in Diabetes 2022 Diabetes Care 45 Suppl 1 S125 S143 doi 10 2337 dc22 s009 PMID 34964831 S2CID 245538347 a b Cosentino F Grant PJ Aboyans V Bailey CJ Ceriello A Delgado V et al January 2020 2019 ESC Guidelines on diabetes pre diabetes and cardiovascular diseases developed in collaboration with the EASD European Heart Journal 41 2 255 323 doi 10 1093 eurheartj ehz486 PMID 31497854 a b c d e f g h i j k Metformin Hydrochloride The American Society of Health System Pharmacists Archived from the original on 24 December 2016 Retrieved 2 January 2017 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 11 740 751 doi 10 7326 M15 2650 PMID 27088241 S2CID 32016657 de Silva VA Suraweera C Ratnatunga SS Dayabandara M Wanniarachchi N Hanwella R October 2016 Metformin in prevention and treatment of antipsychotic induced weight gain a systematic review and meta analysis BMC Psychiatry 16 1 341 doi 10 1186 s12888 016 1049 5 PMC 5048618 PMID 27716110 Type 2 diabetes and metformin First choice for monotherapy weak evidence of efficacy but well known and acceptable adverse effects Prescrire International 23 154 269 272 November 2014 PMID 25954799 a b Triggle 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 PMID 26680745 S2CID 312517 Blumenberg A Benabbas R Sinert R Jeng A Wiener SW April 2020 Do Patients Die with or from Metformin Associated Lactic Acidosis MALA Systematic Review and Meta analysis of pH and Lactate as Predictors of Mortality in MALA Journal of Medical Toxicology 16 2 222 229 doi 10 1007 s13181 019 00755 6 PMC 7099117 PMID 31907741 Lipska KJ Bailey CJ Inzucchi SE June 2011 Use of metformin in the setting of mild to moderate renal insufficiency Diabetes Care 34 6 1431 7 doi 10 2337 dc10 2361 PMC 3114336 PMID 21617112 a b Coll AP Chen M Taskar P Rimmington D Patel S Tadross JA et al February 2020 GDF15 mediates the effects of metformin on body weight and energy balance Nature 578 7795 444 448 doi 10 1038 s41586 019 1911 y PMC 7234839 PMID 31875646 Day EA Ford RJ Smith BK Mohammadi Shemirani P Morrow MR Gutgesell RM et al December 2019 Metformin induced increases in GDF15 are important for suppressing appetite and promoting weight loss Nature Metabolism 1 12 1202 1208 doi 10 1038 s42255 019 0146 4 PMID 32694673 S2CID 213199603 a b Pappachan JM Viswanath AK January 2017 Medical Management of Diabesity Do We Have Realistic Targets Current Diabetes Reports 17 1 4 doi 10 1007 s11892 017 0828 9 PMID 28101792 S2CID 10289148 a b LaMoia TE Butrico GM Kalpage HA Goedeke L Hubbard BT Vatner DF et al March 2022 Metformin phenformin and galegine inhibit complex IV activity and reduce glycerol derived gluconeogenesis Proceedings of the National Academy of Sciences of the United States of America 119 10 e2122287119 Bibcode 2022PNAS 11922287L doi 10 1073 pnas 2122287119 PMC 8916010 PMID 35238637 a b c Fischer J 2010 Analogue based Drug Discovery II John Wiley amp Sons p 49 ISBN 978 3 527 63212 1 Archived from the original on 8 September 2017 Stargrove MB Treasure J McKee DL 2008 Herb nutrient and drug interactions clinical implications and therapeutic strategies St Louis Mo Mosby Elsevier p 217 ISBN 978 0 323 02964 3 Archived from the original on 8 September 2017 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 The Top 300 of 2021 ClinCalc Archived from the original on 15 January 2024 Retrieved 14 January 2024 Metformin Drug Usage Statistics ClinCalc Retrieved 14 January 2024 a b Lord JM Flight IH Norman RJ October 2003 Metformin in polycystic ovary syndrome systematic review and meta analysis BMJ 327 7421 951 3 doi 10 1136 bmj 327 7421 951 PMC 259161 PMID 14576245 Bennett WL Maruthur NM Singh S Segal JB Wilson LM Chatterjee R et al May 2011 Comparative effectiveness and safety of medications for type 2 diabetes an update including new drugs and 2 drug combinations Annals of Internal Medicine 154 9 602 13 doi 10 7326 0003 4819 154 9 201105030 00336 PMC 3733115 PMID 21403054 a b Inzucchi SE Bergenstal RM Buse JB Diamant M Ferrannini E Nauck M et al June 2012 Management of hyperglycemia in type 2 diabetes a patient centered approach position statement of the American Diabetes Association ADA and the European Association for the Study of Diabetes EASD Diabetes Care 35 6 1364 79 doi 10 2337 dc12 0413 PMC 3357214 PMID 22517736 Qaseem A Humphrey LL Sweet DE Starkey M Shekelle P February 2012 Oral pharmacologic treatment of type 2 diabetes mellitus a clinical practice guideline from the American College of Physicians Annals of Internal Medicine 156 3 218 31 doi 10 7326 0003 4819 156 3 201202070 00011 PMID 22312141 Jia Y Lao Y Zhu H Li N Leung SW January 2019 Is metformin still the most efficacious first line oral hypoglycaemic drug in treating type 2 diabetes A network meta analysis of randomized controlled trials Obesity Reviews 20 1 1 12 doi 10 1111 obr 12753 PMID 30230172 Ryden L Grant PJ Anker SD Berne C Cosentino F Danchin N et al May 2014 ESC guidelines on diabetes pre diabetes and cardiovascular diseases developed in collaboration with the EASD summary Diabetes amp Vascular Disease Research 11 3 133 73 doi 10 1177 1479164114525548 PMID 24800783 Gnesin F Thuesen AC Kahler LK Madsbad S Hemmingsen B et al Cochrane Metabolic and Endocrine Disorders Group June 2020 Metformin monotherapy for adults with type 2 diabetes mellitus The Cochrane Database of Systematic Reviews 2020 6 CD012906 doi 10 1002 14651858 CD012906 pub2 PMC 7386876 PMID 32501595 a b Johansen K January 1999 Efficacy of metformin in the treatment of NIDDM Meta analysis Diabetes Care 22 1 33 7 doi 10 2337 diacare 22 1 33 PMID 10333900 Golay A January 2008 Metformin and body weight International Journal of Obesity 32 1 61 72 doi 10 1038 sj ijo 0803695 PMID 17653063 Mead E Atkinson G Richter B Metzendorf MI Baur L Finer N et al November 2016 Drug interventions for the treatment of obesity in children and adolescents The Cochrane Database of Systematic Reviews 11 11 CD012436 doi 10 1002 14651858 CD012436 hdl 10149 620651 PMC 6472619 PMID 27899001 a b c d Maharani U 2009 Chapter 27 Diabetes Mellitus amp Hypoglycemia In Papadakis MA McPhee SJ eds Current Medical Diagnosis and Treatment 2010 49th ed McGraw Hill Medical pp 1092 93 ISBN 978 0 07 162444 2 a b c Bolen S Feldman L Vassy J Wilson L Yeh HC Marinopoulos S et al September 2007 Systematic review comparative effectiveness and safety of oral medications for type 2 diabetes mellitus Annals of Internal Medicine 147 6 386 99 doi 10 7326 0003 4819 147 6 200709180 00178 PMID 17638715 DiPiro JT Talbert RL Yee GC Matzke GR Wells BG Posey LM 2005 Pharmacotherapy a pathophysiologic approach New York McGraw Hill ISBN 978 0 07 141613 9 Glucophage package insert Princeton NJ Bristol Myers Squibb Company 2009 Archived from the original on 29 August 2021 via DailyMed a b c d Madsen KS Chi Y Metzendorf MI Richter B Hemmingsen B et al Cochrane Metabolic and Endocrine Disorders Group December 2019 Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus The Cochrane Database of Systematic Reviews 2019 12 CD008558 doi 10 1002 14651858 CD008558 pub2 PMC 6889926 PMID 31794067 a b Morley LC Tang T Yasmin E Norman RJ Balen AH November 2017 Insulin sensitising drugs metformin rosiglitazone pioglitazone D chiro inositol for women with polycystic ovary syndrome oligo amenorrhoea and subfertility The Cochrane Database of Systematic Reviews 11 2 CD003053 doi 10 1002 14651858 CD003053 pub6 PMC 6486196 PMID 29183107 Our updated review suggests that metformin alone may be beneficial over placebo for live birth although the evidence quality was low Ghazeeri GS Nassar AH Younes Z Awwad JT June 2012 Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome an overview Acta Obstetricia et Gynecologica Scandinavica 91 6 658 78 doi 10 1111 j 1600 0412 2012 01385 x PMID 22375613 S2CID 41145972 Kumar P Khan K May 2012 Effects of metformin use in pregnant patients with polycystic ovary syndrome Journal of Human Reproductive Sciences 5 2 166 9 doi 10 4103 0974 1208 101012 PMC 3493830 PMID 23162354 Tay CT Joham AE Hiam DS Gadalla MA Pundir J Thangaratinam S et al November 2018 Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome An overview of systematic reviews Clinical Endocrinology 89 5 535 553 doi 10 1111 cen 13753 hdl 10536 DRO DU 30151483 PMID 29846959 a b c d e Tso 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 PMID 33347618 Dodd JM Grivell RM Deussen AR Hague WM July 2018 Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes The Cochrane Database of Systematic Reviews 2018 7 CD010564 doi 10 1002 14651858 CD010564 pub2 PMC 6513233 PMID 30039871 National Collaborating Centre for Women s and Children s Health 2004 Fertility assessment and treatment for people with fertility problems PDF London Royal College of Obstetricians and Gynaecologists pp 58 59 ISBN 978 1 900364 97 3 Archived PDF from the original on 11 July 2009 Balen A December 2008 Metformin therapy for the management of infertility in women with polycystic ovary syndrome PDF Scientific Advisory Committee Opinion Paper 13 Royal College of Obstetricians and Gynaecologists Archived from the original PDF on 18 December 2009 Retrieved 13 December 2009 The Thessaloniki ESHRE ASRM Sponsored PCOS Consensus Workshop Group March 2008 Consensus on infertility treatment related to polycystic ovary syndrome Human Reproduction 23 3 462 77 doi 10 1093 humrep dem426 PMID 18308833 a b Diamanti Kandarakis E Economou F Palimeri S Christakou C September 2010 Metformin in polycystic ovary syndrome Annals of the New York Academy of Sciences 1205 1 192 8 Bibcode 2010NYASA1205 192D doi 10 1111 j 1749 6632 2010 05679 x PMID 20840272 S2CID 44203632 Diamanti Kandarakis E Christakou CD Kandaraki E Economou FN February 2010 Metformin an old medication of new fashion evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome European Journal of Endocrinology 162 2 193 212 doi 10 1530 EJE 09 0733 PMID 19841045 Zhang J Wen L Zhou Q He K Teng L 16 September 2020 Preventative and Therapeutic Effects of Metformin in Gastric Cancer A New Contribution of an Old Friend Cancer Management and Research 12 8545 8554 doi 10 2147 CMAR S264032 PMC 7505710 PMID 32982447 Sharma A 29 October 2023 The Role of Metformin in Gastric Cancer Treatment Witfire Retrieved 3 November 2023 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 PMID 27150509 S2CID 3418227 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 PMID 19104375 S2CID 28115952 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 PMID 26117686 a b Balsells M Garcia Patterson A Sola I Roque M Gich I Corcoy R January 2015 Glibenclamide metformin and insulin for the treatment of gestational diabetes a systematic review and meta analysis BMJ Systematic Review amp Meta Analysis 350 h102 doi 10 1136 bmj h102 PMC 4301599 PMID 25609400 Alqudah A McKinley MC McNally R Graham U Watson CJ Lyons TJ et al February 2018 Risk of pre eclampsia in women taking metformin a systematic review and meta analysis Diabetic Medicine 35 2 160 172 doi 10 1111 dme 13523 hdl 10453 130987 PMID 29044702 S2CID 40045912 Archived from the original on 29 April 2023 Retrieved 7 April 2023 Sivalingam VN Myers J Nicholas S Balen AH Crosbie EJ 2014 Metformin in reproductive health pregnancy and gynaecological cancer established and emerging indications Human Reproduction Update 20 6 853 68 doi 10 1093 humupd dmu037 PMID 25013215 Tarry Adkins JL Aiken CE Ozanne SE August 2019 Neonatal infant and childhood growth following metformin versus insulin treatment for gestational diabetes A systematic review and meta analysis PLOS Medicine 16 8 e1002848 doi 10 1371 journal pmed 1002848 PMC 6684046 PMID 31386659 Yerevanian A Soukas AA June 2019 Metformin Mechanisms in Human Obesity and Weight Loss Current Obesity Reports 8 2 156 164 doi 10 1007 s13679 019 00335 3 PMC 6520185 PMID 30874963 Choi YJ 2015 Efficacy of adjunctive treatments added to olanzapine or clozapine for weight control in patients with schizophrenia a systematic review and meta analysis TheScientificWorldJournal 2015 970730 doi 10 1155 2015 970730 PMC 4310265 PMID 25664341 Praharaj SK Jana AK Goyal N Sinha VK March 2011 Metformin for olanzapine induced weight gain a systematic review and meta analysis British Journal of Clinical Pharmacology 71 3 377 82 doi 10 1111 j 1365 2125 2010 03783 x PMC 3045546 PMID 21284696 Siskind DJ Leung J Russell AW Wysoczanski D Kisely S 2016 Metformin for Clozapine Associated Obesity A Systematic Review and Meta Analysis PLOS ONE 11 6 e0156208 Bibcode 2016PLoSO 1156208S doi 10 1371 journal pone 0156208 PMC 4909277 PMID 27304831 Vella S Buetow L Royle P Livingstone S Colhoun HM Petrie JR May 2010 The use of metformin in type 1 diabetes a systematic review of efficacy Diabetologia 53 5 809 20 doi 10 1007 s00125 009 1636 9 PMID 20057994 a b Novelle MG Ali A Dieguez C Bernier M de Cabo R March 2016 Metformin A Hopeful Promise in Aging Research Cold Spring Harbor Perspectives in Medicine 6 3 a025932 doi 10 1101 cshperspect a025932 PMC 4772077 PMID 26931809 Kulkarni AS Gubbi S Barzilai N July 2020 Benefits of Metformin in Attenuating the Hallmarks of Aging Cell Metabolism 32 1 15 30 doi 10 1016 j cmet 2020 04 001 PMC 7347426 PMID 32333835 Campbell JM Stephenson MD de Courten B Chapman I Bellman SM Aromataris E 2018 Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes A Systematic Review and Meta Analysis Journal of Alzheimer s Disease 65 4 1225 1236 doi 10 3233 jad 180263 PMC 6218120 PMID 30149446 Campbell JM Stephenson MD de Courten B Chapman I Bellman SM Aromataris E August 2017 Metformin and Alzheimer s disease dementia and cognitive impairment a systematic review protocol JBI Database of Systematic Reviews and Implementation Reports 15 8 2055 2059 doi 10 11124 JBISRIR 2017 003380 PMID 28800055 a b c Metformin medicine to treat type 2 diabetes National Health Service 25 February 2019 Archived from the original on 11 March 2021 Retrieved 15 October 2020 a b c d METFORMIN HYDROCHLORIDE NICE Archived from the original on 10 June 2021 Retrieved 15 October 2020 Khurana R Malik IS January 2010 Metformin safety in cardiac patients Heart 96 2 99 102 doi 10 1136 hrt 2009 173773 PMID 19564648 S2CID 9746741 Heaf J June 2014 Metformin in chronic kidney disease time for a rethink Peritoneal Dialysis International 34 4 353 7 doi 10 3747 pdi 2013 00344 PMC 4079480 PMID 24711640 a b Fujita Y Inagaki N January 2017 Metformin New Preparations and Nonglycemic Benefits Current Diabetes Reports 17 1 5 doi 10 1007 s11892 017 0829 8 PMID 28116648 S2CID 9277684 Wulffele MG Kooy A Lehert P Bets D Ogterop JC Borger van der Burg B et al November 2003 Effects of short term treatment with metformin on serum concentrations of homocysteine folate and vitamin B12 in type 2 diabetes mellitus a randomized placebo controlled trial Journal of Internal Medicine 254 5 455 63 doi 10 1046 j 1365 2796 2003 01213 x PMID 14535967 S2CID 12507226 Andres E Noel E Goichot B October 2002 Metformin associated vitamin B12 deficiency Archives of Internal Medicine 162 19 2251 2 PMID 12390080 Gilligan MA February 2002 Metformin and vitamin B12 deficiency Archives of Internal Medicine 162 4 484 5 PMID 11863489 de Jager J Kooy A Lehert P Wulffele MG van der Kolk J Bets D et al May 2010 Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B 12 deficiency randomised placebo controlled trial BMJ 340 c2181 doi 10 1136 bmj c2181 PMC 2874129 PMID 20488910 Ting RZ Szeto CC Chan MH Ma KK Chow KM October 2006 Risk factors of vitamin B 12 deficiency in patients receiving metformin Archives of Internal Medicine 166 18 1975 9 doi 10 1001 archinte 166 18 1975 PMID 17030830 Nathan DM Buse JB Davidson MB Ferrannini E Holman RR Sherwin R et al January 2009 Medical management of hyperglycaemia in type 2 diabetes mellitus a consensus algorithm for the initiation and adjustment of therapy a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes Diabetologia 52 1 17 30 doi 10 1007 s00125 008 1157 y PMID 18941734 Stang M Wysowski DK Butler Jones D June 1999 Incidence of lactic acidosis in metformin users Diabetes Care 22 6 925 7 doi 10 2337 diacare 22 6 925 PMID 10372243 Salpeter SR Greyber E Pasternak GA Salpeter EE November 2003 Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus systematic review and meta analysis Archives of Internal Medicine 163 21 2594 602 doi 10 1001 archinte 163 21 2594 PMID 14638559 Inzucchi SE Lipska KJ Mayo H Bailey CJ McGuire DK 2014 Metformin in patients with type 2 diabetes and kidney disease a systematic review JAMA 312 24 2668 75 doi 10 1001 jama 2014 15298 PMC 4427053 PMID 25536258 FDA Drug Safety Communication FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function U S Food and Drug Administration FDA 14 November 2017 Archived from the original on 25 May 2021 Retrieved 21 December 2018 a b Shu 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 amp Wilkins pp 540 41 ISBN 978 0 7817 4678 6 a b Kirpichnikov D McFarlane SI Sowers JR July 2002 Metformin an update Annals of Internal Medicine 137 1 25 33 doi 10 7326 0003 4819 137 1 200207020 00009 PMID 12093242 S2CID 9140541 Davis SN 2006 Chapter 60 Insulin Oral Hypoglycemic Agents and the Pharmacology of the Endocrine Pancreas In Brunton L Lazo J Parker K eds Goodman amp Gilman s The Pharmacological Basis of Therapeutics 11th ed New York McGraw Hill ISBN 978 0 07 142280 2 Forrester MB July 2008 Adult metformin ingestions reported to Texas poison control centers 2000 2006 Human amp Experimental Toxicology 27 7 575 83 Bibcode 2008HETox 27 575F CiteSeerX 10 1 1 1031 9486 doi 10 1177 0960327108090589 PMID 18829734 S2CID 5413561 Suchard JR Grotsky TA August 2008 Fatal metformin overdose presenting with progressive hyperglycemia The Western Journal of Emergency Medicine 9 3 160 4 PMC 2672258 PMID 19561734 a b Calello 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 PMID 25860205 S2CID 13861731 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 PMID 19783231 R Baselt Disposition of Toxic Drugs and Chemicals in Man 8th edition Biomedical Publications Foster City CA 2008 pp 939 940 Teale KF Devine A Stewart H Harper NJ July 1998 The management of metformin overdose Anaesthesia 53 7 698 701 doi 10 1046 j 1365 2044 1998 436 az0549 x PMID 9771180 S2CID 45218798 Somogyi A Stockley C Keal J Rolan P Bochner F May 1987 Reduction of metformin renal tubular secretion by cimetidine in man British Journal of Clinical Pharmacology 23 5 545 51 doi 10 1111 j 1365 2125 1987 tb03090 x PMC 1386190 PMID 3593625 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 PMID 12222753 S2CID 26919498 May M Schindler C April 2016 Clinically and pharmacologically relevant interactions of antidiabetic drugs Therapeutic Advances in Endocrinology and Metabolism 7 2 69 83 doi 10 1177 2042018816638050 PMC 4821002 PMID 27092232 Rena G Pearson ER Sakamoto K September 2013 Molecular mechanism of action of metformin old or new insights Diabetologia 56 9 1898 906 doi 10 1007 s00125 013 2991 0 PMC 3737434 PMID 23835523 a b Burcelin R May 2014 The antidiabetic gutsy role of metformin uncovered Gut 63 5 706 7 doi 10 1136 gutjnl 2013 305370 PMID 23840042 S2CID 42142919 Madiraju AK Erion DM Rahimi Y Zhang XM Braddock DT Albright RA et al June 2014 Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase Nature 510 7506 542 6 Bibcode 2014Natur 510 542M doi 10 1038 nature13270 PMC 4074244 PMID 24847880 Vazquez Borrego MC Fuentes Fayos AC Gahete MD Castano JP Kineman RD Luque RM 2018 The Pituitary Gland is a Novel Major Site of Action of Metformin in Non Human Primates a Potential Path to Expand and Integrate Its Metabolic Actions Cellular Physiology and Biochemistry 49 4 1444 1459 doi 10 1159 000493448 PMID 30205369 Hundal RS Krssak M Dufour S Laurent D Lebon V Chandramouli V et al December 2000 Mechanism by which metformin reduces glucose production in type 2 diabetes Diabetes 49 12 2063 9 doi 10 2337 diabetes 49 12 2063 PMC 2995498 PMID 11118008 Zhou G Myers R Li Y Chen Y Shen X Fenyk Melody J et al October 2001 Role of AMP activated protein kinase in mechanism of metformin action The Journal of Clinical Investigation 108 8 1167 74 doi 10 1172 JCI13505 PMC 209533 PMID 11602624 Towler MC Hardie DG February 2007 AMP activated protein kinase in metabolic control and insulin signaling Circulation Research 100 3 328 41 doi 10 1161 01 RES 0000256090 42690 05 PMID 17307971 Kim YD Park KG Lee YS Park YY Kim DK Nedumaran B et al February 2008 Metformin inhibits hepatic gluconeogenesis through AMP activated protein kinase dependent regulation of the orphan nuclear receptor SHP Diabetes 57 2 306 14 doi 10 2337 db07 0381 PMID 17909097 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 PMID 17369473 Ma T Tian X Zhang B Li M Wang Y Yang C et al March 2022 Low dose metformin targets the lysosomal AMPK pathway through PEN2 Nature 603 7899 159 165 Bibcode 2022Natur 603 159M doi 10 1038 s41586 022 04431 8 PMC 8891018 PMID 35197629 Miller RA Chu Q Xie J Foretz M Viollet B Birnbaum MJ February 2013 Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP Nature 494 7436 256 60 Bibcode 2013Natur 494 256M doi 10 1038 nature11808 PMC 3573218 PMID 23292513 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 PMID 16478780 Bailey CJ Turner RC February 1996 Metformin The New England Journal of Medicine 334 9 574 9 doi 10 1056 NEJM199602293340906 PMID 8569826 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 PMID 3745404 Musi N Hirshman MF Nygren J Svanfeldt M Bavenholm P Rooyackers O et al July 2002 Metformin increases AMP activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes Diabetes 51 7 2074 2081 doi 10 2337 diabetes 51 7 2074 PMID 12086935 Hardie DG Ross FA Hawley SA March 2012 AMPK a nutrient and energy sensor that maintains energy homeostasis Nature Reviews Molecular Cell Biology 13 4 251 262 doi 10 1038 nrm3311 PMC 5726489 PMID 22436748 a b LaMoia TE Shulman GI January 2021 Cellular and Molecular Mechanisms of Metformin Action Endocrine Reviews 42 1 77 96 doi 10 1210 endrev bnaa023 PMC 7846086 PMID 32897388 a b Nikolakis 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 PMID 31073704 S2CID 149443722 Luque Ramirez M Nattero Chavez L Ortiz Flores AE Escobar Morreale HF March 2018 Combined oral contraceptives and or antiandrogens versus insulin sensitizers for polycystic ovary syndrome a systematic review and meta analysis Human Reproduction Update 24 2 225 241 doi 10 1093 humupd dmx039 PMID 29293982 Weersma RK Zhernakova A Fu J August 2020 Interaction between drugs and the gut microbiome Gut 69 8 1510 1519 doi 10 1136 gutjnl 2019 320204 PMC 7398478 PMID 32409589 MacNeil LT Schertzer JD Steinberg GR January 2020 Bacteria transmit metformin associated lifespan extension Nature Reviews Endocrinology 16 1 9 10 doi 10 1038 s41574 019 0278 3 PMID 31645681 S2CID 204836737 Jones GR Molloy MP June 2020 Metformin Microbiome and Protection Against Colorectal Cancer Digestive Diseases and Sciences 66 5 1409 1414 doi 10 1007 s10620 020 06390 4 PMID 32533543 S2CID 219607625 Guerrieri D Moon HY van Praag H March 2017 Exercise in a Pill The Latest on Exercise Mimetics Brain Plasticity 2 2 153 169 doi 10 3233 BPL 160043 PMC 5928571 PMID 29765854 Boule NG Robert C Bell GJ Johnson ST Bell RC Lewanczuk RZ et al July 2011 Metformin and exercise in type 2 diabetes examining treatment modality interactions Diabetes Care 34 7 1469 1474 doi 10 2337 dc10 2207 PMC 3120188 PMID 21602430 a b Heller JB 2007 Metformin overdose in dogs and cats PDF Veterinary Medicine April 231 33 Archived from the original PDF on 23 October 2007 Rosilio C Ben Sahra I Bost F Peyron JF May 2014 Metformin a metabolic disruptor and anti diabetic drug to target human leukemia Cancer Letters 346 2 188 96 doi 10 1016 j canlet 2014 01 006 PMID 24462823 a b Pryor R Cabreiro F November 2015 Repurposing metformin an old drug with new tricks in its binding pockets The Biochemical Journal 471 3 307 22 doi 10 1042 bj20150497 PMC 4613459 PMID 26475449 Graham GG Punt J Arora M Day RO Doogue MP Duong JK et al February 2011 Clinical pharmacokinetics of metformin Clinical Pharmacokinetics 50 2 81 98 doi 10 2165 11534750 000000000 00000 PMID 21241070 S2CID 1440441 a b Robert F Fendri S Hary L Lacroix C Andrejak M Lalau JD June 2003 Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects Diabetes amp Metabolism 29 3 279 83 doi 10 1016 s1262 3636 07 70037 x PMID 12909816 Tilley J Grimsby J Erickson S Berthel S 2010 Diabetes Drugs Present and Emerging Burger s Medicinal Chemistry and Drug Discovery pp 1 38 doi 10 1002 0471266949 bmc198 ISBN 978 0471266945 a b Werner E Bell J 1922 The preparation of methylguanidine and of bb dimethylguanidine by the interaction of dicyandiamide and methylammonium and dimethylammonium chlorides respectively J Chem Soc Trans 121 1790 95 doi 10 1039 CT9222101790 Archived from the original on 8 June 2021 Retrieved 4 September 2020 Shapiro SL Parrino VA Freedman L 1959 Hypoglycemic Agents I Chemical Properties of b Phenethylbiguanide A New Hypoglycemic Agent J Am Chem Soc 81 9 2220 25 doi 10 1021 ja01518a052 Procede de preparation de chlorhydrate de dimethylbiguanide Patent FR 2322860 in French 1975 Pharmaceutical Manufacturing Encyclopedia Sittig s Pharmaceutical Manufacturing Encyclopedia Vol 3 3rd ed Norwich NY William Andrew 2007 p 2208 ISBN 978 0 8155 1526 5 Lam TG Jeong YS Kim SA Ahn SG March 2018 New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin like growth factor AKT mammalian target of rapamycin pathways Cancer Science 109 3 699 709 doi 10 1111 cas 13482 PMC 5834796 PMID 29285837 Tsogbadrakh B Ju KD Lee J Han M Koh J Yu Y et al 2018 HL156A a novel pharmacological agent with potent adenosine monophosphate activated protein kinase AMPK activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model PLOS ONE 13 8 e0201692 Bibcode 2018PLoSO 1301692T doi 10 1371 journal pone 0201692 PMC 6116936 PMID 30161162 Jeong YS Lam TG Jeong S Ahn SG August 2020 Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6 ERK1 2 Signaling in Multidrug Resistant Human Cancer Cells Pharmaceuticals 13 9 218 doi 10 3390 ph13090218 PMC 7560051 PMID 32872293 Kim SA Lam TG Yook JI Ahn SG September 2018 Antioxidant modifications induced by the new metformin derivative HL156A regulate metabolic reprogramming in SAMP1 kl mice Aging 10 9 2338 2355 doi 10 18632 aging 101549 PMC 6188477 PMID 30222592 Choi J Lee JH Koh I Shim JK Park J Jeon JY et al October 2016 Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide HL156A Oncotarget 7 40 65643 65659 doi 10 18632 oncotarget 11595 PMC 5323181 PMID 27582539 Ju KD Kim HJ Tsogbadrakh B Lee J Ryu H Cho EJ et al March 2016 HL156A a novel AMP activated protein kinase activator is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis American Journal of Physiology Renal Physiology 310 5 F342 50 doi 10 1152 ajprenal 00204 2015 PMID 26661649 a b Witters LA October 2001 The blooming of the French lilac The Journal of Clinical Investigation 108 8 1105 7 doi 10 1172 JCI14178 PMC 209536 PMID 11602616 See Chemical Abstracts v 23 42772 1929 Slotta KH Tschesche R 1929 Uber 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 a b Campbell 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 amp Vascular Disease 7 5 247 52 doi 10 1177 14746514070070051001 Dawes GS Mott JC March 1950 Circulatory and respiratory reflexes caused by aromatic guanidines British Journal of Pharmacology and Chemotherapy 5 1 65 76 doi 10 1111 j 1476 5381 1950 tb00578 x PMC 1509951 PMID 15405470 About Eusebio Y Garcia see Carteciano J 2005 Search for DOST NRCP Dr Eusebio Y Garcia Award Philippines Department of Science and Technology Archived from the original on 24 October 2009 Retrieved 5 December 2009 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 PMID 14779282 About Janusz Supniewski see Wolkow PP Korbut R April 2006 Pharmacology at the Jagiellonian University in Kracow short review of contribution to global science and cardiovascular research through 400 years of history PDF Journal of Physiology and Pharmacology 57 Suppl 1 119 136 PMID 16766803 Archived from the original PDF on 24 October 2009 Retrieved 22 December 2009 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 PMID 13269290 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 Academie Polonaise des Sciences Classe 3 Mathematique Astronomie Physique Chimie Geologie et Geographie in French 2 Classe II 161 65 a b c Bailey CJ Day C 2004 Metformin its botanical background Practical Diabetes International 21 3 115 17 doi 10 1002 pdi 606 S2CID 208203689 Archived from the original on 17 December 2012 Hadden DR October 2005 Goat s rue French lilac Italian fitch Spanish sainfoin gallega officinalis and metformin the Edinburgh connection PDF The Journal of the Royal College of Physicians of Edinburgh 35 3 258 60 PMID 16402501 Archived PDF from the original on 25 October 2020 Retrieved 21 December 2009 FDA Approves New Diabetes Drug Press release U S Food and Drug Administration FDA 30 December 1994 Archived from the original on 29 September 2007 Retrieved 6 January 2007 Drug Approval Package Glucophage metformin PDF U S Food and Drug Administration FDA Archived PDF from the original on 5 February 2020 Retrieved 8 January 2007 Posselt M Jaeger A Schaper JL Radke M Benskin JP December 2018 Determination of polar organic micropollutants in surface and pore water by high resolution sampling direct injection ultra high performance liquid chromatography tandem mass spectrometry Environmental Science Processes amp Impacts 20 12 1716 1727 doi 10 1039 C8EM00390D PMID 30350841 a b Christofides EA July 2019 Practical Insights Into Improving Adherence to Metformin Therapy in Patients With Type 2 Diabetes Clinical Diabetes 37 3 234 241 doi 10 2337 cd18 0063 PMC 6640881 PMID 31371854 a b Kaushik D Karnes RJ Eisenberg MS Rangel LJ Carlson RE Bergstralh EJ January 2014 Effect of metformin on prostate cancer outcomes after radical prostatectomy Urologic Oncology 32 1 43 e1 7 doi 10 1016 j urolonc 2013 05 005 PMC 4006350 PMID 23810664 Metformin use at time of RP was extracted from the Mayo Clinic electronic medical record EMR by searching in the 3 months prior to the RP for the terms metformin Glucophage Glumetza Riomet Fortamet Obimet Gluformin Dianben Diabex Diaformin or Metsol a b c Metformin Drugs com Archived from the original on 28 November 2020 Retrieved 17 July 2020 Bailey CJ Day C June 2009 Fixed dose single tablet antidiabetic combinations Diabetes Obesity amp Metabolism 11 6 527 33 doi 10 1111 j 1463 1326 2008 00993 x PMID 19175373 S2CID 6569131 Sheehan MT July 2003 Current therapeutic options in type 2 diabetes mellitus a practical approach Clinical Medicine amp Research 1 3 189 200 doi 10 3121 cmr 1 3 189 PMC 1069045 PMID 15931309 FDA Approves GlaxoSmithKline s Avandamet rosiglitazone maleate and metformin HCl The Latest Advancement in the Treatment of Type 2 Diabetes Press release GlaxoSmithKline 12 October 2002 Archived from the original on 21 January 2007 Retrieved 27 December 2006 Drugs FDA FDA Approved Drugs U S Food and Drug Administration FDA Archived from the original on 21 March 2021 Retrieved 21 July 2020 2009 Top 200 branded drugs by total prescriptions PDF Archived from the original PDF on 14 July 2011 96 5 KB Drug Topics 17 June 2010 Retrieved 2 September 2010 Questions and Answers about the Seizure of Paxil CR and Avandamet Press release U S Food and Drug Administration FDA 4 March 2005 Archived from the original on 14 October 2007 Retrieved 27 December 2006 Teva Pharm announces settlement of generic Avandia Avandamet and Avandaryl litigation with GlaxoSmithKline Press release Reuters 27 September 2007 Archived from the original on 3 May 2021 Retrieved 17 February 2009 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 PMID 17517853 European Medicines Agency recommends suspension of Avandia Avandamet and Avaglim European Medicines Agency EMA 23 September 2010 Archived from the original on 24 September 2015 Call to suspend diabetes drug BBC News Online 23 September 2010 Archived from the original on 24 September 2010 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 17 September 2013 Diabetes drug withdrawn Stuff co nz NZPA 17 February 2011 Archived from the original on 13 October 2013 Retrieved 5 November 2011 Harris G 19 February 2010 Controversial Diabetes Drug Harms Heart U S Concludes The New York Times Archived from the original on 19 March 2017 Updated Risk Evaluation and Mitigation Strategy REMS U S Food and Drug Administration FDA 1 July 2021 Retrieved 6 March 2023 FDA Drug Safety Communication FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone containing diabetes medicines U S Food and Drug Administration FDA 21 June 2019 Archived from the original on 4 September 2022 Retrieved 6 March 2023 Glaxo s Avandia Cleared From Sales Restrictions by FDA Bloomberg Archived from the original on 9 November 2014 FDA requires removal of certain restrictions on the diabetes drug Avandia U S Food and Drug Administration FDA Press release 25 November 2013 Archived from the original on 4 May 2015 US agency reverses stance on controversial diabetes drug Archived from the original on 11 December 2015 Glubrava EPAR European Medicines Agency EMA 17 September 2018 Archived from the original on 9 June 2021 Retrieved 31 March 2020 Competact EPAR European Medicines Agency EMA 17 September 2018 Archived from the original on 9 June 2021 Retrieved 31 March 2020 Pioglitazone marketed as Actos Actoplus Met Duetact and Oseni Information U S Food and Drug Administration FDA 11 January 2017 Archived from the original on 17 January 2021 Retrieved 31 March 2020 FDA Drug Safety Communication FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function U S Food and Drug Administration FDA 3 April 2013 Archived from the original on 25 May 2021 Retrieved 31 March 2020 FDA Drug Safety Communication Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer U S Food and Drug Administration FDA 4 August 2011 Archived from the original on 26 January 2021 Retrieved 31 March 2020 Janumet sitagliptin and metformin hydrochloride tablet film coated DailyMed 12 August 2019 Archived from the original on 9 June 2021 Retrieved 15 May 2020 Janumet EPAR European Medicines Agency EMA 17 September 2018 Archived from the original on 9 June 2021 Retrieved 15 May 2020 Kombiglyze XR saxagliptin and metformin hydrochloride tablet film coated extended release DailyMed 24 October 2019 Archived from the original on 25 September 2020 Retrieved 15 May 2020 Komboglyze EPAR European Medicines Agency EMA 17 September 2018 Archived from the original on 30 October 2020 Retrieved 15 May 2020 Kazano alogliptin and metformin hydrochloride tablet film coated DailyMed 14 June 2019 Archived from the original on 9 June 2021 Retrieved 15 May 2020 Vipdomet EPAR European Medicines Agency EMA 17 September 2018 Archived from the original on 9 June 2021 Retrieved 15 May 2020 Jentadueto EPAR European Medicines Agency EMA 17 September 2018 Archived from the original on 9 June 2021 Retrieved 31 March 2020 Jentadueto linagliptin and metformin hydrochloride tablet film coated DailyMed 18 July 2019 Archived from the original on 9 June 2021 Retrieved 31 March 2020 Jentadueto XR linagliptin and metformin hydrochloride tablet film coated extended release DailyMed Archived from the original on 5 October 2021 Retrieved 4 October 2021 Linagliptin and Metformin Hydrochloride FDA Approved Drugs U S Food and Drug Administration FDA Archived from the original on 25 September 2021 Retrieved 24 September 2021 a b Grant JS Graven LJ September 2016 Progressing From Metformin to Sulfonylureas or Meglitinides Workplace Health amp Safety 64 9 433 9 doi 10 1177 2165079916644263 PMID 27621259 a b Madsen KS Kahler P Kahler LK Madsbad S Gnesin F Metzendorf MI et al Cochrane Metabolic and Endocrine Disorders Group April 2019 Metformin and second or third generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus The Cochrane Database of Systematic Reviews 4 4 CD012368 doi 10 1002 14651858 CD012368 pub2 PMC 6472662 PMID 30998259 The Use of Medicines in the United States Review of 2010 PDF Archived PDF from the original on 22 April 2011 1 79 MB IMS Institute for Healthcare Informatics April 2011 Retrieved 28 April 2011 Drug Approval Package PrandiMet repaglinide metformin HCI fixed dose combination NDA 22386 U S Food and Drug Administration FDA Archived from the original on 21 July 2020 Retrieved 21 July 2020 Drugs FDA FDA Approved Drugs U S Food and Drug Administration FDA Archived from the original on 22 July 2020 Retrieved 21 July 2020 Drugs FDA FDA Approved Drugs U S Food and Drug Administration FDA Archived from the original on 22 March 2021 Retrieved 21 July 2020 Qternmet XR dapagliflozin saxagliptin and metformin hydrochloride extended release tablets for oral use Initial U S Approval 2019 DailyMed Archived from the original on 6 March 2023 Retrieved 5 March 2023 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 PMID 15260389 Statement from Janet Woodcock M D director of FDA s Center for Drug Evaluation and Research on impurities found in diabetes drugs outside the U S U S Food and Drug Administration FDA 5 December 2019 Archived from the original on 18 January 2021 Retrieved 4 February 2020 nbsp This article incorporates text from this source which is in the public domain Recalls and safety alerts Health Canada evaluating NDMA in metformin drugs 5 December 2019 Archived from the original on 17 April 2020 Retrieved 4 February 2020 Laboratory Tests Metformin U S Food and Drug Administration FDA 3 February 2020 Archived from the original on 25 February 2020 Retrieved 4 February 2020 FDA Updates and Press Announcements on NDMA in Metformin U S Food and Drug Administration FDA 4 February 2020 Archived from the original on 25 February 2020 Retrieved 4 February 2020 APO Metformin 2020 02 04 Health Canada 4 February 2020 Archived from the original on 27 December 2020 Retrieved 2 June 2020 Ranbaxy Metformin Product Recall 2020 02 26 Health Canada 26 February 2020 Archived from the original on 26 November 2020 Retrieved 2 June 2020 Jamp Metformin Product Recall 2020 03 10 Health Canada 10 March 2020 Archived from the original on 26 November 2020 Retrieved 2 June 2020 FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended Release Products Press release U S Food and Drug Administration FDA 28 May 2020 Archived from the original on 22 March 2021 Retrieved 2 June 2020 Questions and Answers NDMA impurities in metformin products U S Food and Drug Administration FDA 28 May 2020 Archived from the original on 2 March 2021 Retrieved 5 June 2020 Amneal Pharmaceuticals LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets USP 500 mg and 750 mg Due to Detection of N Nitrosodimethylamine NDMA Impurity U S Food and Drug Administration FDA 29 May 2020 Archived from the original on 16 January 2021 Retrieved 2 June 2020 Apotex Corp Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets 500mg Due to the Detection of N nitrosodimethylamine NDMA U S Food and Drug Administration FDA 27 May 2020 Archived from the original on 4 March 2021 Retrieved 2 June 2020 Teva Pharmaceuticals USA Inc Initiates Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets USP 500 mg and 750 mg Due to Detection of N Nitrosodimethylamine NDMA U S Food and Drug Administration FDA 2 June 2020 Archived from the original on 21 January 2021 Retrieved 5 June 2020 Marksans Pharma Limited Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets USP 500mg Due to the Detection of N Nitrosodimethylamine NDMA U S Food and Drug Administration FDA 2 June 2020 Archived from the original on 23 January 2021 Retrieved 5 June 2020 Cavazzoni P 28 May 2020 Re Docket No FDA 2020 P 0978 PDF U S Food and Drug Administration FDA Archived PDF from the original on 8 February 2021 Retrieved 2 June 2020 a b c Laboratory Tests Metformin U S Food and Drug Administration FDA 5 June 2020 Archived from the original on 22 April 2021 Retrieved 5 June 2020 nbsp This article incorporates text from this source which is in the public domain Lupin Pharmaceuticals Inc Issues Voluntarily Nationwide Recall of Metformin Hydrochloride Extended Release Tablets 500mg and 1000mg Due to the Detection of N Nitrosodimethylamine NDMA Impurity Press release Lupin Pharmaceuticals Inc Archived from the original on 9 June 2021 Retrieved 9 July 2020 via PR Newswire Bayshore Pharmaceuticals LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets USP 500 mg and 750 mg Due to the Detection of N Nitrosodimethylamine NDMA Impurity U S Food and Drug Administration FDA 19 August 2020 Archived from the original on 19 December 2020 Retrieved 25 August 2020 Jalali M Rahimlou M Mahmoodi M Moosavian SP Symonds ME Jalali R et al September 2020 The effects of metformin administration on liver enzymes and body composition in non diabetic patients with non alcoholic fatty liver disease and or non alcoholic steatohepatitis An up to date systematic review and meta analysis of randomized controlled trials Pharmacological Research 159 104799 doi 10 1016 j phrs 2020 104799 PMID 32278041 S2CID 215741792 Blazina I Selph S November 2019 Diabetes drugs for nonalcoholic fatty liver disease a systematic review Systematic Reviews 8 1 295 doi 10 1186 s13643 019 1200 8 PMC 6884753 PMID 31783920 Leoni S Tovoli F Napoli L Serio I Ferri S Bolondi L August 2018 Current guidelines for the management of non alcoholic fatty liver disease A systematic review with comparative analysis World Journal of Gastroenterology 24 30 3361 3373 doi 10 3748 wjg v24 i30 3361 PMC 6092580 PMID 30122876 Ibanez L Ong K Valls C Marcos MV Dunger DB de Zegher F August 2006 Metformin treatment to prevent early puberty in girls with precocious pubarche The Journal of Clinical Endocrinology and Metabolism 91 8 2888 91 doi 10 1210 jc 2006 0336 PMID 16684823 Ibanez L Lopez Bermejo A Diaz M Marcos MV de Zegher F August 2011 Early metformin therapy age 8 12 years in girls with precocious pubarche to reduce hirsutism androgen excess and oligomenorrhea in adolescence The Journal of Clinical Endocrinology and Metabolism 96 8 E1262 7 doi 10 1210 jc 2011 0555 PMID 21632811 Ibanez L Diaz R Lopez Bermejo A Marcos MV March 2009 Clinical spectrum of premature pubarche links to metabolic syndrome and ovarian hyperandrogenism Reviews in Endocrine amp Metabolic Disorders 10 1 63 76 doi 10 1007 s11154 008 9096 y PMID 18726694 S2CID 9129907 Ben Sahra I Le Marchand Brustel Y Tanti JF Bost F May 2010 Metformin in cancer therapy a new perspective for an old antidiabetic drug Molecular Cancer Therapeutics 9 5 1092 9 doi 10 1158 1535 7163 MCT 09 1186 PMID 20442309 Malek M Aghili R Emami Z Khamseh ME September 2013 Risk of cancer in diabetes the effect of metformin ISRN Endocrinology 2013 636927 doi 10 1155 2013 636927 PMC 3800579 PMID 24224094 a b Campbell 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 PMID 28802803 S2CID 20334490 Soukas AA Hao H Wu L October 2019 Metformin as Anti Aging Therapy Is It for Everyone Trends in Endocrinology and Metabolism 30 10 745 755 doi 10 1016 j tem 2019 07 015 PMC 6779524 PMID 31405774 Gantois I Popic J Khoutorsky A Sonenberg N January 2019 Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders Annual Review of Medicine 70 167 181 doi 10 1146 annurev med 081117 041238 PMID 30365357 S2CID 53093694 Archived from the original on 6 March 2023 Retrieved 9 October 2022 Barzilai N Crandall JP Kritchevsky SB Espeland MA June 2016 Metformin as a Tool to Target Aging Cell Metabolism 23 6 1060 1065 doi 10 1016 j cmet 2016 05 011 PMC 5943638 PMID 27304507 Lee CG Heckman Stoddard B Dabelea D et al Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study Diabetes Care 2021 44 12 2775 2782 doi 10 2337 dc21 1046 Mohammed I Hollenberg MD Ding H Triggle CR 2021 A Critical Review of the Evidence That Metformin Is a Putative Anti Aging Drug That Enhances Healthspan and Extends Lifespan Frontiers in Endocrinology 12 718942 doi 10 3389 fendo 2021 718942 PMC 8374068 PMID 34421827 Further reading editMarkowicz 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 PMID 27908266 McCreight LJ Bailey CJ Pearson ER March 2016 Metformin and the gastrointestinal tract Diabetologia 59 3 426 35 doi 10 1007 s00125 015 3844 9 PMC 4742508 PMID 26780750 Moin T Schmittdiel JA Flory JH Yeh J Karter AJ Kruge LE et al October 2018 Review of Metformin Use for Type 2 Diabetes Prevention American Journal of Preventive Medicine 55 4 565 574 doi 10 1016 j amepre 2018 04 038 PMC 6613947 PMID 30126667 Rena G Hardie DG Pearson ER September 2017 The mechanisms of action of metformin Diabetologia 60 9 1577 1585 doi 10 1007 s00125 017 4342 z PMC 5552828 PMID 28776086 Sanchez Rangel E Inzucchi SE September 2017 Metformin clinical use in type 2 diabetes Diabetologia 60 9 1586 1593 doi 10 1007 s00125 017 4336 x PMID 28770321 Zhou J Massey S Story D Li L September 2018 Metformin An Old Drug with New Applications International Journal of Molecular Sciences 19 10 2863 doi 10 3390 ijms19102863 PMC 6213209 PMID 30241400 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 amp Pharmacotherapy 106 1227 1235 doi 10 1016 j biopha 2018 07 085 PMID 30119191 S2CID 52031602 External links edit nbsp Wikimedia Commons has media related to Metformin Nitrosamine impurities in medications Guidance Health Canada 4 April 2022 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Metformin amp oldid 1214632016, wikipedia, wiki, book, books, library,

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