Metformin

From Wikipedia, the free encyclopedia
Jump to: navigation, search
MetforminC.svg
Metformin3DanJ.gif
Systematic (IUPAC) name
N,N-Dimethylimidodicarbonimidic diamide
Clinical data
Trade names Glucophage, Etform
AHFS/Drugs.com FDA Professional Drug Information
MedlinePlus a696005
Licence data US FDA:link
Pregnancy cat. C (AU) B (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes oral
Pharmacokinetic data
Bioavailability 50–60%[1][2]
Protein binding Minimal[1]
Metabolism Not by liver[1]
Half-life 4-8.7 hours[1]
Excretion Urine (90%)[1]
Identifiers
CAS number 657-24-9 YesY
ATC code A10BA02
PubChem CID 4091
DrugBank DB00331
ChemSpider 3949 YesY
UNII 9100L32L2N YesY
KEGG D04966 YesY
ChEBI CHEBI:6801 YesY
ChEMBL CHEMBL1431 YesY
Chemical data
Formula C4H11N5 
Mol. mass 129.16364

Metformin (BAN, USAN and INN, pronounced /mɛtˈfɔrmɨn/, met-FAWR-min; sold as Glucophage) is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function.[3][4][5] Its use in gestational diabetes has been limited by safety concerns although at least one study has been conducted which showed no concerns for children prenatally exposed to Metformin up to 2 years of age.[6] It is also used in the treatment of polycystic ovary syndrome, and has been investigated for other diseases where insulin resistance may be an important factor.[7] Metformin works by suppressing glucose production from three-carbon molecules (like propionic acid, a by product of dietary fibre fermentation in the large intestine and pyruvate, a by product of glucose breakdown in the muscles) by the liver.[7]

Limited evidence suggests that metformin may prevent the cardiovascular and possibly the cancer complications of diabetes.[7][8][9] It helps reduce LDL cholesterol and triglyceride levels and is not associated with weight gain; in some people it promotes weight loss.[7][8] It is the only antidiabetic possibly associated with reduced risk of cardiovascular complications in those with type II diabetes mellitus. Metformin is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).[10]

Metformin causes few adverse effects when prescribed appropriately (the most common is gastrointestinal upset) and has been associated with a low risk of hypoglycemia.[7] Lactic acidosis (a buildup of lactate in the blood) can be a serious concern in overdose and when it is prescribed to people with contraindications, but otherwise, there is no significant risk.[11]

First synthesized and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to insulin and other antidiabetic drugs. Interest in metformin was rekindled in the late 1940s after several reports that it could reduce blood sugar levels in people, and in 1957, French physician Jean Sterne published the first clinical trial of metformin as a treatment for diabetes. It was introduced to the United Kingdom in 1958, Canada in 1972, and the United States in 1995. Metformin is now believed to be the most widely prescribed antidiabetic drug in the world; in the United States alone, more than 48 million prescriptions were filled in 2010 for its generic formulations.[12][13]

Medical uses[edit]

Metformin is primarily used for type 2 diabetes, but is increasingly being used in polycystic ovary syndrome (PCOS),[14] and in prediabetes.[15]

Type 2 diabetes[edit]

The American Diabetes Association recommends metformin as a first-line agent to treat type 2 diabetes mellitus.[16][17]

Efficacy[edit]

A large cardiovascular outcome trial performed in the late 1980's and early 1990's provided data suggesting that metformin reduces the rate of adverse cardiovascular outcomes in diabetes relative to other anti-hyperglycemic agents. The accumulation of data from other trials has reduced confidence in this conclusion. 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 now describe evidence for the cardiovascular benefits of metformin as equivocal.[18][19] According to the American College of Physicians there is low quality evidence that metformin monotherapy is associated with lower cardiovascular mortality than sulfonylurea monotherapy and there is low quality evidence that metformin monotherapy is associated with fewer cardiovascular events than metformin-sulfonylurea combination therapy. Evidence for other comparisons is described as unclear.[20]

In the UK Prospective Diabetes Study (UKPDS),over 10 years metformin monotherapy reduced diabetes related endpoints and overall mortality in overweight diabetics by about 30% when compared with insulin and sulfonylureas (glibenclamide and chlorpropamide). When compared with the group only given dietary advice, metformin had risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death, and 36% for all-cause mortality. (UKPDS study)[21] This difference held in people who were followed up for five to 10 years after the study.[22] In the UKPDS study metformin was the only drug associated with decreased mortality.[23] Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight people with diabetes, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in this group. In addition, metformin had no effect on body weight: Over the 10-year treatment period, the metformin group gained about 1 kg, the same as the dietary advice group, while the sulfonylureas group gained 3 kg, and the insulin group, 6 kg.[21][24]

In contrast, a 2011 meta analyses found no benefit but also no harm on cardiovascular events in 35 trials. There was an effect on cardiovascular events against placebo, but not against comparator treatments. It found a possibly (nearly significant) survival benefit in mono therapy with metformin against comparators. Survival was reduced when metformin was combined with sulfonylurea. Additional analyses found the drug appeared to be more beneficial in longer trials enrolling younger patients.[25] Another 2012 meta analysis confirmed that if al trials against placebo or no treatment or other anti-diabetics (13 trials) were combined there was no effect on al cause and cardiovascular survival. This meta analysis included treatment arms in which metformin plus a sulfonylurea was compared to treatment with a sulfonylurea alone.[26]


Advantages[edit]

Metformin may be associated with a decreased risk of cardiovascular mortality compared with other oral diabetes agents or placebo.[24] All-cause mortality was slightly lower with metformin than with a sulfonylurea in observational studies, but results differed between trials and observational studies. Risk for bias in the studies was moderate. Cardiovascular mortality was slightly lower with metformin than with a sulfonylurea, but results were imprecise and had moderate risk for bias.(Low strength of evidence). Observational studies were associated with a lower risk for all-cause mortality and cardiovascular disease mortality and morbidity than were sulfonylureas. [16]

Metformin has a lower risk of hypoglycemia than the sulfonylureas,[27][28] although it has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose.[29][30]

Metformin is not associated with weight gain, rather weight loss.[27][28] In comparison with thiazolidinediones or sulfonylureas, the mean differences in body weight were about −2.5 kg.[31]

Metformin modestly reduces LDL and triglyceride levels.[27] Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors.[16]

Metformin is similarly efficacious as most diabetes medications when used as mono therapy and decreased HbA1c levels by 1 absolute percentage point on average over the course of a study. Metformin reduced HbA1c levels more than the DPP-4 inhibitors as mono therapy. Combination therapy (including the combination of metformin and a DPP-4 inhibitor) decreased HbA1c levels more than monotherapy did, by about 1 absolute percentage point.[16]

Metformin is not expensive.[32]

Prediabetes[edit]

Metformin treatment of people at risk for type 2 diabetes may decrease their chances of developing the disease, although intensive physical exercise and dieting work significantly better for this purpose. In a large U.S. study known as the Diabetes Prevention Program, participants were divided into groups and given either placebo, metformin, or lifestyle intervention, and followed for an average of three years. The intensive program of lifestyle modifications included a 16-lesson training on dieting and exercise followed by monthly individualized sessions with the goals to decrease the body weight by 7% and engage in a physical activity for at least 150 minutes per week. The incidence of diabetes was 58% lower in the lifestyle group and 31% lower in those given metformin. Among younger people with a higher body mass index, lifestyle modification was no more effective than metformin, and for older individuals with a lower body mass index, metformin was no better than placebo in preventing diabetes.[33] After ten years, the incidence of diabetes was 34% lower in the group of participants given diet and exercise and 18% lower in those given metformin.[34] It is unclear whether metformin slowed down the progression of prediabetes to diabetes (true preventive effect), or the decrease of diabetes in the treated population was simply due to its glucose-lowering action (treatment effect).[35]

A systematic review analysed children and adolescents with clinical insulin resistance or pre-diabetes. Four randomized controlled trials were identified. All compared the effect of 6 months of metformin plus or minus lifestyle intervention with placebo plus or minus lifestyle intervention. It was found that metformin improves markers of insulin sensitivity and reduces BMI.[15]

Polycystic ovary syndrome[edit]

Antidiabetic therapy has been proposed as a treatment for polycystic ovary syndrome (PCOS), a condition frequently associated with insulin resistance, since the late 1980s.[36] The use of metformin in PCOS was first reported in 1994, in a small study conducted at the University of the Andes, Venezuela.[37][38] 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 have failed to produce results.[39] However, two clinical studies completed in 2006–2007 returned mostly negative results, with metformin being no better than placebo, and a metformin-clomifene combination no better than clomifene alone.[40][41] Reflecting this, subsequent reviews noted large randomized controlled trials have, in general, not shown the promise suggested by the early small studies. UK and international clinical practice guidelines do not recommend metformin as a first-line treatment[42] or do not recommend it at all, except for women with glucose intolerance.[43] The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from the drug treatment.

In a dissenting opinion, a systematic review of four head-to-head comparative trials of metformin and clomifene found them equally effective for infertility.[44] A BMJ editorial noted four positive studies of metformin were in people not responding to clomifene, while the population in the negative studies was drug-naive or uncontrolled for the previous treatment. The editorial suggested metformin should be used as a second-line drug if clomifene treatment fails.[45] Another review recommended metformin unreservedly as a first-line treatment option because it has positive effects not only on anovulation, but also on insulin resistance, hirsutism, and obesity often associated with PCOS.[46] An updated Cochrane Collaboration review found metformin was associated with improved clinical pregnancy but there was no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.[47] However, in a recent multicenter, randomized, double-blind, placebo-controlled study, metformin increased live-birth rates compared to placebo with the most beneficial effect seen in obese women. These results are consistent with another study that evaluated pretreatment with metformin for 3 months before in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Although the role of metformin for ovulation induction in PCOS has been limited, these results suggest that metformin may play an important role in improving live birth rates when administered 3 months prior to and concurrent with standard infertility treatments.[48]

The use of metformin throughout pregnancy in women with polycystic ovary syndrome reduces the rates of early pregnancy loss and preterm labor and protects against fetal growth restriction.[49]

Contraindications[edit]

Metformin is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders (creatinine levels over 150 μmol/l (1.7 mg/dL),[50] although this is an arbitrary limit), lung disease and liver disease. According to the prescribing information, heart failure (in particular, unstable or acute congestive heart failure) increases the risk of lactic acidosis with metformin.[51] A 2007 systematic review of controlled trials, however, suggested metformin is the only antidiabetic drug not associated with any measurable harm in people with heart failure, and that it may reduce mortality in comparison with other antidiabetic agents.[52]

Metformin is recommended to be temporarily discontinued before any radiographic study involving iodinated contrast agents, (such as a contrast-enhanced CT scan or angiogram), as the contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body.[53][54] Metformin can be resumed after two days, assuming kidney function is normal.[53][54]

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 side effects than most other antidiabetic drugs.[28] The most serious potential side effect of metformin use is lactic acidosis; this complication is very rare, and the vast majority of these cases seem to be related to comorbid conditions, such as impaired liver or kidney function, rather than to the metformin itself.[55]

Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism,[56] The clinical significance of this is still unknown.

Gastrointestinal[edit]

In a clinical trial of 286 subjects, 53.2% of the 141 given immediate-release metformin reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.[57]

Metformin was associated with a 4,27 significantly higher incidence of gastrointestinal disturbances than placebo in 5 trials in women with poly cystic ovary syndrome.[47]

Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common.[citation needed]

Vitamin B12 deficiency[edit]

Long-term use of metformin has been associated with increased homocysteine levels[58] and malabsorption of vitamin B12.[59][60] Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency,[61] and some researchers recommend screening or prevention strategies.[62]

Lactic acidosis[edit]

The most serious potential adverse effect of biguanide use is lactic acidosis ("metformin-associated lactic acidosis" or MALA), the incidence for which is 9 per 100,000 person-years.[63] Phenformin, another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis (rate of 40-64 per 100,000 patient-years).[63] However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication as long as it is not prescribed to known high-risk groups, as in advanced renal insufficiency and alcoholism.[64]

Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. In healthy individuals, this slight excess is simply cleared by other mechanisms (including uptake by the kidneys, when their function is unimpaired), and no significant elevation in blood levels of lactate occurs.[27] When there is impaired renal function, however, clearance of metformin and lactate is reduced, leading to increased levels of both, and possibly causing lactic acidosis due to a buildup of lactic acid. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication to its use. Common causes of increased lactic acid production include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate oxygenation of tissues); the most common cause of impaired lactic acid excretion is kidney disease.[65]

Metformin has also been suggested to increase production of lactate in the small intestine; this could potentially contribute to lactic acidosis in those with risk factors.[66] However, the clinical significance of this is unknown, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.[27][65][67]

Overdose[edit]

A review of intentional and accidental metformin overdoses reported to poison control centers over a five-year period found serious adverse events were rare, though the elderly appeared to be at greater risk.[68] A similar study where cases were reported to Texas poison control centers between the years 2000 and 2006 found ingested doses of more than 5,000 mg were more likely to involve serious medical outcomes in adults.[69] Survival following intentional overdoses with up to 63,000 mg (63 g) of metformin have been reported in the medical literature.[70] Fatalities following overdose are rare, but do occur.[71][72][73] In healthy children, unintentional doses of less than 1,700 mg are unlikely to cause any significant toxic effects.[74]

The most common symptoms following overdose appear to include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and, rarely, hypoglycemia or hyperglycemia.[69][72] The major potentially life-threatening complication of metformin overdose is lactic acidosis, which is due to lactate accumulation.[75][76] Treatment of metformin overdose is generally supportive, as there is no specific antidote. Lactic acidosis is initially treated with sodium bicarbonate, although high doses are not recommended, as this may increase intracellular acidosis.[73] Acidosis that does not respond to administration of sodium bicarbonate may require further management with standard hemodialysis or continuous veno-venous hemofiltration. In addition, due to metformin’s low molecular weight and lack of plasma protein binding, these techniques also have the benefit of efficiently removing metformin from blood plasma, preventing further lactate overproduction.[77][78][79]

Metformin may be quantitated in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving the drug therapeutically, 40–120 mg/L in victims of acute overdosage, and 80–200 mg/L in fatalities. Chromatographic techniques are commonly employed.[80][81]

Interactions[edit]

The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys;[82] 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.[83] A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism;[84] theoretically, other cationic medications may produce the same effect.[83]

Mechanism of action[edit]

Metformin decreases glucose production in the liver, increases insulin sensitivity and enhances peripheral glucose uptake. It does not stimulate secretion of endogenous insulin.

Metformin decreases hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis).[66] The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.[85] The molecular mechanism of metformin is incompletely understood: 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) and consequent activation of protein kinase A (PKA), and an effect on gut microbiota have been proposed as potential mechanisms.[86][87] A study in 2001 suggested that activation of AMPK, an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats,[88] was required for metformin's inhibitory effect on the production of glucose by liver cells.[89] Research published in 2008 further showed that activation of AMPK was required for an increase in the expression of SHP, which in turn inhibited the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase.[90] Metformin is frequently used in research along with AICAR as an AMPK agonist. More recent studies using mouse models in which the genes for AMPKα1 and α2 catalytic subunits (Prkaa1/2) or LKB1, an upstream kinase of AMPK, had been knocked out in hepatocytes have raised doubts over the obligatory role of AMPK, since the effect of metformin was not abolished by loss of AMPK function.[86] The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the concentration of cytosolic AMP (as opposed to a change in total AMP or total AMP/ATP).[91] Increased cellular AMP has also been proposed to explain the inhibition of glucagon-induced increase in cAMP and activation of PKA.[86] Metformin and other biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[92] Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice and it has also been proposed that this may contribute to its mode of action possibly through an effect on Glucagon-like peptide-1 (GLP-1) secretion.[87]

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,[93] and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors.[94] The increase in insulin binding after metformin treatment has also been demonstrated in patients with NIDDM [95]. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle.[96] AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms."[97]

Chemistry[edit]

The usual synthesis of metformin, originally described in 1922 and reproduced in multiple later patents and publications, involves the reaction of dimethylamine hydrochloride and 2-cyanoguanidine (dicyandiamide) with heating.[98][99]

Metformin synthesis.svg

According to the procedure described in the 1975 Aron patent,[100] and the Pharmaceutical Manufacturing Encyclopedia,[101] 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.

Structure[edit]

The structure of metformin was generally represented in a wrong tautomeric form for a number of years. This was corrected in 2005.[102] The energy difference between the correct tautomer and the generally represented tautomer is about 37 kJ/mol (9 kcal/mol). The drug is administered as metformin hydrochloride. The structure of the metformin hydrochloride was also corrected recently.[103] According to these studies, the metformin has different electronic structure compared to its protonated form. The neutral species is a simple conjugated system. Upon protonation, (i) the conjugation breaks down, (ii) the intramolecular hydrogen bond breaks down, (iii) the molecule becomes non-planar (iv) two lone pairs get accumulated at the central nitrogen (v) dynamism increases in the system via C=N rotational process and via N-inversion process. Thus, electronically, metformin hydrochloride should be treated as a simple extension of metformin. The nucleophilicity of metformin hydrochloride is moderate and that is a desired property. Metformin is shown to belong to a new class of compounds called nitreones.

Pharmacokinetics[edit]

Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.[83][104] Peak plasma concentrations (Cmax) are reached within one to three hours of taking immediate-release metformin and four to eight hours with extended-release formulations.[83][104] 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 one or two days.[83]

Metformin has acid dissociation constant values (pKa) of 2.8 and 11.5 and, therefore, exists very largely as the hydrophilic cationic species at physiological pH values. The metformin acid dissociation constant values (pKa) make metformin a stronger base than most other basic drugs with less than 0.01% unionized in blood. Furthermore, the lipid solubility of the unionized species is slight as shown by its low logP value [log(10) of the distribution coefficient of the unionized 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. 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 being investigated with the aim of producing prodrugs with better oral absorption than metformin itself.[105]

Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma within 24 hours of a single oral dose.[83][106] The average elimination half-life in plasma is 6.2 hours.[83] Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours[83] (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).[106]

History[edit]

The biguanide class of antidiabetic drugs, 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.[107]

Galega officinalis, a natural source of galegine

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.[98] In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, noting it was the most potent of the biguanide analogs they studied.[108] This result was completely forgotten, as other guanidine analogs, such as the synthalins, took over, and were themselves soon overshadowed by insulin.[109]

Interest in metformin, however, picked up 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.[110] That same year, a prominent Philippine physician, Eusebio Y. Garcia,[111] used metformin (he named it Fluamine) to treat influenza; he noted the drug "lowered the blood sugar to minimum physiological limit" and was nontoxic. Garcia also believed metformin to have bacteriostatic, antiviral, antimalarial, antipyretic and analgesic actions.[112] In a series of articles in 1954, Polish pharmacologist Janusz Supniewski[113] was unable to confirm most of these effects, including lowered blood sugar; he did, however, observe some antiviral effects in humans.[114][115]

While training at the Hôpital de la Pitié, French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from Galega officinalis, which is related in structure to metformin and had seen brief use as an antidiabetic before the synthalins were developed.[12] 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 drug and published his results in 1957.[12][109]

Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona. [116]

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972,[117] but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994.[118] Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995.[119] Generic formulations are now available in several countries, and metformin is believed to have become the most widely prescribed antidiabetic drug in the world.[12]

Formulations[edit]

Generic metformin 500 mg tablets, as sold in the United Kingdom

Metformin is sold under several trade names, including Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, Diaformin, Siofor and Metfogamma.

The liquid metformin is sold under the name Riomet. Each 5 ml of Riomet is equivalent to the 500 mg tablet form of metformin.[120]

Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets. All of these are now available as generic drugs in the U.S.

Metformin SR (slow release) or XR (extended release) was introduced in 2004. It is available in 500 mg, 750 mg and 1000 mg strengths, mainly to counteract the most common gastrointestinal side effects, as well as to increase compliance by reducing pill burden. No difference in effectiveness exists between the two preparations.

Combinations with other drugs[edit]

When used for type 2 diabetes, metformin is often prescribed in combination with other drugs. Several are available as fixed-dose combinations, also with the purpose of reducing pill burden and making administration simpler and more convenient.[121]

As of 2009, the most popular brand-name combination was metformin with rosiglitazone, sold as Avandamet by GlaxoSmithKline since 2002.[122][123] Rosiglitazone actively makes cells more sensitive to insulin, complementing the action of the metformin. In 2005, all current stock of Avandamet was seized by the FDA and removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices.[124] The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year.

In the United States, metformin is also available in combination with pioglitazone (trade name Actoplus Met), the sulfonylureas glipizide (trade name Metaglip) and glibenclamide (known as glyburide in the United States, trade name Glucovance), the dipeptidyl peptidase-4 inhibitor sitagliptin (with the combination sold under the trade name Janumet), the dipeptidyl peptidase-4 inhibitor saxagliptin (with the combination sold under the trade name Kombiglyze XR), and the meglitinide repaglinide (PrandiMet). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter being more popular).[13] A generic formulation of metformin/rosiglitazone from Teva has received tentative approval from the FDA, and is expected to reach the market in early 2012.[125]

In Europe, the combination of metformin and the dipeptidyl peptidase-4 inhibitor linagliptin has approved the trade name Jentadueto.[126]

Research[edit]

There is tentative evidence that metformin may decrease the risk of cancer.[127] A direct action of metformin on cancer cells is suspected. Metformin exhibits a strong and consistent antiproliferative action on several cancer cell lines, including breast, colon, ovarian, pancreatic, lung and prostate cancer cells. These cellular studies were generally completed by preclinical studies showing a reliable antitumoral effect in various mouse models. In addition, the first clinical trials demonstrated a beneficial effect in breast and colon cancer.[128]

Metformin appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight or obese women, to immediate pregnancy outcomes. However, patients with multiple risk factors for insulin resistance may not meet their treatment goals with metformin alone and may require supplementary insulin. Evidence suggests that there are potential advantages for the use of metformin over insulin in gestational diabetes mellitus with respect to maternal weight gain and neonatal outcomes.[49] Nonetheless, several concerns have been raised regarding studies published thus far, and evidence on the long-term safety of metformin for both mother and child is still lacking.[129]

Metformin in conditions as non-alcoholic fatty liver disease (NAFLD)[130] and premature puberty,[131] two diseases that feature insulin resistance are still considered experimental. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary;[132] although some randomized controlled trials have found significant improvement with its use, the evidence is still insufficient.[133][134]

Metformin is seen to possess antiageing properties though the mechanism remains unclear. Using a quantitative proteomics approach metformin was found to extend the lifespan in the model organism (C. elegans) through mitohormesis. The mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. [135]

References[edit]

  1. ^ 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. 
  2. ^ Hundal RS, Inzucchi SE (2003). "Metformin: new understandings, new uses". Drugs 63 (18): 1879–94. doi:10.2165/00003495-200363180-00001. PMID 12930161. 
  3. ^ Clinical Guidelines Task Force, International Diabetes Federation (2005). "Glucose control: oral therapy" PDF (100 KB). In: Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 35–8. Retrieved November 6, 2007.
  4. ^ National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical guideline for management in primary and secondary care (update) [PDF]. London: Royal College of Physicians; 2008. ISBN 978-1-86016-333-3. p. 86.
  5. ^ American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care. 2009;32 Suppl 1:S13–61. doi:10.2337/dc09-S013. PMID 19118286.
  6. ^ Metformin in Gestational Diabetes: The Offspring Follow Up (MiG: TOFU)(October 2011) American Diabetes Association. Metformin in Gestational Diabetes: The Offspring Follow Up (MiG: TOFU). Diabetes Care. 32:2279-2284.
  7. ^ a b c d e Joint Formulary Committee (2013). "Chapter 6: Endocrine system". British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 447–448. ISBN 9780857110848. 
  8. ^ a b El Messaoudi, S; Rongen, GA; de Boer, RA; Riksen, NP (December 2011). "The cardioprotective effects of metformin.". Current Opinion in Lipidology 22 (6): 445–53. doi:10.1097/MOL.0b013e32834ae1a7. PMID 21897229. 
  9. ^ Malek, M; Aghili, R; Emami, Z; Khamseh, ME (2013). "Risk of Cancer in Diabetes: The Effect of Metformin." (PDF). ISRN Endocrinology 2013: 636927. doi:10.1155/2013/636927. PMC 3800579. PMID 24224094. 
  10. ^ (March 2010) WHO Model List of Essential Medicines PDF (433 KB), 16th edition, World Health Organization, p. 24. Retrieved December 22, 2010.
  11. ^ 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. 
  12. ^ a b c d Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes International. 2004;21(3):115–7. doi:10.1002/pdi.606.
  13. ^ a b "The Use of Medicines in the United States: Review of 2010" PDF (1.79 MB). IMS Institute for Healthcare Informatics (April 2011). Retrieved April 28, 2011.
  14. ^ Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327(7421):951–3. doi:10.1136/bmj.327.7421.951. PMID 14576245. PMC 259161.
  15. ^ a b Quinn, SM; Baur, LA; Garnett, SP; Cowell, CT (Oct 2010). "Treatment of clinical insulin resistance in children: a systematic review.". Obesity reviews : an official journal of the International Association for the Study of Obesity 11 (10): 722–30. doi:10.1111/j.1467-789x.2009.00697.x. PMID 20003069. 
  16. ^ a b c d Bennett, Wendy L.; Maruthur, Nisa M.; Singh, Sonal; Segal, Jodi B.; Wilson, Lisa M.; Chatterjee, Ranee; Marinopoulos, Spyridon S.; Puhan, Milo A.; Ranasinghe, Padmini; Block, Lauren; Nicholson, Wanda K.; Hutfless, Susan; Bass, Eric B.; Bolen, Shari (3 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. doi:10.7326/0003-4819-154-9-201105030-00336. 
  17. ^ Inzucchi SE, Bergenstal RM, Buse JB, 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. 
  18. ^ Inzucchi SE, Bergenstal RM, Buse JB, 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. 
  19. ^ "ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - Summary". Diab Vasc Dis Res 11 (3): 133–73. May 2014. doi:10.1177/1479164114525548. PMID 24800783. 
  20. ^ 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". Ann. Intern. Med. 156 (3): 218–31. doi:10.7326/0003-4819-156-3-201202070-00011. PMID 22312141. 
  21. ^ a b Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65. doi:10.1016/S0140-6736(98)07037-8. PMID 9742977.
  22. ^ Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89. doi:10.1056/NEJMoa0806470. PMID 18784090.
  23. ^ Shaughnessy, A. F (31 July 2003). "What happened to the valid POEMs? A survey of review articles on the treatment of type 2 diabetes". BMJ 327 (7409): 266–0. doi:10.1136/bmj.327.7409.266. 
  24. ^ a b Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168(19):2070–80. doi:10.1001/archinte.168.19.2070. PMID 18955635. PMC 2765722.
  25. ^ Lamanna C, Monami M, Marchionni N, Mannucci E (March 2011). "Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials". Diabetes Obes Metab 13 (3): 221–8. doi:10.1111/j.1463-1326.2010.01349.x. PMID 21205121. 
  26. ^ Boussageon R, Supper I, Bejan-Angoulvant T, et al. (2012). "Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials". PLoS Med. 9 (4): e1001204. doi:10.1371/journal.pmed.1001204. PMC 3323508. PMID 22509138. 
  27. ^ a b c d e Maharani U. Chapter 27: Diabetes Mellitus & Hypoglycemia. In: Papadakis MA, McPhee SJ. CURRENT Medical Diagnosis and Treatment 2010. 49th ed. McGraw-Hill Medical; 2009. ISBN 0-07-162444-9. p. 1092–93.
  28. ^ a b c Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147(6):386–99. PMID 17638715.
  29. ^ DiPiro, Joseph T.; Talbert, Robert L.; Yee, Gary C.; Matzke, Gary R.; Wells, Barbara G.; Posey, L. Michael. Pharmacotherapy: a pathophysiologic approach. New York: McGraw-Hill; 2005. ISBN 0-07-141613-7.
  30. ^ "Glucophage package insert". Princeton, NJ: Bristol-Myers Squibb Company; 2009.
  31. ^ Jonas, Dan. "Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations Final Original Report Drug Class Reviews". Oregon Health & Science University;. Retrieved 1 April 2014. 
  32. ^ Clarke, P.; A. Gray, A. Adler, R. Stevens, M. Raikou, C. Cull, I. Stratton, R. Holman (March 2001). "Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with Type II diabetes". Diabetologia 44 (3): 298–304. doi:10.1007/s001250051617. Retrieved 8 April 2014. 
  33. ^ Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. doi:10.1056/NEJMoa012512. PMID 11832527.
  34. ^ Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677–86. doi:10.1016/S0140-6736(09)61457-4. PMID 19878986.
  35. ^ Lilly M, Godwin M. Treating prediabetes with metformin: systematic review and meta-analysis. Can Fam Physician. 2009;55(4):363–9. PMID 19366942.
  36. ^ Kidson W. Polycystic ovary syndrome: a new direction in treatment. Med J Aust. 1998;169(10):537–40. PMID 9861912.
  37. ^ Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metab Clin Exp. 1994;43(5):647–54. PMID 8177055.
  38. ^ Teede H. Insulin sensitizers in polycystic ovary syndrome. In: Kovács GT, Norman RW. Polycystic ovary syndrome. Cambridge, UK: Cambridge University Press; 2007. ISBN 0-521-84849-0. p. 65–81.
  39. ^ National Collaborating Centre for Women’s and Children's Health. Fertility: assessment and treatment for people with fertility problems [pdf]. London: Royal College of Obstetricians and Gynaecologists; 2004. ISBN 1-900364-97-2. p. 58–9.
  40. ^ Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–66. doi:10.1056/NEJMoa063971. PMID 17287476.
  41. ^ Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006;332(7556):1485. doi:10.1136/bmj.38867.631551.55. PMID 16769748.
  42. ^ Balen A. Royal College of Obstetricians and Gynaecologists. Metformin therapy for the management of infertility in women with polycystic ovary syndrome [PDF]; December 2008 [Retrieved 2009-12-13].
  43. ^ The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–77. doi:10.1093/humrep/dem426. PMID 18308833.
  44. ^ Palomba S, Pasquali R, Orio F, Nestler JE. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis. Clin. Endocrinol. (Oxf). 2009;70(2):311–21. doi:10.1111/j.1365-2265.2008.03369.x. PMID 18691273.
  45. ^ Al-Inany H, Johnson N. Drugs for anovulatory infertility in polycystic ovary syndrome. BMJ. 2006;332(7556):1461–2. doi:10.1136/bmj.332.7556.1461. PMID 16793784.
  46. ^ Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician. 2009;79(8):671–6. PMID 19405411.
  47. ^ a b Tang, T; Lord, JM; Norman, RJ; Yasmin, E; Balen, AH (May 16, 2012). "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 5: CD003053. PMID 22592687. 
  48. ^ Sirmans, Susan; Pate, Kirsten (December 2013). "Epidemiology, diagnosis, and management of polycystic ovary syndrome". Clinical Epidemiology: 1. doi:10.2147/CLEP.S37559. 
  49. ^ a b Lautatzis, ME; Goulis, DG; Vrontakis, M (Nov 2013). "Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.". Metabolism: clinical and experimental 62 (11): 1522–34. doi:10.1016/j.metabol.2013.06.006. PMID 23886298. 
  50. ^ Jones G, Macklin J, Alexander W. Contraindications to the use of metformin. BMJ. 2003;326(7379):4–5. doi:10.1136/bmj.326.7379.4. PMID 12511434. PMC 1124930.
  51. ^ U.S. FDA. Glucophage Prescribing Information for the U.S. [PDF] [Retrieved 2009-12-24].
  52. ^ Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 2007;335(7618):497. doi:10.1136/bmj.39314.620174.80. PMID 17761999. PMC 1971204.
  53. ^ a b Weir J (March 19, 1999). Guidelines with Regard to Metformin-Induced Lactic Acidosis and X-ray Contrast Medium Agents. Royal College of Radiologists. Retrieved October 26, 2007 through the Internet Archive.
  54. ^ a b Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol. 2003;76(908):513–8. doi:10.1259/bjr/26964464. PMID 12893691.
  55. ^ Khurana R, Malik IS. Metformin: safety in cardiac patients. Heart. 2010;96(2):99–102. doi:10.1136/hrt.2009.173773. PMID 19564648.
  56. ^ Vigersky RA, Filmore-Nassar A, Glass AR. Thyrotropin suppression by metformin. J Clin Endocrinol Metab. 2006;91(1):225–7. doi:10.1210/jc.2005-1210. PMID 16219720.
  57. ^ Drug Facts and Comparisons 2005. St. Louis, Mo: Facts and Comparisons; 2004. ISBN 1-57439-193-3.
  58. ^ Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD. 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. J Intern Med. 2003;254(5):455–63. doi:10.1046/j.1365-2796.2003.01213.x. PMID 14535967.
  59. ^ Andrès E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002;162(19):2251–2. doi:10.1001/archinte.162.19.2251-a. PMID 12390080.
  60. ^ Gilligan M. Metformin and vitamin B12 deficiency. Arch Intern Med. 2002;162(4):484–5. doi:10.1001/archinte.162.4.484. PMID 11863489.
  61. ^ de Jager J, Kooy A, Lehert P, et al. (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. 
  62. ^ Ting R, Szeto C, Chan M, Ma K, Chow K. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med. 2006;166(18):1975–9. doi:10.1001/archinte.166.18.1975. PMID 17030830.
  63. ^ a b Stang M, Wysowski D K, Butler-Jones D (1999). "Incidence of lactic acidosis in metformin users". Diabetes Care 22 (6): 925–927. doi:10.2337/diacare.22.6.925. PMID 10372243. 
  64. ^ Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med. 2003;163(21):2594–602. doi:10.1001/archinte.163.21.2594. PMID 14638559.
  65. ^ a b Shu AD, Myers Jr MG, Shoelson SE. Chapter 29: Pharmacology of the Endocrine Pancreas. In: Golan ED et al. (eds.). Principles of pharmacology: the pathophysiologic basis of drug therapy. Philadelphia: Lippincott, Williams & Wilkins; 2005. ISBN 0-7817-4678-7. p. 540–41.
  66. ^ a b Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update [PDF]. Ann Intern Med. 2002;137(1):25–33. PMID 12093242.
  67. ^ Davis SN. Chapter 60: Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas. In: Brunton L, Lazo J, Parker K. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2006. ISBN 978-0-07-142280-2.
  68. ^ Spiller HA, Quadrani DA. Toxic effects from metformin exposure. Ann Pharmacother. 2004;38(5):776–80. doi:10.1345/aph.1D468. PMID 15031415.
  69. ^ a b Forrester MB. Adult metformin ingestions reported to Texas poison control centers, 2000–2006. Hum Exp Toxicol. 2008;27(7):575–83. doi:10.1177/0960327108090589. PMID 18829734.
  70. ^ Gjedde S, Christiansen A, Pedersen SB, Rungby J. Survival following a metformin overdose of 63 g: a case report. Pharmacol Toxicol. 2003;93(2):98–9. doi:10.1034/j.1600-0773.2003.930207.x. PMID 12899672.
  71. ^ Nisse P, Mathieu-Nolf M, Deveaux M, Forceville X, Combes A. A fatal case of metformin poisoning. J Toxicol Clin Toxicol. 2003;41(7):1035–6. doi:10.1081/CLT-120026533. PMID 14705855.
  72. ^ a b Suchard JR, Grotsky TA. Fatal metformin overdose presenting with progressive hyperglycemia. West J Emerg Med. 2008;9(3):160–4. PMID 19561734.
  73. ^ a b Teale KF, Devine A, Stewart H, Harper NJ. The management of metformin overdose. Anaesthesia. 1998;53(7):698–701. doi:10.1046/j.1365-2044.1998.436-az0549.x. PMID 9771180.
  74. ^ Spiller HA, Weber JA, Winter ML, Klein-Schwartz W, Hofman M, Gorman SE, Stork CM, Krenzelok EP. Multicenter case series of pediatric metformin ingestion. Ann Pharmacother. 2000;34(12):1385–8. doi:10.1345/aph.10116. PMID 11144693.
  75. ^ Dell'Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW. Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med. 2009;54(6):818–23. doi:10.1016/j.annemergmed.2009.04.023. PMID 19556031.
  76. ^ Lacher M, Hermanns-Clausen M, Haeffner K, Brandis M, Pohl M. Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr. 2005;164(6):362–5. doi:10.1007/s00431-005-1634-y. PMID 15729560.
  77. ^ Harvey B, Hickman C, Hinson G, Ralph T, Mayer A. Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization. Pediatr Crit Care Med. 2005;6(5):598–601. doi:10.1097/01.PCC.0000162451.47034.4F. PMID 16148825.
  78. ^ Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial. 2006;19(1):80–3. doi:10.1111/j.1525-139X.2006.00123.x. PMID 16423187.
  79. ^ Barrueto F, Meggs WJ, Barchman MJ. Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol. 2002;40(2):177–80. doi:10.1081/CLT-120004407. PMID 12126190.
  80. ^ Liu A, Coleman SP. Determination of metformin in human plasma using hydrophilic interaction liquid chromatography-tandem mass spectrometry. J. Chrom. B 877: 3695–3700, 2009.
  81. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 939–940.
  82. ^ Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23(5):545–51. PMID 3593625.
  83. ^ a b c d e f g h Bristol-Myers Squibb. U.S. Food and Drug Administration. Glucophage (metformin hydrochloride tablets) Label Information; August 27, 2008 [Retrieved 2009-12-08].
  84. ^ Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y. Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. Drug Metabol Drug Interact. 2002;19(1):41–8. PMID 12222753.
  85. ^ Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G. Mechanism by which metformin reduces glucose production in type 2 diabetes [PDF]. Diabetes. 2000;49(12):2063–9. doi:10.2337/diabetes.49.12.2063. PMID 11118008. PMC 2995498.
  86. ^ a b c 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. 
  87. ^ a b Burcelin R (July 2013). "The antidiabetic gutsy role of metformin uncovered?". Gut. doi:10.1136/gutjnl-2013-305370. PMID 23840042. 
  88. ^ Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100(3):328–41. doi:10.1161/01.RES.0000256090.42690.05. PMID 17307971.
  89. ^ Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman M, Goodyear L, Moller D. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74. doi:10.1172/JCI13505. PMID 11602624. PMC 209533.
  90. ^ Kim YD, Park KG, Lee YS, et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes. 2008;57(2):306–14. doi:10.2337/db07-0381. PMID 17909097.
  91. ^ Zhang L, He H, Balschi JA. Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol. 2007;293(1):H457–66. doi:10.1152/ajpheart.00002.2007. PMID 17369473.
  92. ^ Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013 Feb 14;494(7436):256-60. doi: 10.1038/nature11808. Epub 2013 Jan 6. PMID 23292513
  93. ^ Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab. 2006;291(1):E182–E189. doi:10.1152/ajpendo.00272.2005. PMID 16478780.
  94. ^ Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9. doi:10.1056/NEJM199602293340906. PMID 8569826.
  95. ^ Fantus IG, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo. J Clin Endocrinol Metab. 1986;63(4):898-905.
  96. ^ Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51(7):2074–81. doi:10.2337/diabetes.51.7.2074. PMID 12086935.
  97. ^ Saeedi R, Parsons HL, Wambolt RB, et al. Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms. Am J Physiol Heart Circ Physiol. 2008;294(6):H2497–506. doi:10.1152/ajpheart.00873.2007. PMID 18375721.
  98. ^ a b Werner E, Bell J. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc, Transactions. 1921;121:1790–5. doi:10.1039/CT9222101790.
  99. ^ Shapiro SL, Parrino VA, Freedman L. Hypoglycemic Agents. I Chemical Properties of β-Phenethylbiguanide. A New Hypoglycemic Agent. J Am Chem Soc. 1959;81(9):2220–5. doi:10.1021/ja01518a052.
  100. ^ Procédé de préparation de chlorhydrate de diméthylbiguanide. Patent FR 2322860. 1975. French.
  101. ^ Pharmaceutical Manufacturing Encyclopedia (Sittig's Pharmaceutical Manufacturing Encyclopedia). 3rd ed. Vol. 3. Norwich, NY: William Andrew; 2007. ISBN 0-8155-1526-X. p. 2208.
  102. ^ Bharatam PV, Patel DS, Iqbal P,. Pharmacophoric Features of Biguanide Derivatives: An Electronic and Structural Analysis. J Med Chem. 2005;48(24):7615–7622. doi:10.1021/jm050602z.
  103. ^ Patel DS, Bharatam PV. Novel N(L)2 species with two lone pairs on nitrogen: systems isoelectronic to carbodicarbenes. Chem Commun. 2009;(9):1064–6. doi:10.1039/b816595e.
  104. ^ a b Heller JB. Metformin overdose in dogs and cats. Veterinary Medicine. 2007;(April):231–233.
  105. ^ Garry G. Graham, Jeroen Punt, Manit Arora, Richard O. Day, Matthew P. Doogue, Janna K. Duong, Timothy J. Furlong, Jerry R. Greenfield, Louise C. Greenup, Carl M. Kirkpatrick, John E. Ray, Peter Timmins and Kenneth M. Williams. Clinical Pharmacokinetics of Metformin. Clin Pharmacokinet 2011; 50 (2): 81-98
  106. ^ a b Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau JD. Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects. Diabetes Metab. 2003;29(3):279–83. PMID 12909816.
  107. ^ Witters L. The blooming of the French lilac. J Clin Invest. 2001;108(8):1105–7. doi:10.1172/JCI14178. PMID 11602616. PMC 209536.
  108. ^ See Chemical Abstracts, v.23, 42772 (1929) K. H. Slotta, R. Tschesche. Uber Biguanide. II. Die Blutzuckersenkende Wirkung der Biguanides. Berichte der Deutschen Chemischen Gesellschaft B: Abhandlungen. 1929;62:1398–1405. doi:10.1002/cber.19290620605.
  109. ^ a b Campbell IW. 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. 2007;7:247–252. doi:10.1177/14746514070070051001.
  110. ^ Dawes GS, Mott JC. Circulatory and respiratory reflexes caused by aromatic guanidines. Br J Pharmacol Chemother. 1950;5(1):65–76. PMID 15405470.
  111. ^ About Eusebio Y. Garcia, see: Carteciano J. Philippines Department of Science and Technology. Search for DOST-NRCP Dr. Eusebio Y. Garcia Award; 2005 [Retrieved 2009-12-05].
  112. ^ Quoted from Chemical Abstracts, v.45, 24828 (1951) Garcia EY. Fluamine, a new synthetic analgesic and antiflu drug. J Philippine Med Assoc. 1950;26:287–93.
  113. ^ About Janusz Supniewski, see: Wołkow PP, Korbut R. Pharmacology at the Jagiellonian University in Kracow, short review of contribution to global science and cardiovascular research through 400 years of history [pdf]. J Physiol Pharmacol. 2006 [Retrieved 2009-12-05];57 Suppl 1:119–36. PMID 16766803.
  114. ^ See Chemical Abstracts, v. 52, 22272 (1958) Supniewski J, Chrusciel T. [N-dimethyl-di-guanide and its biological properties.]. Arch Immunol Ther Exp (Warsz). 1954;2:1–15. Polish. PMID 13269290.
  115. ^ Quoted from Chemical Abstracts, v.49, 74699 (1955) Supniewski J, Krupinska, J. [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. 1954;2(Classe II):161–5. French.
  116. ^ Hadden DR. Goat's rue – French lilac – Italian fitch – Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. J R Coll Physicians Edinb. 2005;35(3):258–60. PMID 16402501.
  117. ^ Lucis OJ. The status of metformin in Canada. Can Med Assoc J. 1983;128(1):24–6. PMID 6847752.
  118. ^ Susan M. Cruzan (December 30, 1994). "FDA Approves New Diabetes Drug" (Press release). U.S. Food and Drug Administration. Archived from the original on September 29, 2007. Retrieved 2007-01-06. 
  119. ^ Glucophage Label and Approval History. U.S. Food and Drug Administration. Retrieved January 8, 2007. Data available for download on FDA website.
  120. ^ http://www.rxwiki.com/Metformin
  121. ^ Bailey CJ, Day C. Fixed-dose single tablet antidiabetic combinations. Diabetes Obes Metab. 2009;11(6):527–33. doi:10.1111/j.1463-1326.2008.00993.x. PMID 19175373.
  122. ^ "FDA Approves GlaxoSmithKline's Avandamet (rosiglitazone maleate and metformin HCl), The Latest Advancement in the Treatment of Type 2 Diabetes" (Press release). GlaxoSmithKline. October 12, 2002. Retrieved 2006-12-27. 
  123. ^ 2009 Top 200 branded drugs by total prescriptions PDF (96.5 KB). Drug Topics (June 17, 2010). Retrieved September 2, 2010.
  124. ^ "Questions and Answers about the Seizure of Paxil CR and Avandamet" (Press release). U.S. Food and Drug Administration. March 4, 2005. Archived from the original on October 14, 2007. Retrieved 2006-12-27. 
  125. ^ "Teva Pharm announces settlement of generic Avandia, Avandamet, and Avandaryl litigation with GlaxoSmithKline" (Press release). Reuters. September 27, 2007. Retrieved 2009-02-17. 
  126. ^ Jentadueto at the European Medicines Agency. First published 25/05/2012
  127. ^ Malek, M; Aghili, R; Emami, Z; Khamseh, ME (2013). "Risk of Cancer in Diabetes: The Effect of Metformin.". ISRN endocrinology 2013: 636927. doi:10.1155/2013/636927. PMID 24224094. 
  128. ^ Ben Sahra I, Le Marchand Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug?. Mol Cancer Therapeutics. 2010;9(5):1092–99. doi:10.1158/1535-7163.MCT-09-1186. PMID 20442309.
  129. ^ Cheung NW. The management of gestational diabetes [pdf]. Vasc Health Risk Manag. 2009;5(1):153–64. PMID 19436673. PMC 2672462.
  130. ^ Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358(9285):893–4. doi:10.1016/S0140-6736(01)06042-1. PMID 11567710.
  131. ^ Ibáñez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F. Metformin treatment to prevent early puberty in girls with precocious pubarche. J Clin Endocrinol Metab. 2006;91(8):2888–91. doi:10.1210/jc.2006-0336. PMID 16684823.
  132. ^ Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20(1):23–28. doi:10.1111/j.1365-2036.2004.02025.x. PMID 15225167.
  133. ^ Angelico F, Burattin M, Alessandri C, Del Ben M, Lirussi F. Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007;24(1):CD005166. doi:10.1002/14651858.CD005166.pub2. PMID 17253544.
  134. ^ Socha P, Horvath A, Vajro P, Dziechciarz P, Dhawan A, Szajewska H. Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review. J Pediatr Gastroenterol Nutr. 2009;48(5):587–96. PMID 19412008.
  135. ^ Wouter De Haes, Lotte Frooninckx, Roel Van Assche, Arne Smolders, Geert Depuydt, Johan Billen, Bart P. Braeckman, Liliane Schoofs, Liesbet Temmerman. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proceedings of The National Academy of Sciences. 2014. doi:10.1073/pnas.1321776111. PMID 24889636.

External links[edit]