Metformin/ja: Difference between revisions

'''メトホルミン'''（'''Metformin'''）は、'''グルコファージ（'''Glucophage'''）などの商品名で販売されており、特に[[overweight/ja|太りすぎ]]の[[diabetes mellitus type 2/ja|2型糖尿病]]の治療のための主要な[[first-line treatment/ja|第一選択]]医薬品である。また、[[polycystic ovary syndrome/ja|多嚢胞性卵巣症候群]]の治療にも用いられる。[[antipsychotic/ja|抗精神病薬]]を服用している人の[[metabolic syndrome/ja|メタボリックシンドローム]]のリスクを軽減するために、適応外の補助薬として使用されることもある。

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== Adverse effects ==

The most common [[adverse drug reaction|adverse effect]] of metformin is gastrointestinal irritation, including [[diarrhea]], cramps, nausea, vomiting, and increased [[flatulence]]. Metformin is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications. The most serious potential adverse effect of metformin is [[lactic acidosis]]; this complication is rare, and seems to be related to impaired liver or kidney function. 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.

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=== Gastrointestinal ===

Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7&nbsp;g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate metformin. Use of slow or extended-release preparations may improve tolerability.

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

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=== Lactic acidosis ===

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Metformin is generally safe in people with mild to moderate chronic kidney disease, with proportional reduction of metformin dose according to severity of [[estimated glomerular filtration rate]] (eGFR) and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement). The 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. Lactate uptake by the liver is diminished with metformin use because lactate is a [[Substrate (biochemistry)|substrate]] for hepatic [[gluconeogenesis]], a process that metformin inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs. Given severely impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include [[alcoholism]] (due to depletion of [[nicotinamide adenine dinucleotide|NAD+]] stores), heart failure, and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.

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=== Overdose ===

The most common symptoms following an overdose include vomiting, [[diarrhea]], abdominal pain, [[tachycardia]], drowsiness, and rarely, [[hypoglycemia]] or [[hyperglycemia]]. Treatment of metformin overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses. 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.

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&nbsp;mg/L in persons receiving therapeutic doses, 40–120&nbsp;mg/L in victims of acute overdosage, and 80–200&nbsp;mg/L in fatalities. Chromatographic techniques are commonly employed.

=== Interactions ===

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

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.

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== Pharmacology ==

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=== Mechanism of action ===

The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain ([[Respiratory complex I|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#GPD2|glycerol-3-phosphate dehydrogenase]] (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on [[gut flora|gut microbiota]].

Metformin exerts an anorexiant effect in most people, decreasing caloric intake. Metformin decreases [[gluconeogenesis]] (glucose production) in the liver. Metformin inhibits basal secretion from the [[pituitary gland]] of [[growth hormone]], [[adrenocorticotropic hormone]], [[follicle stimulating hormone]], and expression of [[proopiomelanocortin]], 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. The average patient with type{{nbsp}}2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.

Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signaling, whole-body energy balance, and the metabolism of glucose and [[lipid|fats]]. AMPK activation is required for an increase in the expression of [[small heterodimer partner]], which in turn inhibited the [[gene expression|expression]] of the hepatic gluconeogenic genes [[phosphoenolpyruvate carboxykinase]] and [[glucose 6-phosphatase]]. Metformin is frequently used in research along with [[AICA ribonucleotide]] as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain: metformin increases the concentration of [[cytosol]]ic [[adenosine monophosphate]] (AMP) (as opposed to a change in total AMP or total AMP/[[adenosine triphosphate]]) which could activate AMPK allosterically at high levels; a newer theory involves binding to [[PEN-2]]. Metformin inhibits cyclic AMP production, blocking the action of [[glucagon]], and thereby reducing fasting glucose levels. Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice, and this may contribute to its mode of action possibly through an effect on [[glucagon-like peptide-1]] secretion.

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral [[glucose uptake]] (by inducing the phosphorylation of [[GLUT4]] enhancer factor), decreases insulin-induced suppression of [[fatty acid metabolism|fatty acid oxidation]], and decreases the absorption of glucose from the [[gastrointestinal tract]]. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. The increase in insulin binding after metformin treatment has also been demonstrated in patients with type{{nbsp}}2 diabetes.

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

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.

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

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=== Pharmacokinetics ===

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

Metformin has acid dissociation constant values (pK_a) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pK_a values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the [[Lipophilicity|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 [[Membrane transport protein|transporter]] [[SLC22A1]] in order for it to enter cells. The logP of metformin is less than that of [[phenformin]] (−0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in [[phenformin]]. More lipophilic derivatives of metformin are presently under investigation with the aim of producing prodrugs with superior oral absorption than metformin.

Metformin is not [[drug metabolism|metabolized]]. It is [[clearance (medicine)|cleared]] from the body by [[renal physiology#Secretion|tubular secretion]] and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose. The average [[biological half-life|elimination half-life]] in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) [[red blood cell]]s, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).

Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to [[portal vein]] absorption and first-pass uptake by the liver in oral administration.

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== Chemistry ==

Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pK_a of metformin is 12.4. The usual [[chemical synthesis|synthesis]] of metformin, originally described in 1922, involves the one-pot reaction of [[dimethylamine]] [[hydrochloride]] and [[2-cyanoguanidine]] over heat.

According to the procedure described in the 1975 Aron patent, and the ''Pharmaceutical Manufacturing Encyclopedia'', [[equivalent weight|equimolar]] amounts of dimethylamine and 2-cyanoguanidine are dissolved in [[toluene]] with cooling to make a [[Concentration#Qualitative description|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 [[precipitate]]s with a 96% [[Yield (chemistry)|yield]].

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===Derivatives===

A new derivative [[HL156A]], also known as IM156, is a potential new drug for medical use.

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[[File:Galega officinalis1UME.jpg|right|thumb|''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 [[Galega officinalis|French lilac]] or goat's rue (''Galega officinalis''), a plant used in folk medicine for several centuries. ''G. officinalis'' itself does not contain any of these medications, but [[Galegine|isoamylene guanidine]]; phenformin, buformin, and metformin are chemically synthesized compounds composed of two guanidine molecules, and are more [[lipophilic]] than the plant-derived parent compound.

Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of ''N'',''N''-dimethylguanidine. In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied. This result was ignored, as other [[guanidine]] analogs such as the [[synthalin]]s, took over and were themselves soon overshadowed by insulin.

Interest in metformin resumed at the end of the 1940s. In 1950, metformin, unlike some other similar compounds, was found not to decrease [[blood pressure]] and [[heart rate]] in animals. That year, Filipino physician Eusebio Y. Garcia used metformin (he named it Fluamine) to treat influenza; he noted the medication "lowered the blood sugar to minimum physiological limit" and was not toxic. Garcia believed metformin to have [[bacteriostatic]], [[Antiviral drug|antiviral]], [[antimalarial]], [[antipyretic]], and [[analgesic]] actions. In a series of articles in 1954, Polish pharmacologist Janusz Supniewski was unable to confirm most of these effects, including lowered blood sugar. Instead he observed antiviral effects in humans.

French diabetologist Jean Sterne studied the antihyperglycemic properties of [[galegine]], an [[alkaloid]] isolated from ''G. officinalis'', which is related in structure to metformin, and had seen brief use as an antidiabetic before the synthalins were developed. Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate the blood sugar-lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the medication and published his results in 1957.

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

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

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==Society and culture==

=== Environmental ===

Metformin and its major transformation product guanylurea are present in [[wastewater treatment plant]] effluents and regularly detected in surface waters. Guanylurea concentrations above 200&nbsp;μg/L have been measured in the German river [[Erpe (Spree)|Erpe]], which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.

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=== Formulations ===

[[File:Metformin 500mg Tablets.jpg|thumb|right|Generic metformin 500-mg tablets, as sold in the United Kingdom]]

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The name "Metformin" is the [[British Approved Name|BAN]], [[United States Adopted Name|USAN]], and [[International Nonproprietary Name|INN]] for this medication, and is sold under several [[trade name]]s. Common brand names include Glucophage, Riomet, Fortamet, and Glumetza in the US. In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor. There are several formulations of Metformin available to the market, and all but the liquid form have generic equivalents. Metformin IR (immediate release) is available in 500-, 850-, and 1000-mg tablets, while Metformin XR (extended release) is available in 500-, 750-, and 1000-mg strengths (also sold as Fortamet, Glumetza, and Glucophage XR in the US). Also available is liquid metformin (sold as Riomet in the US), where 5&nbsp;mL of solution contains the same amount of drug as a 500-mg tablet.

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==== Combination with other medications ====

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

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===== Thiazolidinediones (glitazones) =====

======Rosiglitazone======

A combination of metformin and [[rosiglitazone]] was released in 2002, and sold as Avandamet by [[GlaxoSmithKline]], or as a generic medication. Formulations are 500/1, 500/2, 500/4, 1000/2, and 1000&nbsp;mg/4&nbsp;mg of metformin/rosiglitazone.

In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating [[good manufacturing practice]]s. 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 Pharmaceutical Industries|Teva]] received tentative approval from the FDA and reached the market in early 2012.

However, following a meta-analysis in 2007 that linked the medication's use to an increased risk of [[Myocardial infarction|heart attack]], concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the [[European Medicines Agency]] recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.

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.

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====== Pioglitazone ======

The combination of [[Pioglitazone/metformin|metformin and pioglitazone]] (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union.

===== DPP-4 inhibitors =====

[[Dipeptidyl peptidase-4 inhibitor]]s inhibit [[dipeptidyl peptidase-4]] and thus reduce [[glucagon]] and blood glucose levels.

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

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

=====SGLT-2 inhibitors=====

There are combinations of metformin with the [[SGLT-2 inhibitor]]s [[Dapagliflozin/metformin|dapagliflozin]], [[Empagliflozin/metformin|empagliflozin]], and [[Canagliflozin/metformin|canagliflozin]].

===== Sulfonylureas =====

[[Sulfonylurea]]s act by increasing insulin release from the [[beta cell]]s in the [[pancreas]].

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).

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===== Meglitinide =====

[[Meglitinide]]s are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs' affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas, and require higher blood glucose levels to begin to secrete insulin. Both meglitinides, known as nateglinide and repanglinide, is sold in formulations combined with metformin. A [[repaglinide]]/metformin combination is sold as Prandimet, or as its generic equivalent.

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===== Triple combination =====

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

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

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=== Impurities ===

{{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. Health Canada announced that it was assessing NDMA levels in metformin.

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

In May 2020, the FDA asked five companies to voluntarily recall their [[sustained-release]] metformin products. The five companies were not named, but they were revealed to be Amneal Pharmaceuticals, Actavis Pharma, Apotex Corp, Lupin Pharma, and Marksans Pharma Limited in a letter sent to [[Valisure]], the pharmacy that had first alerted the FDA to this contaminant in metformin via a Citizen Petition.

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

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== Research ==

* [[Non-alcoholic fatty liver disease]]

* [[Premature puberty]]

* [[anti-cancer|Cancer]]

* [[Cardiovascular disease]] in people with diabetes

* [[Ageing|Aging]]

While metformin may reduce body weight in persons with [[fragile X syndrome]], whether it improves neurological or psychiatric symptoms is uncertain. Metformin has been studied in vivo (''[[Caenorhabditis elegans|C. elegans]]'' and [[Acheta domesticus|crickets]]) for effects on aging. A 2017 review found that people with diabetes who were taking metformin had lower all-cause mortality. They also had reduced cancer and cardiovascular disease compared with those on other therapies.

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. Furthermore, some studies suggest that long-term chronic use of metformin by healthy individuals may develop [[vitamin B12 deficiency]].