Metformin

Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes,[5][6] particularly in people who are overweight.[7] It is also used in the treatment of polycystic ovary syndrome.[5] It is not associated with weight gain.[8] It is taken by mouth.[5]

Metformin
Clinical data
Pronunciation/mɛtˈfɔːrmɪn/, met-FOR-min
Trade namesGlucophage, others
Other namesN,N-dimethylbiguanide[1]
AHFS/Drugs.comMonograph
MedlinePlusa696005
License data
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability50–60%[2][3]
    Protein bindingMinimal[2]
    MetabolismNot by liver[2]
    Elimination half-life4–8.7 hours[2]
    ExcretionUrine (90%)[2]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.010.472
    Chemical and physical data
    FormulaC4H11N5
    Molar mass129.164 g·mol−1
    3D model (JSmol)
    Density1.3±0.1[4] g/cm3

    Metformin is generally well tolerated.[9] Common side effects include diarrhea, nausea, and abdominal pain.[5] It has a low risk of causing low blood sugar.[5] High blood lactic acid level is a concern if the medication is prescribed inappropriately or in overly large doses.[10] It should not be used in those with significant liver disease or kidney problems.[5] While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.[5][11] Metformin is a biguanide antihyperglycemic agent.[5] It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues.[5]

    Metformin was discovered in 1922.[12] French physician Jean Sterne began study in humans in the 1950s.[12] It was introduced as a medication in France in 1957 and the United States in 1995.[5][13] Metformin is on the World Health Organization's List of Essential Medicines, which lists the most effective and safe medicines needed in a health system.[14] Metformin is the most widely used medication for diabetes taken by mouth.[12] It is available as a generic medication.[5] The wholesale price in the developed world was between US$0.21 and $5.55 per month as of 2014.[15] In the United States, it costs US$5 to US$25 per month.[5] In 2016, it was the fourth-most prescribed medication in the United States, with more than 81 million prescriptions.[16]

    Medical uses

    Metformin is used to lower the blood sugar in those with type 2 diabetes.[5] It is also used as a second line agent for infertility in those with polycystic ovary syndrome.[5][17]

    Type 2 diabetes

    The American Diabetes Association and the American College of Physicians each recommend metformin as a first-line agent to treat type 2 diabetes.[18][19][20] It is as effective as repaglinide and more effective than all other oral diabetes mellitus type 2 drugs.[21]

    Efficacy

    The UK Prospective Diabetes Study, a large clinical trial performed in 1980–90s, provided evidence that metformin reduced the rate of adverse cardiovascular outcomes in overweight patients with type 2 diabetes relative to other antihyperglycemic agents.[22] However, accumulated evidence from other and more recent trials reduced confidence in the efficacy of metformin for cardiovascular disease prevention.[23][24] Outcomes are improved even in those with some degree of kidney disease, heart failure, or chronic liver disease.[25]

    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.[19][26]

    In 2017, the American College of Physicians's guidelines were updated to recognize metformin as the first-line treatment for type 2 diabetes. These guidelines supersede earlier reviews. For example, a 2014 review found tentative evidence that people treated with sulfonylureas had a higher risk of severe low blood sugar events (RR 5.64), though their risk of nonfatal cardiovascular events was lower than the risk of those treated with metformin (RR 0.67). Not enough data were available at that time to determine the relative risk of death or of death from heart disease.[27]

    Metformin has little or no effect on body weight in type 2 diabetes compared with placebo,[28] in contrast to sulfonylureas which are associated with weight gain.[28] There is some evidence that metformin is associated with weight loss in obesity in the absence of diabetes.[29][30] Metformin has a lower risk of hypoglycemia than the sulfonylureas,[31][32] although hypoglycemia has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose.[33][34] Metformin modestly reduces LDL and triglyceride levels.[31][32]

    Polycystic ovarian syndrome

    In those with polycystic ovarian syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births.[35] This includes in those who have not been able to get pregnant with clomiphene.[36] Metformin does not appear to change the risk of miscarriage.[35] A number of other benefits have also been found both during pregnancy and in nonpregnant people with PCOS.[37][38] In women with PCOS undergoing in vitro fertilization, evidence does not support a benefit with respect to live births.[39] The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women.[40]

    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.[41] 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 medical treatment. Metformin treatment decreases the risk of developing type 2 diabetes mellitus in women with PCOS who exhibited impaired glucose tolerance (IGT) at baseline.[44][45]

    Diabetes mellitus and pregnancy

    A 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.[46] Several observational studies and randomized, controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes.[47][48] Nonetheless, several concerns have been raised and evidence on the long-term safety of metformin for both mother and child is lacking.[49] Compared with insulin, women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre‐eclampsia during pregnancy.[50][49] Babies born to women treated with metformin have less visceral fat, and this may make them less prone to insulin resistance in later life.[51] 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 cardio-metabolic disease.[52]

    Weight gain

    Metformin appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine.[53][54] Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more valuable.[55]

    Use with insulin

    Metformin may reduce the insulin requirement in type 1 diabetes, albeit with an increased risk of hypoglycemia.[56]

    Contraindications

    The FDA most recently revised its prescribing information on metformin in 2016.[57] Current advice is that metformin is contraindicated in people with 1) severe renal impairment (estimated glomerular filtration rate (eGFR) below 30 ml/min/1.73 m2); 2) known hypersensitivity to metformin; or 3) acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Warnings are also given regarding the use of metformin in less severe renal impairment, people aged 65 years old or greater, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, hepatic impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), surgery, and other procedures, or in people having a radiological study with administration of an iodinated contrast agent.

    Metformin is recommended to be temporarily discontinued before any procedure involving use of iodinated contrast agents, (such as a contrast-enhanced CT scan or angiogram) due to the increased risk of lactic acidosis resulting from impaired renal function;[58][59] metformin can be resumed after two days after contrast administration, if renal function is adequate and stable.

    Adverse effects

    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 medications.[32] 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.[60]

    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 grams per day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate metformin.[61] Use of slow- or extended-release preparations may improve tolerability.[61]

    Long-term use of metformin has been associated with increased homocysteine levels[62] and malabsorption of vitamin B12.[63][64] Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency,[65] and some researchers recommend screening or prevention strategies.[66]

    Lactic acidosis

    Lactic acidosis almost never occurs with metformin exposure during routine medical care.[67] Rates of metformin-associated lactic acidosis is about nine per 100,000 person-years, which is similar to the background rate of lactic acidosis in the general population.[68] A systematic review concluded no data exists to definitively link metformin to lactic acidosis.[69]

    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 and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement).[70] The FDA recommends avoiding the use of metformin in more severe chronic kidney disease, below the estimated glomerular filtration rate (eGFR) cutoff of 30 mL/minute/1.73 m2.[71] 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.[31] 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.[72]

    Metformin has been suggested as increasing production of lactate in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors.[73] 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.[31][72][74]

    The risk of metformin-associated lactic acidosis is also increased by massive overdose of metformin, although even quite large doses are often not fatal.[75]

    Overdose

    The most common symptoms following overdose include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and, rarely, hypoglycemia or hyperglycemia.[76][77] Treatment of metformin overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses.[78] Due to metformin's low molecular weight and lack of plasma protein binding, these techniques have the benefit of removing metformin from blood plasma, preventing further lactate overproduction.[78]

    Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a forensic death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/l in persons receiving therapeutic doses, 40–120 mg/l in victims of acute overdosage, and 80–200 mg/l in fatalities. Chromatographic techniques are commonly employed.[79][80]

    Interactions

    The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys;[81] 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.[82] A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism;[83] theoretically, other cationic medications may produce the same effect.[82]

    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.[84]

    Pharmacology

    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 (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), inhibition of mitochondrial glycerophosphate dehydrogenase, and an effect on gut microbiota.[85][86][87] Ultimately, it decreases gluconeogenesis (liver glucose production).[73] It also has an insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovary.[44][88] The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.[89]

    Activation of AMPK was required for metformin's inhibitory effect on liver glucose production.[90] AMPK is an enzyme that plays an important role in insulin signalling, whole body energy balance and the metabolism of glucose and fats.[91] AMPK Activation was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase.[92] Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate).[93] Increased cellular AMP has been proposed to explain the inhibition of glucagon-induced increase in cAMP and activation of PKA.[85] Metformin and other biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[94] 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.[86]

    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,[95] and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors.[96] The increase in insulin binding after metformin treatment has also been demonstrated in patients with NIDDM.[97]

    AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle.[98] AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms.

    Metformin has indirect antiandrogenic effects in women with insulin resistance, such as those with polycystic ovary syndrome, due to its beneficial effects on insulin sensitivity.[99] It may reduce testosterone levels in such women by 50%.[99]

    Pharmacokinetics

    Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.[82][100] 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.[82][100] 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.[82]

    Metformin has acid dissociation constant values (pKa) of 2.8 and 11.5, so 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.[101][102] 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.[103]

    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.[82][104] The average elimination half-life in plasma is 6.2 hours.[82] Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours[82] (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).[104]

    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 pKa of metformin is 12.4.[105] The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat.[106][107]

    According to the procedure described in the 1975 Aron patent,[108] and the Pharmaceutical Manufacturing Encyclopedia,[109] 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.

    History
    Galega officinalis, 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.[110] Galega 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.[110]

    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.[106] In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied.[111] This result was completely forgotten, as other guanidine analogs, such as the synthalins, took over and were themselves soon overshadowed by insulin.[112]

    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.[113] That year, Filipino physician Eusebio Y. Garcia[114] 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.[115] In a series of articles in 1954, Polish pharmacologist Janusz Supniewski[116] was unable to confirm most of these effects, including lowered blood sugar. Instead he observed antiviral effects in humans.[117][118]

    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.[119] 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.[112][119]

    Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona.[120]

    Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972,[121] but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994.[122] Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the U.S., beginning on March 3, 1995.[123] Generic formulations are now available in several countries, and metformin is believed to have become the world's most widely prescribed antidiabetic medication.[119]

    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 μg L−1 have been measured in a German river which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.[124]

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

    The name "Metformin" is the BAN, USAN and INN for the medication. It is sold under several trade names, including Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, Diaformin, Siofor, Metfogamma and Glifor.

    Liquid metformin is sold under the name Riomet in India. Each 5 ml of Riomet is equivalent to the 500-mg tablet form.[125]

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

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

    Combination with other medications

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

    Several are available as fixed-dose combinations, to reduce pill burden and simplify administration.[126]

    Thiazolidinediones (glitazones)

    Rosiglitazone

    A combination of metformin and rosiglitazone was released in 2002 and sold as Avandamet by GlaxoSmithKline.[127]

    By 2009 it had become the most popular metformin combination.[128]

    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.[129] 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.[130]

    However, following a meta-analysis in 2007 that linked the medication's use to an increased risk of heart attack,[131] concerns were raised over the safety of medicines containing rosiglitazone. In September 2010 the European Medicines Agency (EMA) recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.[132][133]

    It was withdrawn from the market in the UK and India in 2010,[134] and in New Zealand and South Africa in 2011.[135] From November 2011 until November 2013 the FDA[136] 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.[137]

    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.[138][139][140]

    Pioglitazone

    The combination of metformin and pioglitazone (Actoplus Met, Piomet, Politor) remains available in U.S. and Europe.[141][142]

    DPP-4 inhibitors

    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 and a saxagliptin combination (Komboglyze), and with alogliptin as Kazano among others.

    In Europe, Canada, and elsewhere metformin combined with linagliptin is marketed under the trade name Jentadueto.[143]

    Sulfonylureas

    Sulfonylureas act by increasing insulin release from the beta cells 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).[144]

    Meglitinide

    Meglitinides are similar to sulfonylureas.

    A repaglinide/metformin combination is sold as Prandimet.

    Triple combination

    The combination of metformin with pioglitazone and glibenclamide[145] is available in India as Triformin.

    Research

    Metformin has been studied for its effects on multiple other conditions, including:

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