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Metformin is generally well tolerated. Common adverse effects include diarrhea, nausea, and abdominal pain. It has a small risk of causing low blood sugar. High blood lactic acid level is a concern if the medication is used in overly large doses or prescribed in people with severe kidney problems. It is not recommended...
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Metformin is a biguanide antihyperglycemic agent. It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues, and increasing GDF15 secretion, which reduces appetite and caloric intake.
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Metformin was discovered in 1922. French physician Jean Sterne began the study in humans in the 1950s. It was introduced as a medication in France in 1957 and the United States in 1995. It is on the World Health Organization's List of Essential Medicines. Metformin is the most widely used medication for diabetes taken ...
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Metformin is used to lower the blood sugar in those with type 2 diabetes. It is also used as a second-line agent for infertility in those with polycystic ovary syndrome.
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The American Diabetes Association and the American College of Physicians both recommend metformin as a first-line agent to treat type 2 diabetes. It is as effective as repaglinide and more effective than all other oral diabetes mellitus type 2 drugs.
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Treatment guidelines for major professional associations, including the European Association for the Study of Diabetes, the European Society for Cardiology, and the American Diabetes Association, describe evidence for the cardiovascular benefits of metformin as equivocal. A 2020 Cochrane systematic review did not find ...
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The use of metformin reduces body weight in people with type 2 diabetes mellitus in contrast to sulfonylureas, which are associated with weight gain. Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes. Metformin has a lower risk of hypoglycemia than the sulfonylureas...
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In individuals with prediabetes, a 2019 systematic review compared the effects of Metformin with other interventions in the reduction of risk of developing type 2 diabetes. They found moderate-quality evidence that Metformin reduced the risk of developing type 2 diabetes when compared to diet and exercise or a placebo....
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In those with polycystic ovarian syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births. This includes in those who have not been able to get pregnant with clomiphene. Metformin does not appear to change the risk of miscarriage. A number of other benefits have also been found bot...
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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. UK and international clinical practice guidelines do not recommend metformin...
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A total review of metformin use during pregnancy compared to insulin alone found good short-term safety for both the mother and baby, but unclear long-term safety. Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diab...
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Metformin use is typically associated with weight loss. It appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine. Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more v...
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Metformin may reduce the insulin requirement in type 1 diabetes, albeit with an increased risk of hypoglycemia.
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There is some evidence metformin may be helpful in extending lifespan, even in otherwise healthy people. It has received substantial interest as an agent that delays aging, possibly through similar mechanisms as its treatment of diabetes (insulin and carbohydrate regulation). This is controversial, and an area of activ...
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The possibility that metformin can delay the onset or progression of Alzheimer's disease, or even prevent it, is under investigation. There has been a variety of research published in this field in an effort to establish a correlation between type 2 diabetes and Alzheimer's disease. Research now includes studies with p...
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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), surg...
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Metformin is recommended to be temporarily discontinued before any procedure involving use of iodinated contrast agents, (such as a contrast-enhanced CT scan or angiogram) due to the increased risk of lactic acidosis resulting from impaired kidney function; metformin can be resumed after two days after contrast adminis...
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The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence; metformin is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications. The most serious potential adverse effect of metformin...
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Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7 g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate ...
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Long-term use of metformin has been associated with increased homocysteine levels and malabsorption of vitamin B. Higher doses and prolonged use are associated with increased incidence of vitamin B deficiency, and some researchers recommend screening or prevention strategies.
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Lactic acidosis almost never occurs with metformin exposure during routine medical care. Rates of metformin-associated lactic acidosis are about nine per 100,000 persons/year, which is similar to the background rate of lactic acidosis in the general population. A systematic review concluded no data exists to definitive...
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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 FDA recommends avoid...
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Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. The clinical significance of this is unknown, though, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepati...
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The risk of metformin-associated lactic acidosis is also increased by a massive overdose of metformin, although even quite large doses are often not fatal.
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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 ...
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Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or to assist in a forensic death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving therapeutic doses, 40–120 mg/L in victims of acute overdosage, and...
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The H-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys; 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 t...
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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...
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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 (cAM...
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Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signalling, whole-body energy balance, and the metabolism of glucose and fats. AMPK activation was required for an increase in the expression of small heterodimer part...
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In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal ...
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AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by ...
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Metformin has indirect antiandrogenic 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 and...
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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.
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Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (C) 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...
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Metformin has acid dissociation constant values (pK) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pK values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the lipid solubility of...
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Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose. The average elimination half-life in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cel...
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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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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 of metformin is 12.4. The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydroc...
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According to the procedure described in the 1975 Aron patent, and the "Pharmaceutical Manufacturing Encyclopedia", equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begi...
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The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goat's rue ("Galega officinalis"), a plant used in folk medicine for several centuries. "G. officinalis" itself does not contain any of these medications, but isoamylene...
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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 complete...
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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 t...
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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 ...
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Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona.
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Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972, but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994. Produced under license by Bristol-Myers Squibb, Glucophage was th...
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Metformin and its major transformation product guanylurea are present in wastewater treatment plant effluents and regularly detected in surface waters. Guanylurea concentrations above 200 μg/L have been measured in the German river Erpe, which are amongst the highest reported for pharmaceutical transformation products ...
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The name "Metformin" is the BAN, USAN, and INN for this medication, and is sold under several trade names. Common brand names include Glucophage, Riomet, Fortamet, and Glumetza in the US. In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor. The...
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Several are available as fixed-dose combinations, with the potential to reduce pill burden, decrease cost, and simplify administration.
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A combination of metformin and rosiglitazone was released in 2002, and sold as Avandamet by GlaxoSmithKline, or as a generic medication. Formulations are 500/1, 500/2, 500/4, 1000/2, and 1000 mg/4 mg of metformin/rosiglitazone.
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In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices. The medication pair continued to be prescribed separately, and Avandamet was again available by the end of that year. A generic formulation of metformin/ros...
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However, following a meta-analysis in 2007 that linked the medication's use to an increased risk of heart attack, concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the European Medicines Agency recommended that the medication be suspended from the European market because the...
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It was withdrawn from the market in the UK and India in 2010, and in New Zealand and South Africa in 2011. From November 2011 until November 2013 the FDA did not allow rosiglitazone or metformin/rosiglitazone to be sold without a prescription; moreover, makers were required to notify patients of the risks associated wi...
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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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The combination of metformin and pioglitazone (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union.
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Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels.
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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).
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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.
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Sulfonylureas act by increasing insulin release from the beta cells in the pancreas. They often can be used as secondary therapy if metformin alone is not sufficiently effective at reaching normal blood glucose levels.
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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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Meglitinides are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs' affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas, and require higher blood glucose levels to begin to ...
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The combination of metformin with dapagliflozen and saxagliptin is available in the United States as Qternmet XR.
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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.
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In December 2019, the U.S. FDA announced that it learned that some metformin medicines manufactured outside the United States might contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen, at low levels. Health Canada announced that it was assessing NDMA levels in ...
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In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.
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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.
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On 29 May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products. The five companies were not named, but they were revealed to be Amneal Pharmaceuticals, Actavis Pharma, Apotex Corp, Lupin Pharma, and Marksans Pharma Limited in a letter sent to Valisure, the pharmacy that ha...
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In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested. It found NDMA in certain lots of ER metformin, and is recommending companies recall lots with levels of NDMA above the acceptable intake limit of 96 nanograms per day. The FDA is also collaborating with internation...
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In July 2020, Lupin Pharmaceuticals pulled all lots (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.
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While metformin may reduce body weight in persons with fragile X syndrome, whether it improves neurological or psychiatric symptoms is uncertain. Metformin has been studied in vivo ("C. elegans" and crickets) for effects on aging. A 2017 review found that people with diabetes who were taking metformin had lower all-cau...
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Lithium (from ) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid element. Like all alkali metals, lithium is highly reactive and flammable, and must be stored in vacuum, inert atmosphe...
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The nucleus of the lithium atom verges on instability, since the two stable lithium isotopes found in nature have among the lowest binding energies per nucleon of all stable nuclides. Because of its relative nuclear instability, lithium is less common in the solar system than 25 of the first 32 chemical elements even t...
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Lithium and its compounds have several industrial applications, including heat-resistant glass and ceramics, lithium grease lubricants, flux additives for iron, steel and aluminium production, lithium metal batteries, and lithium-ion batteries. These uses consume more than three-quarters of lithium production.
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Lithium is present in biological systems in trace amounts; its functions are uncertain. Lithium salts have proven to be useful as a mood stabilizer and antidepressant in the treatment of mental illness such as bipolar disorder.
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The alkali metals are also called the lithium family, after its leading element. Like the other alkali metals (which are sodium (Na), potassium (K), rubidium (Rb), caesium (Cs), and francium (Fr)), lithium has a single valence electron that is easily given up to form a cation. Because of this, lithium is a good conduct...
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Lithium metal is soft enough to be cut with a knife. When cut, it possesses a silvery-white color that quickly changes to gray as it oxidizes to lithium oxide. Its melting point of and its boiling point of are each the highest of all the alkali metals while its density of 0.534 g/cm is the lowest.
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Lithium has a very low density (0.534 g/cm), comparable with pine wood. It is the least dense of all elements that are solids at room temperature; the next lightest solid element (potassium, at 0.862 g/cm) is more than 60% denser. Apart from helium and hydrogen, as a solid it is less dense than any other element as a l...
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Lithium's coefficient of thermal expansion is twice that of aluminium and almost four times that of iron. Lithium is superconductive below 400 μK at standard pressure and at higher temperatures (more than 9 K) at very high pressures (>20 GPa). At temperatures below 70 K, lithium, like sodium, undergoes diffusionless ph...
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Lithium has a mass specific heat capacity of 3.58 kilojoules per kilogram-kelvin, the highest of all solids. Because of this, lithium metal is often used in coolants for heat transfer applications.
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Naturally occurring lithium is composed of two stable isotopes, Li and Li, the latter being the more abundant (92.5% natural abundance). Both natural isotopes have anomalously low nuclear binding energy per nucleon (compared to the neighboring elements on the periodic table, helium and beryllium); lithium is the only l...
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Li is one of the primordial elements (or, more properly, primordial nuclides) produced in Big Bang nucleosynthesis. A small amount of both Li and Li are produced in stars during stellar nucleosynthesis, but it is further "burned" as fast as produced. Li can also be generated in carbon stars. Additional small amounts of...
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Lithium isotopes fractionate substantially during a wide variety of natural processes, including mineral formation (chemical precipitation), metabolism, and ion exchange. Lithium ions substitute for magnesium and iron in octahedral sites in clay minerals, where Li is preferred to Li, resulting in enrichment of the ligh...
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Nuclear weapons manufacture and other nuclear physics applications are a major source of artificial lithium fractionation, with the light isotope Li being retained by industry and military stockpiles to such an extent that it has caused slight but measurable change in the Li to Li ratios in natural sources, such as riv...
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Both stable isotopes of lithium can be laser cooled and were used to produce the first quantum degenerate Bose-Fermi mixture.
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Although it was synthesized in the Big Bang, lithium (together with beryllium and boron) is markedly less abundant in the universe than other elements. This is a result of the comparatively low stellar temperatures necessary to destroy lithium, along with a lack of common processes to produce it.
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According to modern cosmological theory, lithium—in both stable isotopes (lithium-6 and lithium-7)—was one of the three elements synthesized in the Big Bang. Though the amount of lithium generated in Big Bang nucleosynthesis is dependent upon the number of photons per baryon, for accepted values the lithium abundance c...
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Lithium is also found in brown dwarf substellar objects and certain anomalous orange stars. Because lithium is present in cooler, less-massive brown dwarfs, but is destroyed in hotter red dwarf stars, its presence in the stars' spectra can be used in the "lithium test" to differentiate the two, as both are smaller than...
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On 27 May 2020, astronomers reported that classical nova explosions are galactic producers of lithium-7.
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Although lithium is widely distributed on Earth, it does not naturally occur in elemental form due to its high reactivity. The total lithium content of seawater is very large and is estimated as 230 billion tonnes, where the element exists at a relatively constant concentration of 0.14 to 0.25 parts per million (ppm), ...
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Estimates for the Earth's crustal content range from 20 to 70 ppm by weight. Lithium constitutes about 0.002 percent of Earth's crust. In keeping with its name, lithium forms a minor part of igneous rocks, with the largest concentrations in granites. Granitic pegmatites also provide the greatest abundance of lithium-co...
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According to the "Handbook of Lithium and Natural Calcium", "Lithium is a comparatively rare element, although it is found in many rocks and some brines, but always in very low concentrations. There are a fairly large number of both lithium mineral and brine deposits but only comparatively few of them are of actual or ...
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Chile is estimated (2020) to have the largest reserves by far (9.2 million tonnes), and Australia the highest annual production (40,000 tonnes). One of the largest "reserve bases" of lithium is in the Salar de Uyuni area of Bolivia, which has 5.4 million tonnes. Other major suppliers include Australia, Argentina and Ch...
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In June 2010, "The New York Times" reported that American geologists were conducting ground surveys on dry salt lakes in western Afghanistan believing that large deposits of lithium are located there. These estimates are "based principally on old data, which was gathered mainly by the Soviets during their occupation of...
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Lithium is found in trace amount in numerous plants, plankton, and invertebrates, at concentrations of 69 to 5,760 parts per billion (ppb). In vertebrates the concentration is slightly lower, and nearly all vertebrate tissue and body fluids contain lithium ranging from 21 to 763 ppb. Marine organisms tend to bioaccumul...
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Studies of lithium concentrations in mineral-rich soil give ranges between around 0.1 and 50−100 ppm, with some concentrations as high as 100−400 ppm, although it is unlikely that all of it is available for uptake by plants. Lithium concentration in plant tissue is typically around 1 ppm, with some plant families bioac...
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The monovalent lithium ion competes with other ions such as sodium (immediately below lithium on the periodic table), which like lithium is also a monovalent alkali metal.
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Lithium also competes with bivalent magnesium ions, whose ionic radius (86 pm) is approximately that of the lithium ion (90 pm).
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For instance, sodium channels (both voltage-gated and epithelial) are particularly major pathways of entry for lithium.
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Lithium ions can also permeate through ligand-gated ion channels as well as cross both nuclear and mitochondrial membranes.
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Like sodium, lithium can enter and partially block (although not permeate) potassium channels and calcium channels.
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