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Metformin is primarily used for type 2 diabetes, but is increasingly being used in polycystic ovary syndrome due to the linkage between these two conditions. The American Diabetes Association and the American College of Physicians each recommend metformin as a first-line agent to treat type 2 diabetes.

The UK Prospective Diabetes Study, a large clinical trial performed in s, provided evidence that metformin reduced the rate of adverse cardiovascular outcomes in overweight patients with type 2 diabetes relative to other antihyperglycemic agents. 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.

In , 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 review found tentative evidence that people treated with sulfonylureas had a higher risk of severe low blood sugar events RR 5.

There was not enough data available at that time to determine the relative risk of death or of death from heart disease. Metformin has little or no effect on body weight in type 2 diabetes compared with placebo , [27] in contrast to sulfonylureas which are associated with weight gain. Metformin treatment of people at a prediabetes stage of 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. 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. Antidiabetic therapy has been proposed as a treatment for polycystic ovary syndrome PCOS , a condition frequently associated with insulin resistance, since the late s.

UK and international clinical practice guidelines do not recommend metformin as a first-line treatment [43] or do not recommend it at all, except for women with glucose intolerance. Metformin treatment decreases the risk of developing type 2 diabetes mellitus in women with PCOS who exhibited impaired glucose tolerance IGT at baseline. Metformin or clomiphene are both first line treatments for infertility in women with PCOS. Four positive studies of metformin were in women not responding to clomifene, while the population in the negative studies was drug-naive or uncontrolled for the previous treatment.

Metformin should be used as a second-line medication if clomifene treatment fails. The use of metformin during all parts of pregnancy is controversial.

Metformin use among women with PCOS before they are pregnant does not appear to reduce abortion risk. Several observational studies and randomized, controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes. Nonetheless, several concerns were raised and evidence on the long-term safety of metformin for both mother and child is lacking. Metformin is safe in pregnancy and women with gestational diabetes treated with metformin have less weight gain during pregnancy than those treated with insulin.

Metformin appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine. Metformin may reduce the insulin requirement in type 1 diabetes.

According to the prescribing information , heart failure in particular, unstable or acute congestive heart failure increases the risk of lactic acidosis with metformin. 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.

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. Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism. In a clinical trial of subjects, 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. Long-term use of metformin has been associated with increased homocysteine levels [71] and malabsorption of vitamin B The most serious potential adverse effect of biguanide use is metformin-associated lactic acidosis MALA. Though the incidence for MALA is about nine per , person-years, [76] this is similar to the background incidence of lactic acidosis in the general population.

A systematic review concluded no data exists to definitively link metformin to lactic acidosis. Phenformin , another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis rate of per , patient-years. 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 cleared by other mechanisms including uptake by unimpaired kidneys , and no significant elevation in blood levels of lactate occurs.

Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. 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. Lactic acidosis is initially treated with sodium bicarbonate , although high doses are not recommended, as this may increase intracellular acidosis. A review of 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.

The most common symptoms following overdose include vomiting, diarrhea , abdominal pain, tachycardia , drowsiness, and, rarely, hypoglycemia or hyperglycemia. Extracorporeal treatments are recommended in severe overdoses. Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a forensic death investigation.

Chromatographic techniques are commonly employed. The H 2 -receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys; [91] 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.

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.

Metformin's main effect is to decrease liver glucose production. Metformin decreases high blood sugar , primarily by suppressing liver glucose production hepatic gluconeogenesis. Multiple potential mechanisms of action have been proposed, including; 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.

Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. 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 absorption of glucose from the gastrointestinal tract.

Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle.

The usual synthesis of metformin, originally described in , involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat. According to the procedure described in the 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.

Steady state is usually reached in one or two days. Metformin has acid dissociation constant values pKa of 2. The metformin pKa values make metformin a stronger base than most other basic medications with less than 0.

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 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. More lipophilic derivatives of metformin are presently under investigation with the aim of producing prodrugs with superior oral absorption than metformin.

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.

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. Metformin was first described in the scientific literature in , by Emil Werner and James Bell, as a product in the synthesis of N , N -dimethylguanidine.

Interest in metformin resumed at the end of the s. In , metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals. 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 , antimalarial , antipyretic and analgesic actions.

Instead he observed antiviral effects in humans. 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.

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 Metformin became available in the British National Formulary in 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 s. Metformin was approved in Canada in , [] but did not receive approval by the U.

Liquid metformin is sold under the name Riomet in India. Metformin IR immediate release is available in , , and mg tablets. All of these are available as generic medications in the U. Metformin SR slow release or XR extended release was introduced in It is available in , , and 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.

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. A combination of metformin and rosiglitazone was released in and sold as Avandamet by GlaxoSmithKline. By it had become the most popular metformin combination. In , the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices.

However, following a meta-analysis in 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 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. In November , the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 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.

Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels. In Europe, Canada, and elsewhere metformin combined with linagliptin is marketed under the trade name Jentadueto. Sulfonylureas act by increasing insulin release from the beta cells in the pancreas.

These students include those enrolled in local educational agencies LEAs such as elementary, high, and unified school districts, county offices of education, and charter schools. LEAs must also test all students in alternate programs, including, but not limited to, continuation schools, independent study, community day schools, county community schools, and nonpublic schools.

Students who are physically unable to take the entire test battery are to be given as much of the test as his or her condition will permit. This program also provides results that are used to monitor changes in the physical fitness of California students. The Cooper Institute established these criteria using current research and expert opinions.

These criteria represent a level of fitness that offers some protection against the diseases associated with physical inactivity. The statewide physical fitness testing program was first authorized in and reestablished in as part of the California Assessment of Academic Achievement Act Assembly Bill [AB] which added EC Section Understanding the PFT Includes a variety of resources to communicate with different audiences.

Prior year news releases and reports to the Governor and Legislature from — Additional resources for the PFT, including links to: California Department of Education. For more information about the PFT, contact your local school district.

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