The biguanide class of anti-diabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac (''Galega officinalis''), a plant used in folk medicine for several centuries.
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, noting that it was the most potent of the biguanide analogs they studied. This result was completely forgotten as other guanidine analogs, such as the synthalins, took over, and were themselves soon overshadowed by insulin.
Interest in metformin, however, picked up at the end of the 1940s. In 1950, metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals.
That same year, a prominent Philippine physician, Eusebio Y. Garcia, used metformin (he named it ''Fluamine'') to treat influenza; he noted that the drug "lowered the blood sugar to minimum physiological limit" in treated patients and was non-toxic. Garcia also believed metformin to have bacteriostatic, 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; he did, however, observe some antiviral effects in humans.
While training at the Hôpital de la Pitié, French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from ''Galega officinalis'', which is related in structure to metformin and had seen brief use as an anti-diabetic before the synthalins were developed.
Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to re-investigate the blood sugar lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the drug and published his results in 1957.
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 the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995.
Generic formulations are now available in several countries, and metformin is believed to have become the most widely prescribed anti-diabetic drug in the world. Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients. In addition, metformin had no effect on body weight.
Over the 10-year treatment period, the metformin group gained about 1 kg, the same as the dietary advice group, while the sulfonylureas group gained 3 kg, and the insulin group, 6 kg. As metformin affords a similar level of blood sugar control to insulin and sulfonylureas, it appears to decrease mortality primarily through decreasing heart attacks, strokes and other cardiovascular complications.
Metformin has a lower risk of hypoglycemia than the sulfonylureas, Metformin is also not associated with weight gain, and modestly reduces LDL and triglyceride levels.
Non-alcoholic fatty liver disease (NAFLD) and premature puberty, three other diseases that feature insulin resistance; these indications are considered experimental. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary; although some randomized controlled trials have found significant improvement with its use, the evidence is still insufficient.
Metformin treatment of people at risk for type 2 diabetes may decrease their chances of developing the disease, although intensive physical exercise and dieting work significantly better for this purpose.
In a large U.S. study known as the Diabetes Prevention Program, participants were divided into groups and given either placebo, metformin, or lifestyle intervention, and followed for an average of three years.
The intensive program of lifestyle modifications included a 16-lesson training on dieting and exercise followed by monthly individualized sessions with the goals to decrease the body weight by 7% and engage in a physical activity for at least 150 minutes per week.
The incidence of diabetes was 58% lower in the lifestyle group and 31% lower in those given metformin. Among younger people with a higher body mass index, lifestyle modification was no more effective than metformin, and for older individuals with a lower body mass index, metformin was no better than placebo in preventing diabetes.
After ten years, the incidence of diabetes was 34% lower in the group of participants given diet and exercise and 18% lower in those given metformin. It is unclear whether metformin slowed down the progression of pre-diabetes to diabetes (true preventive effect), or the decrease of diabetes in the treated population was simply due to its glucose-lowering action (treatment effect).
Polycystic ovary syndrome
Antidiabetic therapy has been proposed as a treatment for polycystic ovary syndrome (PCOS), a condition frequently associated with insulin resistance, since the late 1980s.
The use of metformin in PCOS was first reported in 1994, in a small study conducted at the University of the Andes. 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 therapy has failed to produce results.
However, two large clinical studies completed in 2006–2007 returned mostly negative results, with metformin being no better than placebo and metformin-clomifene combination no better than clomifene alone.
Reflecting this, subsequent reviews noted that large randomized control trials have in general not shown the promise suggested by the early small studies. U.K. and international clinical practice guidelines do not recommend metformin as a first-line treatment or do not recommend it at all, except for women with glucose intolerance. The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from the drug treatment.
In a dissenting opinion, a systematic review of four head-to-head comparative trials of metformin and clomifene found them equally effective for infertility.
A BMJ editorial noted that four positive studies of metformin were in patients not responding to clomifene, while the population in the negative studies was drug-naive or uncontrolled for the previous treatment.
The editorial suggested that metformin should be used as a second-line drug if clomifene treatment fails. Another review recommended metformin unreservedly as a first-line treatment option because it has positive effects not only on anovulation but also on insulin resistance, hirsutism, and obesity often associated with PCOS.
A large Cochrane Collaboration review of 27 randomized clinical trials found that metformin improves ovulation and pregnancy rates, particularly when combined with clomifene, but is not associated with any increase in the number of live births.
The design of the negative trials may be one of the explanations for the contradictory results. For example, using live birth rate instead of pregnancy as the endpoint may have biased some trials against metformin, which works slower than clomifene. Another explanation may be different efficacy of metformin in different populations of patients.
The negative trials contained large percent of obese and previously untreated patients whose response to metformin may be weaker. and a small case-control study has suggested that the children of women given metformin instead of insulin may be healthier in the neonatal period. Nonetheless, several concerns have been raised regarding studies published thus far, and evidence on the long-term safety of metformin for both mother and child is still lacking.
A large case-control study conducted at M.D. Anderson Cancer Center has suggested that metformin may protect against pancreatic cancer. The risk of pancreatic cancer in study participants having taken metformin was found to be 62% lower than in participants never having taken it, whereas participants that had used insulin or secretagogues (such as the sulfonylureas) were found to have a 5-fold and 2.5-fold higher risk of pancreatic cancer, respectively, compared to participants that had been treated with neither.
The study had several limitations, however, and the reason for this risk reduction is still unclear.
Several epidemiological and case-controlled studies found that diabetics using metformin may have lower cancer risk in comparison to those using other anti-diabetic medications. The causes of this phenomenon are unclear, and the results require confirmation in controlled studies.
A single randomized controlled trial suggested that metformin may reduce weight gain in patients taking atypical antipsychotics, in particular, when combined with lifestyle interventions (education, dieting, and exercise).
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