Metformin, sold as Glucophage, treats type 2 diabetes and polycystic ovary syndrome. It reduces glucose production and insulin sensitivity, and is well tolerated with common side effects like diarrhea and nausea. Metformin was first described in 1922 and is widely used worldwide.
In 1772, Galega officinalis was used anecdotally to treat symptoms of diabetes, laying the foundation for the eventual development of Metformin.
In 1918, the sugar-reducing properties of the plant Gallegos officinalis, also known as goat’s rue or French lilac, were identified.
Metformin, also known as dimethylbiguanide, was synthesized by Werner and Bell in 1922.
In 1923, a research group in Edinburgh, UK confirmed the precise structure of galegine, the active ingredient in French lilac that lowers blood glucose levels.
In 1929, Slotta and Tschesche discovered metformin's sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied.
In 1949, tests conducted by Eusebio Garcia in the Philippines found that metformin, originally modified from proguanil, was helpful in treating a local influenza outbreak.
In 1950, metformin was found not to decrease blood pressure and heart rate in animals, setting it apart from other similar compounds.
Jean Sterne, a physician at Aron Laboratories in Paris, played a crucial role in recognizing metformin's potential as a diabetes therapy in 1956.
In 1957, metformin was studied in several trials in Paris and shown to lower blood glucose in patients with type 2 diabetes. It did not stimulate insulin release but primarily reduced the release of glucose from the liver. Metformin also showed adverse gastrointestinal effects.
In 1958, metformin was introduced as a medication for diabetes in the United Kingdom.
In 1959, McKendry, Kuwayti, and Rado conducted a study on the clinical experience of using DBI (phenformin) for managing diabetes.
In 1968, a study conducted in Scotland compared metformin with chlorpropamide and found that glucose control was similar with both drugs. However, patients on metformin experienced less hypoglycemia and weight loss compared to those on chlorpropamide.
Phenformin was withdrawn from the University Group Diabetes Program (UGDP) trial in the USA in 1971 due to the risk of lactic acidosis. It was later removed from the market in the USA in 1978.
Metformin was approved in Canada in 1972, expanding its availability to a new market.
In 1975, the Aron patent described a procedure for the synthesis of metformin involving the reaction of dimethylamine and 2-cyanoguanidine in toluene with hydrogen chloride, resulting in metformin hydrochloride with a 96% yield.
In 1977, another study conducted in Scotland compared metformin with chlorpropamide and found that glucose control was similar with both drugs. However, patients on metformin experienced less hypoglycemia and weight loss compared to those on chlorpropamide.
Hermann LS conducted a review in 1979 on the pharmacological properties and therapeutic use of metformin.
In 1983, Schäfer provided a review on the history, pharmacodynamics, and therapy of biguanides.
In 1986, metformin underwent an intensive assessment process to gain marketing approval in the US, facing an avalanche of questions from the FDA before ultimately launching in 1995.
Metformin was approved by the FDA in the USA on December 29, 1994, following a thorough reassessment initiated by Lipha Pharmaceuticals. The approval marked a significant milestone in the introduction of metformin to the US market.
The branded formulation of metformin, Glucophage, was marketed in the U.S. by Bristol-Myers Squibb starting on 3 March 1995, making it more accessible to the American population.
The UK Prospective Diabetes Study (UKPDS) in 1998 identified the long-term cardiovascular benefits of metformin, leading to its adoption as the preferred initial therapy for managing hyperglycemia in type 2 diabetes.
In 2000, an extended-release formulation of metformin was approved, offering reduced gastrointestinal side effects for patients. This development aimed to enhance the tolerability and efficacy of metformin therapy.
In 2002, research demonstrated that metformin could reduce the progression from prediabetes to diabetes.
In 2004, the UK National Institute for Health and Clinical Excellence recommended 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.
In 2005, the stock of Avandamet was removed from the market due to violations of good manufacturing practices. However, it became available again by the end of the year.
In 2007, a meta-analysis linked the use of rosiglitazone to an increased risk of heart attack, raising concerns over the safety of medications containing rosiglitazone.
In September 2010, the European Medicines Agency recommended the suspension of rosiglitazone from the European market due to the risks outweighing the benefits.
In 2011, Metformin was discovered as a significant drug for controlling diabetes. It has been widely used in the treatment of diabetes to help manage blood sugar levels.
In 2012, diabetes experts in the USA and Europe officially recommended metformin as the first-choice treatment for all patients with type 2 diabetes, based on its confirmed anti-atherosclerotic and cardioprotective effects.
In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial, which did not show elevated risk of heart attack or death associated with the medication.
In 2016, a citizens' petition in the USA led to an update in the metformin product label, allowing prescribing for individuals with mild renal impairment. This update reflected the continuous evaluation and adaptation of metformin guidelines.
In December 2019, the US FDA announced 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.
In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.
In May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products due to NDMA contamination.
In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested, recommending companies recall lots with levels of NDMA above the acceptable intake limit.
In July 2020, Lupin Pharmaceuticals pulled all lots of metformin after discovering unacceptably high levels of NDMA in tested samples.
In August 2020, Bayshore Pharmaceuticals recalled two lots of metformin tablets.
A recent study discovered that Metformin enhances the production of the appetite-suppressing metabolite N-lactoyl phenylalanine (Lac-Phe).