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Metformin

Main first-line medication for type 2 diabetes.

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.

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Timeline

Galega officinalis used to treat diabetes symptoms

In 1772, Galega officinalis was used anecdotally to treat symptoms of diabetes, laying the foundation for the eventual development of Metformin.

Discovery of sugar-reducing properties of Gallegos officinalis

In 1918, the sugar-reducing properties of the plant Gallegos officinalis, also known as goat’s rue or French lilac, were identified.

Discovery of Metformin

Metformin was first described in scientific literature in 1922 by Emil Werner and James Bell.

Discovery of Galegine Structure

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.

Discovery of Metformin's Sugar-Lowering Action

In 1929, Slotta and Tschesche discovered metformin's sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied.

Discovery of Metformin's Anti-Influenza Properties

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.

Metformin's Unique Properties

In 1950, metformin was found not to decrease blood pressure and heart rate in animals, setting it apart from other similar compounds.

Jean Sterne's Contribution to Metformin Development

Jean Sterne, a physician at Aron Laboratories in Paris, played a crucial role in recognizing metformin's potential as a diabetes therapy in 1956.

Metformin Trials in Paris

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.

Metformin introduced as a diabetes medication in the UK

In 1958, metformin was introduced as a medication for diabetes in the United Kingdom.

Clinical experience with DBI (phenformin) in the management of diabetes

In 1959, McKendry, Kuwayti, and Rado conducted a study on the clinical experience of using DBI (phenformin) for managing diabetes.

Comparison of Metformin with Chlorpropamide in Scotland

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.

Withdrawal of Phenformin

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.

Approval of Metformin in Canada

Metformin was approved in Canada in 1972, expanding its availability to a new market.

Aron Patent for Metformin Synthesis

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.

Comparison of Metformin with Chlorpropamide in Scotland

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.

Metformin: a review of its pharmacological properties and therapeutic use

Hermann LS conducted a review in 1979 on the pharmacological properties and therapeutic use of metformin.

Biguanides: a review of history, pharmacodynamics and therapy

In 1983, Schäfer provided a review on the history, pharmacodynamics, and therapy of biguanides.

Intensive assessment process for Metformin to gain marketing approval in the US

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.

FDA approval of metformin in the USA

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.

Market Launch of Glucophage in the U.S.

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.

UK Prospective Diabetes Study Identifies Long-term Cardiovascular Benefits of Metformin

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.

Approval of extended-release formulation of metformin

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.

Metformin shown to reduce progression from prediabetes to diabetes

In 2002, research demonstrated that metformin could reduce the progression from prediabetes to diabetes.

UK National Institute for Health and Clinical Excellence recommends metformin for women with PCOS

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.

Removal of Avandamet from the market

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.

Meta-analysis linking rosiglitazone to increased risk of heart attack

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.

Suspension of rosiglitazone from the European market

In September 2010, the European Medicines Agency recommended the suspension of rosiglitazone from the European market due to the risks outweighing the benefits.

Metformin included in the essential medications list of the World Health Organization

In 2011, metformin was added to the essential medications list of the World Health Organization.

Metformin declared as first-choice treatment for all patients with type 2 diabetes

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.

FDA lifting restrictions on rosiglitazone

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.

Update to metformin product label in the USA

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.

FDA Announcement on NDMA in Metformin

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.

FDA Findings on NDMA Levels in Metformin Samples

In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.

FDA Request for Voluntary Recall of Sustained-Release Metformin

In May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products due to NDMA contamination.

FDA Laboratory Results on NDMA in Metformin Products

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.

Lupin Pharmaceuticals Recall of Metformin Lots

In July 2020, Lupin Pharmaceuticals pulled all lots of metformin after discovering unacceptably high levels of NDMA in tested samples.

Bayshore Pharmaceuticals Recall of Metformin Lots

In August 2020, Bayshore Pharmaceuticals recalled two lots of metformin tablets.

Metformin boosts appetite-suppressing metabolite

A recent study discovered that Metformin enhances the production of a metabolite that helps in suppressing appetite.

End of the Timeline
Metformin

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