Metformin - History

History

The biguanide class of antidiabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries.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 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 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 the drug "lowered the blood sugar to minimum physiological limit" and was nontoxic. 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 antidiabetic before the synthalins were developed. Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate 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.

Metformin became available in the British National Formulary in 1958. 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 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 antidiabetic drug in the world.