Herbal beginnings

The plant Galega officinalis, more commonly known as goat’s rue or French lilac, gets a mention in Culpepper’s Complete Herbal of 1653. However, this was for the treatment of worms, fever and epilepsy rather than diabetes. About the same time, the famous English physician, Thomas Wills, described the symptoms of diabetes, including thirst, frequent urination and the sweetness of the urine. Tasting urine was common practice in ancient medicine but probably not something clinicians would be happy to contemplate today. The mellitus in diabetes mellitus comes from the latin word for honeyed or sweet tasting!. In 1772, John Hill, described the use of Galega to treat thirst and frequent urination.  In the mid 1800s chemists found that Galega was rich in guanidines marking the start of the development of metformin itself.

From herbs to chemistry

In 1918 guanidine was noted to lower blood sugar levels in animal studies, kick starting attempts to synthesise a range of guanidines with the aim of controlling blood dugar levels. In 1920, two such compounds, called galegine and synthalin (see figure 1 below) were synthesised and tested. Whilst showing the desired effect of lowering blood sugar levels, both were very toxic, making them unsuitable for consideration as drug candidates.

In 1922 Werner and Bell successfully synthesised metformin (dimethyl biguanide) but it wasn’t until 1929 that metformin, along with other biguanides, were tested for blood glucose lowering activity in animals. Whilst bloog glucose lowering effects were seen, because only normal animals were used, very high doses had to be given to achieve a significant effect. It was noted however that the biguanides, particularly metformin, were not as toxic as previously tested guanidines. However, because of the very high doses required there was no attempt to further develop metformin as a therapy at this time.

Defining studies

In 1956 the physician Jean Sterne and his pharmacist colleague, Denise Duval, were working for Aron Labs, near Paris in France. Sterne was aware of the previous work on biguanides and conceived the idea of revisiting the animal studies but using both normal and diabetic animals. Metformin was finally shown to be effective, with low toxicity, at acceptable dose levels. In 1957 Aron Labs marketed metformin under the brand name Glucophage (literally glucose eater).

The competition

Around the same time however, labs in Germany and the USA were reporting success with the related compounds phenformin and buformin. Phenformin gained popularity in the US, whereas buformin was more popular in Europe. In the late 1950 safety testing was much less rigorous than it is today. Thalidomide, probably the most infamous of drugs, was first marketed in 1958, and its effects changed the way drug were regulated subsequently. Both phenformin and buformin were withdrawn from sale in 1970 due to toxic side effects, in particular lactic acidosis, in which the blood becomes too acidic with potentially lethal consequences.