Metformin: historical overview

Abstract

Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.

The effects of metformin on gut microbiota and the immune system as research frontiers

“…Elucidation of the rather unexpected molecular mechanisms of action followed much later, and remains incomplete. As detailed elsewhere [1], mediaeval treatments for polyuria included extracts of the plant Galega officinalis. These extracts were presumably beneficial for a subset of patients complaining of excess urination, specifically those suffering from the disease we now know as type 2 diabetes, which when poorly controlled is a cause of polyuria.…”

60 years of metformin use: a glance at the past and a look to the future

“…Our series begins with an introduction to the drug by Clifford Bailey [21], who outlines its herbal history, tracing it to Galega officinalis, which was first indicated to treat diabetes-associated symptoms in 1772. Bailey describes how it was not until 1957 that a physician named Jean Sterne reawakened interest in metformin.…”

Repurposing metformin for the prevention of cancer and cancer recurrence

“…It decreases hepatic gluconeogenesis and improves insulin sensitivity by increasing peripheral glucose uptake and use, lowering both basal and postprandial plasma glucose [1]. It was first approved in the UK in 1958, followed by Canada in 1972, and then the USA in 1994 [2]. The most common side effects that occur in > 5% of patients include diarrhoea, nausea/vomiting, flatulence, indigestion, abdominal discomfort, lack of energy and headache [1].…”