Metformin: myths, misunderstandings and lessons from history

Abstract

Clinical trials of new drugs may overstate efficacy and not identify adverse effects. It is therefore unusual for the passage of time to reveal that a drug is less toxic, has greater efficacy and a wider range of uses than first claimed. For decades metformin was misunderstood, vilified and banned in many countries, but it is now one of the most prescribed drugs in the world. In 2010 there were more than 100 million prescriptions worldwide for metformin, alone and in combination tablets. Metformin was developed from a herb, Galega officinalis*, which was used for centuries to treat many ailments including polyuria. It is a rich source of the toxic substance guanidine. A less toxic alkaloid, galegine, was identified in France just before World War I. Its pharmacology and toxicology were studied in Paris and its structure was identified in Edinburgh. In 1922 metformin (dimethyl biguanide) was synthesised in Dublin and shown to lower blood glucose with fewer gastrointestinal adverse effects than its predecessors. However, in the same year insulin was used for the first time, distracting interest from other glucose-lowering drugs. In Paris in 1957 metformin, by then called glucophage (‘glucose eater’), was studied in trials and shown to lower blood glucose in patients with type 2 diabetes, but not in people without diabetes. Unlike sulfonylureas, metformin did not stimulate insulin release, but increased its peripheral uptake and also reduced the release of glucose from the liver. Metformin had gastrointestinal adverse effects which could be minimised by a ‘start low, go slow’ approach to dosing.