Metformin is a drug with the unusual distinction of having been rediscovered twice in this century. The generic class of substances to which it belongs was recognized to have a useful oral hypoglycemic effect in diabetic humans even before the discovery of insulin, and these substances were used in Europe in the 1930s. Enthusiasm for the use of these agents decreased, however, because of a lack of distribution and ill-defined concerns about toxicity. In the 1950s, metformin was rediscovered at the same time the sulfonylureas were introduced; and, although its therapeutic potential was not fully achieved because of continued uncertainty about its mode of action, use of metformin continued in Europe for the treatment of non–insulin-dependent diabetes (NIDDM). Today, it is a popular agent in the United Kingdom, with about one-quarter of the market for oral hypoglycemic drugs. Phenformin, which was more widely distributed and the only biguanide licensed in the United States, was also extensively used in Europe. This drug was withdrawn from the US market in October 1977 because of documented lactic acidosis as a side effect in patients with existing renal or hepatic disease and because of adverse publicity associated with the controversial University Group Diabetes Program (UGDP),<sup>88 University Group Diabetes Program A study of the effects of hypoglycaemic agents on vascular complications in patients with adult onset diabetes, V Diabetes 1975 ;  24 (suppl 1) : 65

Cliquez ici pour aller à la section Références</sup> an outcome study which showed increased mortality in maturity-onset diabetic patients treated with either tolbutamide or phenformin in comparison with placebo.

Metformin was produced in the 1950s almost entirely by a small French pharmaceutical company and, although widely distributed in Europe, was never licensed on the US market despite its more favorable side effect profile. When it became clear in the 1980s that the hypoglycemic action of the biguanide compounds was caused by a reduction of insulin resistance,<sup>20 De Fronzo R.A., Barzilai N.I.R., Simonson D.C. Mechanism of metformin action in obese and lean non–insulin-dependent diabetic subjects J Clin Endocrinol Metab 1991 ;  73 : 1294

Cliquez ici pour aller à la section Références, 40 Hollenbeck C.B., Johnston P., Varasteh B.B. , et al. Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non–insulin-dependent diabetes by glucose tolerance test criteria Diabetes Metab 1991 ;  17 : 483

Cliquez ici pour aller à la section Références</sup> and that this was likely to be beneficial in the hypertensive and hyperlipidemic aspects of NIDDM, metformin was intensively reinvestigated as a therapeutic agent.