Synthalin, Buformin, Phenformin, Metformin: A Century Of Intestinal„ -Clearance“ as Oral Antidiabetic Strategy in Overweight/Obese Patients

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside), because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. Metformin (1-1-dimethylbiguanide), first synthesized 1922 but first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977-1997), released in the USA after a short-term prospective trial in healthy overweight type 2 diabetics in 1995 for oral treatment of diabetes type 2,mostly to multimorbid older (above 65 years of age) and is now the most used drug worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase of its (metformin) intestinal concentration (up to 300-fold compared to that measured in the blood) , to reduced absorption of glucose from the diet and to decrease of insulin serum level through increased hepatic uptake and decreased production. Acute gastrointestinal side effects accompanied by fluid loss often led to dose-reduction of the drugs and strongly limit adherence to therapy. Main long-term consequences are „chronic“ dehydration, deficiency of vitamin B12 and of iron and as observed for all the biguanides, to „chronic“ increase of fasting and postprandial lactate plasma level and also to a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Intravenously injected F18-labelled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is similar to that observed in patients after bowel-cleansing or chronically taking different types of laxatives where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to „attraction“ of glucose from the hepatocyte to the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Metformin is not different from the other biguanides, synthalin B, buformin and phenformin. The mechanism of action, and the side effects are comparable if not even stronger (abdominal pain and fluid loss) to those of laxatives.