The Phantom of Lactic Acidosis due to Metformin in Patients With Diabetes

Metformin is the only biguanide that is available in the U.S. Another biguanide, phenformin, had been used since the 1950s, but was declared an “imminent hazard” in 1976 because of lactic acidosis (1). At the time of its removal from the market, there had been 306 documented cases of phenformin-associated lactic acidosis (2), including 1 fatal and 2 nonfatal cases in the randomized controlled trial of the University Group Diabetes Program (3). Metformin was marketed as Glucophage by Bristol-Myers Squibb in early 1995, with a boxed warning concerning the risk of lactic acidosis. Metformin had been used widely in Europe for several years, where it had been recognized that the risk of lactic acidosis from metformin was no greater than the risk of hypoglycemia from sulfonylureas (4). Although the clinical utility of metformin had been recognized in the U.S. (5), its approval was undoubtedly delayed by the specter of phenformin and the lingering concern that metformin might also cause lactic acidosis. The eventual approval of metformin was unusually controversial. Crofford (6) predicted that metformin “will be widely used and will improve the outlook for many patients” with diabetes. But fear of lactic acidosis led the consumer advocacy group Public Citizen (7) to issue the warning: “Do not use Glucophage.” Based on data from Sweden, it was estimated that the risk of lactic acidosis in patients taking phenformin was ∼10-fold higher than the risk in patients taking metformin. A later report from Sweden (9) concluded that discontinuing metformin in aging patients when they developed renal or cardiovascular disease could further reduce the risk of lactic acidosis. The labeling …