Early setbacks
Metformin has been in clinical use now for over 50 years, a stellar run that’s bested only by aspirin. (Insulin, as a category, is closing in on the 100-year mark, but no one formulation of insulin comes even close to metformin’s Golden Jubilee.) But it didn’t have an easy childhood.
Fears of lactic acidosis, a wickedly dangerous side effect from some members of the biguanide family of medicines, of which metformin is a part, delayed its approval by the Food and Drug Administration (FDA) in the United States until 1995 — fully 38 years after the drug’s deployment in Europe. Lactic acidosis is a metabolic crisis in which the blood becomes acidic. It frightens doctors and patients alike because of its reputation as a one-way street, with an overall mortality rate above 75% and a median survival time of only 28 hours.
But what’s the risk of lactic acidosis from metformin, really? Cartoon character SpongeBob SquarePants may have said it best in the famous episode on sea bears: “Sea bears are no laughing matter. Why once I met this guy, who knew this guy, who knew this guy, who knew this guy, who knew this guy, who knew this guy, who knew this guy, who knew this guy, who knew this guy, who knew this guy’s cousin…” Like sea bears, very few doctors have actually seen a case of metformin-induced lactic acidosis with their own eyes. But these rumors and hearsay kept prescriptions low during metformin’s early years in the United States, despite its already long clinical career in Europe.
But now, after 50 years in the trenches, we know just how safe metformin really is. At the very worst, the rate of lactic acidosis associated with metformin is 3 cases per 100,000 patient-years. And on those exceptionally rare occasions when lactic acidosis is seen in metformin users, the fatality rate appears to be much lower than is usually seen when other drugs or conditions cause lactic acidosis. By comparison, the arthritis medicine celecoxib (Celebrex) carries an associated all-cause mortality rate of 1,140 per 100,000 patient-years.
But does metformin really cause lactic acidosis at all? One study, first published in the Cochrane Database, looked at pooled data from 347 recent clinical studies. In all of these clinical studies, there were no cases of lactic acidosis among participants who were assigned to take metformin. The new study also points out that people with diabetes are more prone to lactic acidosis than the general population in the first place. Other studies have shown that rates of lactic acidosis in non-metformin arms of clinical studies are actually higher than in metformin arms, seriously calling into question the conventional wisdom that metformin causes lactic acidosis.
Why, then, has this fear been so widespread? Metformin actually wasn’t the first member of the biguanide family of drugs to hit the market. It was preceded by buformin and by phenformin, which is now banned nearly everywhere. In contrast to metformin’s theoretical lactic acidosis rate of 3 cases per 100,000 patient-years, phenformin had a rate more than 20 times higher. It was pulled from the market following a number of high-profile deaths in France in the 1970s.
By the way, even if metformin does cause lactic acidosis, it’s not the only cheap pill to do so. Lactic acidosis is also associated with overdoses of acetaminophen, more commonly known by its brand name, Tylenol.
Click on page 4, below, to learn about how metformin made it big.
