The Unauthorized Biography





The birth of metformin





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 recent 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.

Metformin makes it big

Once a small-town kid suspected of mischief, metformin is now embraced by the International Diabetes Federation, the American Diabetes Association (ADA), and the European Association for the Study of Diabetes as the first-line drug for Type 2 diabetes. In fact, a few years ago the ADA dropped its long-standing recommendation to start Type 2 diabetes treatment with just diet and exercise. Now the group recommends diet, exercise, and, when necessary, metformin.

So how did metformin achieve this career transformation? It wasn’t until the UK Prospective Diabetes Study (UKPDS) was released in 1998 that the floodgates of acceptance opened. The UKPDS gave American doctors solid clinical evidence of metformin’s effectiveness at both lowering blood glucose and improving cardiovascular outcomes, just at the time when medicine in the United States was moving to a more evidence-based framework. Metformin began to pick up speed, and it hasn’t really hit any stumbling blocks since then.

According to the IMS Health National Prescription Audit, roughly 80 million prescriptions for metformin were dispensed in the United States alone in 2015. If you’re wondering how 29.1 million people with diagnosed diabetes can use nearly three times as many prescriptions, it’s because each time someone refills a 30- or 90-day supply of metformin, it counts as one prescription. Still, that’s a lot of metformin. Even at a measly four bucks a pop, the drug grosses nearly half a billion dollars per year in the United States alone. And globally, metformin is the most widely prescribed diabetes drug. Its father, Dr. Sterne, would be proud.

Metformin gets married

Metformin works well with other medicines, giving rise to precious few drug interactions. More than that, combinations of metformin and other glucose-lowering drugs have been shown to be significantly more potent than either medicine alone — and sometimes even more potent than the sum of each drug’s individual effect. Since getting people to take multiple prescription drugs can be a challenge, metformin has been married to a number of other diabetes medicines to create “polypills,” capsules or tablets with more than one drug in them.

Metformin has been combined in diabetes polypills with sulfonylureas (in Metaglip, Glucovance, Amaryl M), thiazolidinediones (ACTOplus met), DPP-4 inhibitors (Janumet, Galvumet, Kombiglyze XR), and SGLT2 inhibitors (Invokamet, Xigduo XR, Synjardy). Globally, there are now more than 20 polypills containing metformin, and the list is likely to continue to grow as new diabetes drugs are developed.

Metformin’s descendents

Although garden-variety metformin hasn’t really changed in 50 years, several new formulations have been introduced since that time. For people who have a hard time swallowing pills, metformin comes in a liquid formulation called Riomet. The most popular variant, however, is an extended-release version of the drug. Metformin is only absorbed within the body at the very upper part of the gastrointestinal tract, and any portion of the drug that passes further “downstream” is simply excreted. The trick to extending the action of the drug, then, is to keep the pill in the stomach longer while releasing the medicine slowly.

The most commonly prescribed extended-release version of metformin is Glucophage XR. This pill accomplishes its mission with a polymer that turns into a gel in the stomach, which blocks quick absorption of the medicine. This XR formulation has been shown to prolong the absorption of the drug to a peak of around seven hours, compared with traditional metformin’s three-hour peak in working action.

Indian researchers have also experimented with a floating pill that would stay in the stomach for even longer, slowly releasing metformin the entire time. For as long as metformin remains a popular diabetes drug, it is a safe bet that researchers will be trying to create new and innovative ways to deliver it to the body.

A promising future

As of today, metformin is FDA-approved only for use in Type 2 diabetes as a blood-glucose-lowering agent. However, it is increasingly used off-label by people with Type 1 diabetes to reduce insulin requirements, which it most likely achieves through its insulin-sensitizing effects. Some doctors also prescribe it to people with Type 1 diabetes who are overweight, to counteract the weight gain from insulin that some people experience.

Beyond diabetes, metformin is an effective treatment for polycystic ovary syndrome (PCOS), for which it can increase ovulation rates fourfold. While it is not FDA-approved for this use, metformin features prominently in the treatment guidelines for PCOS of many organizations worldwide, including the American College of Obstetricians and Gynecologists. In the area of HIV/AIDS treatment, metformin is sometimes used to reduce cardiovascular risk factors. And far on the cutting edge of medical research, metformin is being evaluated for its potential to reduce the growth of tumors.

Closer to its original home, metformin is increasingly used in efforts to prevent Type 2 diabetes, or at least to delay the onset of full-blown diabetes in people with prediabetes. Although metformin is not FDA-approved for prediabetes, more and more doctors prescribe it to keep blood glucose levels in the normal range for as long as possible.

After more than 50 years, it is safe to say that metformin is still going strong.