Sometimes it takes a long time for a drug to reach patients.
For decades metformin, the leading medication for type 2 diabetes, was neglected and even banned. Its story teaches two lessons: how scientists can turn a promising plant into a useful drug, and the sometimes long slow path to acceptance.
In medieval times, people ate the plant Galega officinalis, also known as Goat’s rue, French lilac, or Italian fitch, to relieve frequent urination, one symptom of diabetes. The plant has a long history as a folk remedy, though it can also be toxic, particularly to livestock. When scientists discovered that one of the chemicals it contained lowered blood sugar levels, they looked for safer variations.
Just before World War I, researchers in Paris identified a key chemical, other scientists chipped in in Edinburgh, and, in 1922, researchers in Dublin synthesized metformin, or dimethyl biguanide. The new form was safe and easier on the digestive track than earlier compounds. Starting with a low dose and increasing slowly also helped minimize gastrointestinal side effects. But around the same time, insulin stole the stage as a diabetes treatment.
By the late 1950s, metformin had been named “Glucophage,” which means “glucose eater.” Around the same time, an American group discovered phenformin, or phenylethyl biguanide. Ciba-Geigy marketed it around the world, although reports emerged that it could cause a condition called lactic acidosis, and lead to deaths. Metformin was manufactured by a small French company and became popular only in France and Scotland.
In the 1970s, the evidence that phenformin posed a fatal risk of lactic acidosis mounted and, in 1977, it was banned in the United States and elsewhere. Some countries put restrictions on metformin as well. However, phenformin is metabolised by the liver and accumulates in patients with a genetic deficiency of a particular enzyme. Metformin is excreted in urine. It has been tied to lactic acidosis in overdoses or in people with advanced renal failure, but is generally safe.
In France and Scotland, where early discoveries had been made, endocrinologists had been getting good results with metformin, and they continued to prescribe it widely.
Research continued to show that metformin, used correctly, was safe and effective. Still, Americans didn’t get the benefit of metformin until the mid-90s.
In 2012, the American Diabetes Association and its European counterpart declared that metformin should be the first choice treatment for obese people with type 2 diabetes. It is also used to treat polycystic ovary syndrome and gestational diabetes. Interestingly, people who are taking metformin seem to have lower rates of pancreas, colon, and liver cancers, and researchers are hot on the trail to use metformin for cancer prevention.
Yet it may still be under prescribed, particularly for diabetes prevention. The main recommendation for prevention is eating better, losing weight, and exercising. In 2008, a panel for the American Diabetes Association concluded that doctors should also consider metformin for patients who are severely obese, or those with prediabetes — blood sugar above normal but not yet in the diabetes range. In one study with a national sample of more than 17,000 working-age adults, researchers discovered that doctors offered only 3.7 percent of patients with prediabetes metformin in the 3 years from 2010 to 2012. “Our findings indicate that metformin is rarely prescribed for diabetes prevention despite a strong evidence base in the literature for more than 10 years and inclusion in practice guidelines for more than 6 years,” wrote the authors, led by Tannaz Moin, MD, of the University of California, Los Angeles
Who should be tested for diabetes or pre-diabetes? Adults who are overweight or obese and over the age of 45, and any overweight person who has an additional risk factor. The risk factors include inactivity; a parent, brother, or sister with diabetes; giving birth to a baby weighing more than 9 pounds; high blood pressure; low “good” cholesterol or high triglycerides; polycystic ovary syndrome, or a history of heart disease.
A caveat: People with an under-active thyroid may aggravate that problem with metformin, some research shows. If your doctor hasn’t suggested metformin to treat your prediabetes, ask why. The answer may be that you’d be better off losing weight and getting more exercise, not just “popping a pill.” But taking medication can sometimes get you to focus on a problem. Evaluate for yourself whether taking metformin will sap or enhance your motivation to change your ways. Develop a clear strategy to lower your own diabetes risk that includes every resource available to you, which might be a gym buddy or joining a weight-loss group.
February 28, 2020
Christopher Nystuen, MD, MBA