Metformin

Metformin, most commonly known by the brand name Glucophage, is a biguanide drug that lowers blood sugar. It is the standard first choice for treating type 2 diabetes, especially in people who are overweight. The medication is also prescribed for polyendocrine metabolic ovarian syndrome and, off-label, to help reduce the risk of metabolic syndrome in those taking antipsychotic drugs. It has been found to curb inflammation and does not cause weight gain. Metformin is taken orally and is usually well tolerated; the most frequent side effects are diarrhea, nausea, and abdominal pain. There is a small chance of low blood sugar, and a high dose or use in people with severe kidney problems can lead to dangerously high blood lactic acid levels.

The drug works by reducing the liver’s production of glucose, improving how the body’s tissues respond to insulin, and boosting secretion of GDF15, a hormone that lowers appetite and calorie intake. First described in scientific literature in 1922 by Emil Werner and James Bell, it was studied in humans by French physician Jean Sterne in the 1950s and launched as a medication in France in 1957. It appears on the World Health Organization’s List of Essential Medicines and is available as a generic. In 2023, it was the second most prescribed medication in the United States, with over 85 million prescriptions, and was among the top ten most prescribed drugs in Australia from 2017 to 2023.

For type 2 diabetes, the American Diabetes Association and the American College of Physicians recommend metformin as the first treatment. It works as well as repaglinide and is more effective than other oral diabetes drugs. In people without diabetes who are obese, some evidence links metformin to weight loss. It carries a lower risk of hypoglycemia than sulfonylureas, though low blood sugar can occasionally occur with intense exercise, calorie restriction, or when combined with other glucose-lowering agents. The drug also modestly lowers LDL cholesterol and triglycerides. In prediabetes, a 2019 systematic review found moderate-quality evidence that metformin reduces the risk of developing type 2 diabetes compared to diet and exercise or placebo. However, when compared to intensive diet or exercise alone, metformin did not show a reduction in risk, and adding it to intensive lifestyle changes offered no clear advantage or disadvantage.

In polyendocrine metabolic ovarian syndrome, tentative evidence suggests metformin increases the rate of live births, including in women who have not become pregnant with clomiphene. It does not appear to change the risk of miscarriage. A Cochrane review on metformin before or during IVF/ICSI in women with this condition found no conclusive improvement in live birth rates. In long GnRH-agonist protocols, there was uncertain evidence of improved live births but a possible increase in clinical pregnancy; in short GnRH-antagonist protocols, metformin may reduce live births. It may lower the risk of ovarian hyperstimulation syndrome but could cause more side effects. The evidence does not support routine use during pregnancy for obese women to improve maternal or infant outcomes. In 2004, the UK’s National Institute for Health and Clinical Excellence recommended metformin for anovulation and infertility in women with a BMI over 25 when other treatments fail. Current UK and international guidelines do not recommend it as a first-line treatment or recommend it only for those with glucose intolerance, instead suggesting clomiphene first and emphasizing lifestyle changes. Metformin does reduce the risk of developing type 2 diabetes in women with the syndrome who have impaired glucose tolerance. In Poland, it is approved and reimbursed for this condition.

For diabetes during pregnancy, a review comparing metformin to insulin alone found good short-term safety for both mother and baby, but long-term safety remains unclear. Several studies found metformin as effective and safe as insulin for managing gestational diabetes, though concerns about long-term effects on mother and child persist.