Weekly Dose: metformin, the diabetes drug developed from French lilac

Metformin is the most widely used drug to treat type 2 diabetes globally. In Australia, approximately two-thirds of patients with type 2 diabetes are prescribed metformin, either alone or in combination with other pills, or with insulin injections.

Alongside diet and exercise, metformin is considered the first-choice drug to improve glucose control in type 2 diabetes.

Metformin hydrochloride is the scientific or generic name for the active ingredient in tablets sold in Australia under 40 different proprietary or brand names.

History

Metformin was originally developed from natural compounds found in the plant Galega officinalis, known as French lilac or goat’s rue.

Synthetic biguanides were developed in the 1920s in Germany, but their use was limited due to side effects. During the 1940s, however, French physician Jean Sterne examined a new biguanide called dimethylbiguanide or metformin. At the time, it was being studied for the treatment of influenza, but Sterne recognised it had glucose-lowering properties. He proposed calling it glucophage, meaning glucose eater, a name with which it is still commercially associated today.

Metformin has been used to treat diabetes since the late 1950s. It is now on the World Health Organisation’s List of Essential Medicines needed for a basic health care system.

How does it work?

Insulin suppresses the production of glucose by the liver. One reason glucose levels remain high in those with type 2 diabetes is due to insufficient insulin. The liver continues to inappropriately make large amounts of glucose, even when glucose levels are already high.

Metformin is able to reduce glucose production by the liver by approximately one-third, through mechanisms that remain to be fully understood. When taken as directed, it will reduce the HbA1c, a marker of glucose control, by approximately 0.5% to 1%.

Who uses it?

Metformin is only indicated for lowering glucose levels in people with type 2 diabetes. However, it is also used off-label (when medications are prescribed for conditions other than what they’ve been approved for) to treat women with polycystic ovarian syndrome (PCOS) where it can be effective in some cases.

Metformin is not used to treat people with gestational diabetes or type 1 diabetes, who must take insulin injections as required to control their glucose levels.

How is it used?

To work effectively, most people will take two to three grams of metformin every day. To fit this much into a tablet, all medications containing metformin are the size of a small bullet and easily the biggest tablets people with type 2 diabetes will have to take.

Most people take their metformin twice a day (morning and night), although extended release formulations also allow for once-daily dosing.

Because metformin is most commonly used in combination with other glucose-lowering drugs to manage type 2 diabetes, fixed-dose combinations combining metformin with other oral glucose-lowering agents are also available.

What are the side effects?

The most commonly reported side effects from metformin are gastrointestinal disturbances, such as nausea, diarrhoea, cramping and flatulence. These effect around one in five people to some degree.

Usually the symptoms are mild and seen when people use high doses, when first starting metformin or increasing doses.

The likelihood of developing side effects can be reduced by starting off with low doses and increasing them gradually. It is also recommended to take metformin with or after meals to reduce the initial risk of side effects. But even despite these precautions, side effects prevent about 10% of people with type 2 diabetes from taking meformin.

Metformin is associated with a rare but life-threatening condition known as lactic acidosis, where the body builds up too much lactic acid. This can be caused by factors such as heart, liver or kidney failure. There is still controversy over whether metformin is the cause of lactic acidosis or whether it exacerbates the condition.

Unlike some other anti-diabetic medications, low blood-glucose levels are seldom observed when metformin is used on its own. Metformin also has the advantage over other agents in that it does not cause weight gain and in some people (especially women) with type 2 diabetes it may reduce their weight slightly.

Because metformin is largely removed from the body by the kidneys, people with type 2 diabetes who have impaired kidney function will require lower doses to maintain safe levels and prevent side effects.

How much does it cost

Metformin is fully funded through the Pharmaceutical Benefits Scheme for use in people with type 2 diabetes, with a maximum consumer price of A$19.08.

Drug interactions

Metformin competes for clearance by the kidneys with drugs including digoxin (for heart rhythm problems) trimethoprim and vancomycin (antibiotics), ranitidine and cimetidine (for heartburn), nifedipine and furosemide (for blood pressure) which all have the potential to modestly increase metformin levels.

In practice, metformin can be safely given in people taking these other agents with cautious observation.

Controversies

Metformin was not approved by the United States Federal Drug Agency (FDA) until late 1994. This was because one arm of a large clinical trial was stopped prematurely in 1971 when participants receiving a potent biguanide (known as phenformin) died more often and had an increased risk of lactic acidosis.

It remains controversial as to whether metformin can be used to prevent diabetes as well as treat it. Some clinical trials have shown that metformin is at least as effective as diet and exercise for preventing diabetes in those at high risk of developing it.

The requirement to always discontinue metformin in patients with renal impairment has also undergone a rethink in the last few years, as the risks of its use appear to be less than those associated with alternative therapies that expose patients to risk of hypoglycaemia, fluid retention or other side effects.

Merlin Thomas has received honoraria for educational symposia conducted on behalf of pharmaceutical companies that manufacture drugs for the management of diabetes, including metformin. He has received funding from NHMRC and JDRF for research into diabetes.