How does metformin work? Researchers don't know exactly

Metformin has been used for diabetes treatment since the 1950s, along with lifestyle changes like a low-carb diet and increased physical activity. Even after all this time, scientists still don’t know precisely how it works. 

Under normal circumstances, when you eat or drink, your blood carries glucose (sugar) to cells in your body to use for energy. It is insulin’s job to get the glucose out of your bloodstream and into your cells. 

In type 2 diabetes, your blood sugar levels get too high (hyperglycemia), usually because either your body doesn’t respond to insulin as it should or because your body isn’t producing enough insulin to keep up with the high sugars. High blood sugars can cause damage to your nerves, eyes, blood vessels, and kidneys and increases your risk of developing heart disease, heart attacks, and strokes. 

Metformin belongs to a drug class called biguanides. It lowers the amount of sugar (glucose) in your blood by blocking gluconeogenesis, glucose production by the liver (Rena, 2017). However, this may not be all. Research suggests that metformin may also lower blood sugar by enhancing your muscle tissue’s ability to remove glucose from the bloodstream and use it for energy (Musi, 2002). 

In addition, metformin stimulates the good bacteria that live in your gut to use more glucose, thereby decreasing your blood sugar levels (Rena, 2017). It also increases your body’s insulin sensitivity, the ability to respond to the hormone insulin (MedlinePlus, 2020). Metformin does not work for type 1 diabetes, a condition where your body does not make insulin.

There is still much to be learned about metformin and how it works. But it is clear that it is an effective treatment for type 2 diabetes—it is one of the most widely prescribed medicines for type 2 diabetes (Wang, 2014). 

Based on guidelines from the American Diabetes Association (ADA), if you are diagnosed with type 2 diabetes, your healthcare provider will likely prescribe metformin—along with instructions on getting regular physical activity and eating a healthy diet (ADA, 2020). The goal? To help you gain control over blood glucose levels. 

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The U.S. Food and Drug Administration (FDA) approved metformin to treat type 2 diabetes in 1995. Like many other drugs, metformin is used “off label” to treat other conditions that are not FDA-approved uses, including (UpToDate, n.d.): 

Polycystic Ovary Syndrome (PCOS)

PCOS is a common female endocrine (hormonal) disorder that affects as many as 10% of women. Women with this condition often experience menstrual irregularity, high androgen (male hormone) level, weight gain, facial hair growth, and insulin resistance (meaning the body doesn’t respond to insulin as it should). Metformin can help make women with PCOS more sensitive to insulin leading to lower blood glucose levels and weight loss. It also helps normalize the hormonal imbalance, thereby improving overall symptoms (Banaszewska, 2019). Even though the evidence is not conclusive, many women with PCOS are treated with metformin.

Gestational diabetes

During pregnancy, a woman can develop diabetes—this is called gestational diabetes. Treatment usually entails lifestyle and diet modifications, but if that is not enough, medications may be needed. Gestational diabetes often goes away after the baby is born, but it can increase your risk of developing type 2 diabetes in the future. Metformin is one of the options offered to women dealing with gestational diabetes, as it is both safe and effective (Balsells, 2015).

Prediabetes

Prediabetes is a condition where you have increased blood sugar levels, but not high enough to be called diabetes. Metformin helps you get control over blood sugar levels—the goal is to stop your blood sugar control from getting worse and turning into full-blown diabetes. The ADA recommends using metformin, along with diet and exercise, to treat prediabetes in certain high-risk individuals, such as people under 60 years, those with a body mass index (BMI) of 35 kg/m or greater, and women who had gestational diabetes (ADA, 2019).

Preventing weight gain caused by antipsychotic medications

People with schizophrenia or other psychotic disorders are often treated with antipsychotics; examples include clozapine and olanzapine. While they can help with psychiatric illness, these drugs often come with the side effect of weight gain. Metformin can be given to people on these medications to prevent the associated weight gain, leading to obesity and an increased risk of heart disease (de Silva, 2016).

While metformin isn’t FDA-approved for weight loss in people with (or without) diabetes, people often drop weight for extended periods while on metformin—around 5-6 pounds on average (DPP Research Group, 2012). Scientists are not sure about the exact mechanism for the weight loss, but metformin seems to decrease appetite, increase the production of a weight-loss promoting hormone and affects how the gut absorbs food (Yerevanian, 2019). 

Most people feel fine on metformin. It’s widely used and considered safe and effective for type 2 diabetes (ADA, 2012).

The most common side effect that people report with metformin is diarrhea—around 50% of people will have diarrhea, especially when starting the medicine (DailyMed, 2017). Fortunately, this side effect usually improves over time. Up to a third of people experience side effects like nausea, vomiting, and abdominal pain (ADA, 2012). 

Experts recommend taking metformin with food to lessen these side effects. You may improve these effects by increasing your metformin dosage gradually over time instead of all at once (DPP Research Group, 2012). Ask your healthcare provider or pharmacist for guidance.  

If you’ve taken metformin for many months or years, your healthcare provider may check your vitamin B-12 levels from time to time; since metformin affects how your gut absorbs nutrients, it can decrease your vitamin B-12 absorption and lead to vitamin B-12 deficiency.

Is metformin considered safe? Or dangerous in any way?

Overall, metformin is considered safe for preventing and treating type 2 diabetes. There is a small risk that taking metformin causes low blood sugar, a condition called hypoglycemia. However, this is more likely to happen when you take other medicines that lower blood sugar levels, such as insulin, at the same time (DPP Research Group, 2012). 

The U.S. Food and Drug Administration (FDA) has issued a black box warning that metformin can rarely cause lactic acidosis, the most serious adverse effect with metformin (DailyMed, 2017). Lactic acidosis means lactic acid builds up to dangerously high levels in your blood. It’s rare, affecting just 1 in 30,000 people a year, and is more likely in people who have other serious kidney or liver problems (Wang, 2017). 

Signs of lactic acidosis include rapid and shallow breathing, vomiting, nausea, abdominal pain, weakness, lethargy or unusual sleepiness, and headaches. Lactic acidosis is a medical emergency requiring prompt medical attention (DailyMed, 2017). Again, this is a rare occurrence.  

There are a few scenarios in which taking metformin is contraindicated (DailyMed, 2017). 

• Kidney disease or poor kidney function

• Current or history of lactic acidosis

• Allergy or hypersensitivity to metformin

If you need radiological studies with intravenous contrast, like a CT scan, you should temporarily stop your metformin (with guidance from your healthcare provider) to prevent kidney problems. Also, people with liver disease, in general, should avoid using metformin because it increases your risk of developing lactic acidosis (DailyMed, 2017). 

Metformin has wide-ranging effects on the body, so it’s a good idea to be aware of how it may interact with other things, like alcohol, food, and other medications. 

Metformin and alcohol

Don’t drink heavily while taking metformin because using both can increase lactic acid levels, potentially leading to lactic acidosis. To avoid this rare but severe risk, people taking metformin should limit alcohol intake (DailyMed, 2017).

Metformin and food

There are no foods that are off-limits with metformin. However, you should be eating a healthy diet to help control your diabetes. When you eat sugar and metformin, your body will have to work harder to lower your blood sugars. Check out ingredient labels to determine how much sugar is lurking in your cereal, pasta, or other food. Talk to your healthcare provider and consider consulting a nutritionist or dietician if you still have diet questions. 

Metformin drug interactions

Before starting metformin, check with your pharmacist or healthcare provider regarding other medicines you may be taking, especially those that can affect your blood sugar levels and potentially your blood glucose control, including (DailyMed, 2017):

• Corticosteroids, like prednisone

• Thiazides and other diuretics (water pills), like furosemide 

• Other diabetes medications, including sulfonylureas, like glyburide

• Blood pressure medications like calcium-channel blockers

• Asthma and cold medicines

• Estrogens or oral contraceptive pills

Many people have heard of Glucophage and wonder how it’s related to metformin. The answer? It’s a brand name version of metformin. Other brand name formulations include Fortamet, Riomet, and Glumetza. 

In addition to immediate-release tablets and liquids that are usually taken twice a day, there are extended-release formulations you only take once daily. Your healthcare provider will usually start you on a low dose and gradually build up to the strength that best controls your blood sugars (UpToDate, n.d.).

People wonder if it is better to take metformin at night or in the morning. If you are taking metformin twice a day, take it with your breakfast and dinner. For those taking it only once daily, most people take it in the evening. However, the most important thing is to take it consistently—with your biggest meal—at the same time every day. 

If you skip a dose, take it as soon as you remember; however, if it is almost time for the next pill, do not take a double dose to make up for the missed one (MedlinePlus, 2020).

Be sure to take it as directed. If you’re dealing with diarrhea or other side effects, remember these usually resolve within two weeks or so after adjusting a dosage. Do not just stop taking metformin on your own. Metformin controls diabetes but does not cure it, and you should not stop taking it without talking to your healthcare provider.

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Current version

October 14, 2020

Written by

Andrea Pierce

Fact checked by

Chimene Richa, MD

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About the medical reviewer

Chimene Richa, MD

Dr. Richa is a board-certified Ophthalmologist and medical writer for Ro.