Metformin: interactions, side effects, and warnings

Have you ever wondered why you have to answer so many questions about the medications you take when you go to a new healthcare provider? 

One important reason is that drug interactions—the way different medications interact with one another in your body—can change the way your body responds to those medications. In some cases, drug interactions can be extremely dangerous.

Metformin, a medication used to treat type 2 diabetes mellitus, is generally a safe drug that most people tolerate well, but there are certain drug interactions you should know about. Before starting on metformin, be sure to tell your healthcare provider about any current or recent medications.

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Metformin has almost no serious drug interactions, though there are certain medications or substances that can cause unwanted responses in your body (Maideen, 2017). If you're taking any of these, your healthcare provider may want to monitor you closely or may recommend an alternative treatment option. 

Some possible drug interactions include (Song, 2016): 

• Iodinated contrast (used in imaging tests)

• Certain anticancer drugs (specifically vandetanib and drugs that fall under the class called tyrosine kinase inhibitors)

• Some antimicrobial drugs (such as cephalexin and rifampin)

• Alcohol (but only in excessive amounts)

• Certain HIV medications (such as dolutegravir)

Most of these substances or medications have one thing in common: When taken with metformin, they can raise the body's levels of lactic acid. That raises some concerns since the most serious (though exceedingly rare) adverse effect associated with metformin is a life-threatening condition called lactic acidosis, in which the body's lactic acid levels become dangerously high (Foucher, 2020). 

Metformin and alcohol

You may notice that alcohol is included in the list of drug interactions above, but only in excessive amounts. It's fine to drink moderate amounts of alcohol while taking metformin (generally defined as one drink for women or two drinks for men per day), but you'll want to avoid drinking more heavily than that while on this medication (U.S. Department of Health and Human Services, 2015). 

Heavy drinking isn't a good idea while taking metformin because excessive alcohol drinking is a known risk factor for lactic acidosis (Fulop, 1989). Since taking metformin may increase the risk of lactic acidosis on its own, it's important to avoid behaviors that put you at even higher risk while taking this drug. 

Metformin and other foods 

While excessive alcohol isn't a good idea while taking metformin, it's fine to eat or drink any other foods while taking this medication. 

Unlike fast-acting insulins and some other diabetes drugs, metformin primarily works to lower blood sugar between meals, along with lowering a compound called hemoglobin a1c (which is a marker that gives a good estimate of blood sugar levels over a longer period of time). Since it works this way, it doesn't have much impact on blood sugar levels immediately following a meal (also called postprandial glucose). 

There's no problem with eating sugar or any other type of food while taking metformin. (Of course, eating excessive amounts of sugar, especially if you have type 2 diabetes, can raise your blood sugar even if you are taking metformin). 

It's generally a good idea to take metformin with meals since that may cut down on any gastrointestinal (GI) side effects. If you don't have any GI symptoms, though, you can take metformin without food, too—whatever you prefer.

Metformin is known by several different brand names, including Glucophage, Glumetza, Riomet, and Fortamet (US. National Library of Medicine, 2018). It's part of a class of drugs called biguanides and has been used as a successful treatment for type 2 diabetes for decades (Markowicz-Piasecka, 2017). It's also effective at preventing diabetes in patients with prediabetes or moderate insulin resistance (Lilly, 2009).

Many healthcare providers also use metformin off-label to treat polycystic ovary syndrome (PCOS), which is associated with hormonal symptoms like infertility, acne, early pregnancy loss, and diabetes in pregnant women (Markowicz-Piasecka, 2017). Metformin use can improve these symptoms, though it is not FDA-approved to treat PCOS. 

There's been some research showing that metformin might be useful in other medical conditions, but we don't have any conclusive evidence at this point. Cancer, aging, and heart disease are just a few of the diseases being studied. As of now, metformin is only FDA-approved to treat type 2 diabetes, not type 1 diabetes. 

Metformin is effective at treating type 2 diabetes because it lowers the body's blood glucose levels and improves glycemic control (blood sugar control) by reducing glucose production in the liver. In type 2 diabetes, the body doesn't process sugar properly, which leads to high blood sugar. Along with lifestyle changes, metformin can be an integral part of type 2 diabetes care. 

While most patients tolerate metformin well, GI side effects are quite common (Bonnet, 2016). Up to 25% of people can experience symptoms like nausea, diarrhea, vomiting, heartburn, and other side effects related to the gut, but only about 5% of those people have such severe symptoms that they need to stop taking metformin altogether (McCreight, 2016). Let's look at these and other side effects more closely. 

Metformin's effects on the GI tract

Why are there so many GI side effects of metformin? The body absorbs metformin primarily in the small intestine and has several key interactions with the gut. It increases a hormone in the gut called GLP-1, changes the gut microbiome, and boosts bile acid production in the intestine (McCreight, 2016). All of these actions lead to higher rates of GI side effects. 

To decrease these uncomfortable side effects, it's sometimes recommended that people start out on a lower dose of metformin and gradually work their way up to their prescribed dose. Taking metformin with meals can help, too, as can switching to the extended-release tablets instead of the immediate-release formula (Blonde, 2004).

Metformin diarrhea

The most common side effect you might experience on metformin is diarrhea—more than 60% of patients who complain of GI symptoms on metformin have diarrhea (Fatima, 2018). While we don't know the exact reason taking metformin can cause diarrhea, we do know that:

• Metformin increases the gut's serotonin signaling levels.

• Taking metformin lowers the level of bile salts that get absorbed into the gut. 

When serotonin signaling is raised and bile salt absorption is lowered, the body responds by contracting the muscles in the gut while pulling more fluids into it. What do you get when you combine muscular contractions and fluids in the gut? Diarrhea. 

It's also important to note that patients with type 2 diabetes experience higher rates of diarrhea (about 20% of patients with type 2 diabetes), even without taking metformin (Gould, 2009). Taking metformin bumps up diarrhea rates in this population to as high as 50%.

Other metformin side effects

Vitamin B12 deficiency is another common side effect, showing up in about one-fifth of all patients taking metformin (de Jager, 2010). This side effect is easy to manage with a vitamin B12 supplement. 

The most serious adverse effect associated with metformin is lactic acidosis, a life-threatening condition that occurs when the levels of lactic acid in the blood become dangerously high (Foucher, 2020). While lactic acidosis is an exceedingly rare complication of metformin, there is concern about anything that may increase your risk while on this medication (Stang, 1999). That's the primary reason you may need additional monitoring if you are taking certain other drugs.

If the high rates of diarrhea scare you, here's a possible positive side effect associated with metformin: weight loss—or, at the very least, weight maintenance. Metformin can contribute to modest weight loss, but weight maintenance is where it really shines (Apolzan, 2019). This is a welcome contrast to other commonly prescribed diabetes medications, which are associated with dramatic weight gain (Provilus, 2011). The antidiabetic drugs that tend to cause weight gain are: 

• Insulin

• Sulfonylureas (examples include glimepiride, glipizide, and glyburide)

• Thiazolidinediones (also called TZDs—the two drugs in this class are rosiglitazone and pioglitazone) 

Many patients with type 2 diabetes are concerned about obesity and weight gain, so metformin can be a good option. Metformin is no miracle weight loss drug, but even helping patients avoid weight gain is valuable.

When discussing drug interactions and side effects, safety is probably top of mind. How safe is metformin? For the vast majority of people, it's very safe and has been associated with virtually no safety issues (Diabetes Prevention Program Research Group, 2012). Beyond being generally safe, research shows that taking metformin can lower death rates in patients from all causes, including diabetes-related deaths (Markowicz-Piasecka, 2017). 

Still, metformin is not the best drug for all patients, particularly patients at higher risk for lactic acidosis, which happens when lactic acid levels become dangerously high. One of the potential outcomes of lactic acidosis is liver or kidney failure, so patients with advanced liver disease or severely diminished kidney function are at increased risk of developing this condition and shouldn't take metformin. 

Patients with mild to moderate chronic kidney disease, though, can probably take metformin safely (MacCallum, 2019). They may just need to be closely monitored. 

There was some concern about metformin being unsafe for patients with congestive heart failure (CHF) or a history of heart attack, but we now know that heart failure is not a contraindication for taking metformin and might even improve symptoms of CHF (Tahrani, 2007). 

Metformin warnings

While metformin is safe for most patients and can even be taken alongside most drugs, there is a boxed warning on the drug information label about the risk of lactic acidosis (Crowley, 2016). The FDA strongly discourages anyone with advanced kidney disease from taking metformin since those patients are at a higher risk for developing lactic acidosis.

Can you just stop taking metformin?

One of the safety concerns with any medication is how to stop taking it if you need to. With metformin, it's fine to stop taking it without tapering off the medication, but it's important to do so under the medical advice and guidance of your healthcare provider. Of course, when you stop taking metformin, you'll lose any positive effects you might have had while taking it. 

If you're taking any of the medications that interact with metformin, don't be discouraged. Speak with your healthcare provider about any medications you are taking so he or she can address any possible drug interactions and adjust your medications as needed.

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Current version

November 20, 2020

Written by

Rachel Honeyman

Fact checked by

Mike Bohl, MD, MPH, ALM

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About the medical reviewer

Mike Bohl, MD, MPH, ALM

Dr. Mike is a licensed physician and a former Director, Medical Content & Education at Ro.