What are the side effects of metformin?

Few drugs are as synonymous with diabetes treatment as metformin. It’s been used as a go-to first line of therapy in the U.S. since the mid-1990s, meaning it’s usually the medication a doctor will prescribe to someone just diagnosed with diabetes. This long, established history speaks to how confident physicians are in metformin’s ability to help with blood sugar regulation in a safe way. But even so, some people taking the drug can still experience side effects. Here’s what to look for when taking the medication — from the mild to the severe.

What is metformin?

Approved in Europe in the 1950s and by the U.S. Food and Drug Administration in 1994 for treating type 2 diabetes, metformin is a pill that decreases glucose production in the liver, which improves insulin sensitivity and slows the rate of food absorption. That can keep blood sugar from spiking when you eat.

Metformin is also the only medication recommended by the American Diabetes Association for prediabetes, which means the drug can help someone whose blood sugar is elevated, but not quite high enough to be classified as having diabetes. That’s important because treating prediabetes with a medication like metformin may help prevent someone from ultimately developing diabetes. Some physicians may also issue a metformin prescription off-label for purposes like weight management, as it can help reduce appetite.

"Metformin has long been a cornerstone of type 2 diabetes treatment, but in recent years, it’s found itself at the center of conversations about weight loss, healthy aging, and even longevity," says Dr. Pooja Gidwani, M.D., a Los Angeles-based physician board-certified in internal medicine and obesity medicine. "As more people look for ways to prevent disease, optimize metabolism, and live longer, the spotlight on metformin has grown."

There are two formulations available for prescription: immediate-release, which requires taking the oral medication twice per day; and extended-release, which is taken once a day, typically with an evening meal. And while metformin is a generic drug, there are also brand name medications that include metformin alongside other ingredients. Some brands are Glucophage, Invokamet, Janumet, Riomet, and Synjardy.

Common side effects of metformin

Metformin is generally considered safe and well-tolerated, but every medication has potential side effects, and metformin is no exception, according to Dr. Brian Lake, D.O., an endocrinologist who's board-certified in diabetes and metabolism, with a practice in Largo, Florida. Side effects can range from mild to possibly severe, and the most common are:

• Bloating or gas
• Constipation
• Diarrhea
• Headache
• Metallic taste in your mouth
• Nausea or vomiting
• Weight loss

"Gastrointestinal side effects occur in about 10 percent of patients,” says Lake. “Taking the medication with food can diminish these effects, however, and they generally improve over a few weeks. And extended-release metformin can decrease the gastrointestinal side effects by about 50 percent. If the effects aren’t tolerable, though, a lower dose of metformin may be recommended or a switch to another class of medication used to treat diabetes.”

The reason the most common side effects are predominantly gastrointestinal is because the medication alters bile acid metabolism and slows carbohydrate absorption. “These changes help regulate blood sugar and improve insulin sensitivity, but they can also disrupt normal digestion, leading to gas, bloating, and loose stools,” Gidwani says.

For a full list of metformin side effects, look at the prescribing information.

Serious side effects of metformin

While it’s much less common, some people may experience more severe side effects when taking metformin, particularly when used for long-term. Here are some to know about:

Lactic acidosis

The most serious complication with metformin is lactic acidosis, a buildup of lactic acid in the blood that can be fatal, says Gidwani. “This condition occurs almost exclusively in people with significantly impaired kidney function, liver failure, heavy alcohol use, or acute illness involving dehydration or oxygen deprivation. In otherwise healthy individuals, the risk is extremely low,” she adds.

Signs of lactic acidosis include nausea, fatigue, rapid breathing, and muscle cramps. More advanced symptoms are confusion, increasing weakness, and difficulty with coordination.

Vitamin B12 deficiency

Long-term use of metformin is also associated with vitamin B12 deficiency, which can lead to fatigue, cognitive symptoms, nerve damage, or anemia, says Gidwani. Know that this is especially relevant in older adults or anyone with limited dietary B12 intake, such as vegetarians and vegans (B12 is found in animal-based foods). "Annual monitoring is recommended for patients on long-term metformin, and supplementation may be necessary if B12 levels drop," Gidwani says.

Hypoglycemia

Although metformin has lower risk of hypoglycemia (low blood sugar) than other oral antidiabetes drugs, there is still a chance this can occur. Hypoglycemia happens when blood glucose levels drop too low, and it's more likely this will be an issue if metformin is taken along with other diabetes medications, according to Dr. Sue Decotiis, M.D., a triple board-certified physician in internal medicine, antiaging medicine, and obesity medicine, who leads a weight-loss practice in Scarsdale, NY.

Signs of hypoglycemia include feeling shaky, fast heartbeat, feeling lightheaded, hunger, nausea, and sweating. You may also experience blurred or impaired vision, suddenly feeling weak or sleepy, or having tingling or numbness in the lips, tongue, or cheeks.

Managing metformin side effects

For those experiencing metformin side effects, there are a few ways to reduce or eliminate issues, especially the more common gastrointestinal difficulties, according to Gidwani. For one thing, follow your doctor’s recommendations for dosing, increasing it gradually over time. This way your body can get used to the medication You’ll likely start with a low dose — usually 500 mg once daily — and slowly increase it every one to two weeks. "Also, taking the medication with food can reduce nausea and cramping," Gidwani says.

Metformin drug interactions

Metformin has relatively few interactions, but there are some important ones to know, says Decotiis. For example, metformin should be temporarily discontinued right before and after receiving iodinated contrast dye in imaging studies in patients with reduced kidney function. That’s because metformin is cleared by the kidneys, so when they’re impaired and also trying to clear dye during imaging, adding metformin to the mix can be too stressful for them.

"Metformin may also intensify gastrointestinal side effects when combined with other glucose-lowering agents like GLP-1 receptor agonists or SGLT2 inhibitors, especially in the early weeks of treatment,” Gidwani says. These medications also lower blood sugar, raising your risk of hypoglycemia if they’re combined with metformin.

Metformin alternatives

Metformin is not recommended for people with advanced kidney disease, significant liver impairment, or a history of lactic acidosis, Gidwani says. It should also be used cautiously in individuals with heart failure, severe dehydration, alcohol use disorder, or acute infections — especially if food intake is reduced or vomiting is present. That’s because these situations increase the risk of lactic acidosis.

Fortunately, for people who are advised not to take metformin or who aren’t responding well to it, there are other medications that can help meet health goals, says Lake. “An endocrinologist will try to match you with the correct medications for your health issues.” Options include

• GLP-1 receptor agonists such as semaglutide (Ozempic) or tirzepatide (Mounjaro): These are approved for type 2 diabetes and can have a significant impact on blood sugar control, weight loss, and cardiovascular protection.
  
  
• SGLT2 inhibitors like empagliflozin (Jardiance) or dapagliflozin (Farxiga): These are also effective for metabolic health and have added benefits for the heart and kidneys.
  
  
• Pioglitazone: An insulin sensitizer, this medication may be useful in select cases but is associated with weight gain and fluid retention.
  
  
• Acarbose: This drug delays carbohydrate absorption, but it can cause GI upset.

The bottom line

In use for decades, metformin is a type 2 diabetes medication that’s typically well-tolerated but does raise risk of gastrointestinal side effects such as nausea and bloating. Keep in mind that those issues tend to arise in the first few weeks on the drug, while the body gets used to the medication. Because some rare but serious side effects such as hypoglycemia and lactic acidosis can occur with long-term use, make sure you go in for regular monitoring with your doctor to catch any issues early, and to switch to an alternative medication if necessary.