Metformin side effects long-term

In this article:

• Most common side effects
• Long-term side effects
• Serious side effects
• Female side effects long-term
• Male side effects long-term
• Considerations when taking metformin long-term
• How to manage long-term metformin side effects
• Bottom line: Is it safe to take metformin long-term?

In this article

• Most common side effects
• Long-term side effects
• Serious side effects
• Female side effects long-term
• Male side effects long-term
• Considerations when taking metformin long-term
• How to manage long-term metformin side effects
• Bottom line: Is it safe to take metformin long-term?

Metformin and metformin extended-release (ER) are oral medications approved to lower blood sugar in people with Type 2 diabetes and prediabetes. Some healthcare providers also prescribe metformin off-label for gestational diabetes, polycystic ovary syndrome (PCOS), and weight loss. Metformin is considered a safe and affordable first-line treatment in Type 2 diabetes care. That said, metformin can cause both short-term and long-term side effects.

Here’s what to expect and how to reduce the risk of long-term metformin side effects.

Most common side effects of metformin

According to clinical trial data, the most common side effect of metformin is diarrhea, which occurred in more than half of participants. Other common side effects of metformin include:

• Nausea
• Vomiting
• Flatulence
• Indigestion
• Decreased energy
• Headache

Other possible metformin side effects include:

• Change in taste
• Skin flushing
• Muscle aches
• Rash

Some metformin side effects fade as your body adjusts to the medication. It’s important to stay in contact with a healthcare provider if any side effects become severe or debilitating. For instance, metformin’s gastrointestinal side effects range from mild to severe, according to Angela Ginn-Meadow, RN, registered dietitian, and certified diabetes educator, based in Baltimore, Maryland. Tell your prescriber if you experience severe diarrhea or vomiting, as these can quickly lead to dehydration. 

What are the long-term side effects of metformin?

“Long-term side effects of metformin include B12 deficiency and lactic acidosis,” Ginn-Meadow says. Your healthcare provider should regularly screen for these side effects with blood tests.

Up to 30% of long-term metformin users develop low vitamin B12, which can cause chronic fatigue, memory impairment, and nerve damage. “This effect worsens with increasing doses of metformin and accumulates over time,” says David Cutler, MD, a family medicine physician at Providence Saint John’s Health Center in Santa Monica, California. He says additional risk factors for B12 deficiency include:

• Older age
• Eating a vegetarian or vegan diet
• Having atrophic gastritis
• Taking proton pump inhibitors (PPIs) 
• Having had stomach or small bowel surgery

In very rare cases, this diabetes medicine can cause metformin-associated lactic acidosis, a life-threatening condition in which lactic acid builds up in the body. This is more likely in people with liver problems, kidney problems, or alcohol abuse disorder. 

Weight loss can also occur with long-term metformin use. Sometimes it is even prescribed off-label for this purpose.

Serious side effects of metformin

Potentially serious side effects of metformin include:

• Hypoglycemia (low blood sugar) when combined with other diabetes medications
• Lactic acidosis
• Allergic reaction
• Complications from metformin-induced B12 deficiency

The most serious potential side effect of metformin is lactic acidosis. It requires emergency medical attention, as about 25% of cases are fatal. The good news is that the low risk of lactic acidosis can be significantly decreased with regular kidney health monitoring.

Risk factors of lactic acidosis with metformin include:

• Kidney disease
• Liver disease
• Excessive consumption of alcohol
• Taking metformin right before a surgical procedure or CT scan
• Overdosage of metformin

Signs of lactic acidosis include:

• Lightheadedness
• Feeling extremely weak or tired
• Unexplained muscle pains
• Trouble breathing
• Severe stomach pain

Like all medications, metformin can cause allergic reactions. Signs of an allergic reaction include:

• Swelling of the face, throat, or hands
• Shallow breathing
• Sudden skin rash

Finally, vitamin B12 deficiency from long-term metformin use can eventually cause significant health issues such as neuropathy, megaloblastic anemia, and cognitive decline, according to Dr. Cutler. These complications are not direct side effects of the medication, but they are serious health problems to be aware of. People on metformin should have regular blood tests to assess vitamin B12 levels.

Metformin side effects in women long-term

Research on sex-dependent side effects of metformin has found that there is little difference in metformin side effects in female versus male patients over the long term. In general, metformin side effects specific to women are either PCOS-related improvements or a short-term difference in side effect frequency.

By improving insulin resistance, metformin also helps improve PCOS symptoms in some women. Specifically, metformin can help regulate periods and improve fertility. Fortunately, these metformin effects are typically seen as benefits rather than adverse reactions.

Women may also experience more gastrointestinal side effects of metformin than men at the beginning of treatment. In one study, 34% of women versus 25% of men reported side effects such as diarrhea, nausea, abdominal discomfort, flatulence, headache, or fatigue in the first two weeks of metformin use. However, these side effects improved, and the frequency of side effects in women versus men equalized within a few months of starting treatment. Switching to an extended-release version of metformin (metformin XR) can help decrease its GI side effects.

Metformin side effects in men long-term

One small study found that men may be more likely than women to experience metformin-induced vitamin B12 deficiency. Regular screening for nutritional deficiencies can prevent this from becoming a long-term problem. 

Considerations when taking metformin long-term

Metformin is typically a long-term medication. Some people take it daily for the rest of their lives to manage blood sugar levels. Long-term use is considered safe as long as the patient commits to the following:

• Regularly monitoring blood glucose levels
• Scheduling routine check-ups
• Reporting new or worsening side effects to their prescriber
• Consulting their prescriber before starting any new medications (including over-the-counter drugs and supplements)
• Not discontinuing metformin without guidance from a healthcare provider

“Patients taking metformin long-term should have B12 levels checked every two to three years,” Dr. Cutler says. “Testing should be done sooner if neuropathy develops, unexplained anemia develops, or if a patient has additional risk factors.”

Metformin can interact with other diabetes or blood sugar-related medications. To avoid drug interactions, your healthcare provider needs to have a complete list of any prescription drugs, supplements, and over-the-counter medications you currently take.

Finally, never stop taking metformin without a healthcare professional’s guidance. While metformin is not known to cause withdrawal symptoms, quitting this medication can cause high blood sugar and increased A1C. In the short term, high blood sugar can cause extreme hunger or thirst, frequent urination, blurry vision, and mood changes. Over time, elevated A1C can cause diabetes complications such as vision problems, foot problems, increased risk for heart attack and stroke, and irreversible nerve damage. 

How to manage long-term metformin side effects

The good news is that there are ways to prevent long-term metformin side effects, including vitamin B12 deficiency, lactic acidosis, and hypoglycemia:

• Vitamin B12 deficiency: Vitamin B12 deficiency can be detected early through routine screening. And the good news is that supplementation typically resolves the issue, according to Dr. Cutler. 
• Lactic acidosis: This is a very rare metformin side effect that can be prevented if you keep appointments for liver and kidney function screenings, drink alcohol in moderation, and follow any pre-operative and pre-CT scan instructions for metformin dosage. Metformin is often temporarily withheld for two to three days prior to a surgical procedure.
• Hypoglycemia: Low blood sugar is not a long-term side effect of metformin, but it can develop in combination with other diabetes medications. That’s because lifestyle changes like diet and exercise can improve blood sugar control to the point that metformin dosage should be lowered. 

The most important thing to remember about managing metformin side effects is to stay connected with a healthcare team. Report new or worsening side effects. Seek personalized medical advice before starting any new drugs or supplements. When in doubt, consult your prescriber. If you are concerned about metformin side effects or want to switch diabetes medications for any reason, make an appointment to see a healthcare professional.

Bottom line: Is it safe to take metformin long-term?

Metformin is often prescribed for long-term use. It is typically well-tolerated, and initial side effects tend to improve within weeks of starting the medication. Serious side effects are rare, but it’s important to know the signs. Contact a healthcare provider immediately if you experience signs of lactic acidosis (e.g., extreme fatigue, trouble breathing, or stomach pain), allergic reactions (e.g., facial swelling, shortness of breath, or rapid heartbeat), or dangerously low blood sugar (e.g., dizziness, confusion, or loss of consciousness).