What are the two most common side effects of metformin? Understanding GI Issues and B12 Deficiency

October 8, 2025 •

4 min read

Studies indicate that gastrointestinal adverse effects affect up to 20% of patients initiating metformin. Understanding what are the two most common side effects of metformin is essential for new and long-term users, as gastrointestinal upset and long-term vitamin B12 deficiency are the most frequently encountered concerns.

Quick Summary

Metformin's most common side effects are gastrointestinal, including nausea and diarrhea, which typically occur when starting the medication. A significant risk for individuals on long-term therapy is the development of a vitamin B12 deficiency.

Key Points

Gastrointestinal Distress: The most common initial side effect of metformin includes diarrhea, nausea, and stomach pain, but symptoms often decrease over time.
Vitamin B12 Deficiency: Long-term metformin use increases the risk of developing a vitamin B12 deficiency, which can cause symptoms like anemia and nerve damage.
Management Strategies: Mitigate GI side effects by starting with a low dose, increasing it gradually, taking the medication with food, or switching to an extended-release formulation.
Extended-Release Option: The extended-release version of metformin is generally better tolerated and causes fewer GI issues compared to the immediate-release formulation.
Regular Monitoring: Long-term users of metformin, particularly those on higher doses or with risk factors, should have their vitamin B12 levels periodically monitored.
Rare Serious Risk: While extremely rare, lactic acidosis is a severe side effect primarily affecting individuals with kidney impairment, liver disease, or excessive alcohol intake.
Lifestyle Enhancements: Combining metformin with diet and exercise can improve its effectiveness and overall health outcomes.

Metformin: A First-Line Treatment with Common Side Effects

Metformin is a cornerstone medication for managing type 2 diabetes and is also used for other conditions like polycystic ovary syndrome (PCOS). Despite its effectiveness and positive long-term cardiovascular outcomes, a significant number of patients experience side effects. The most common are gastrointestinal problems, which typically arise early in treatment, and vitamin B12 deficiency, a risk that increases with long-term use. These effects, while often manageable, require attention from both patients and healthcare providers to ensure treatment adherence and long-term health.

Gastrointestinal Issues: The Most Frequent Offenders

For many patients, the introduction of metformin is accompanied by a range of gastrointestinal symptoms. These side effects are the most commonly cited reason for discontinuing the medication and can include:

Diarrhea: Often described as loose or watery stools, diarrhea is a very common side effect, potentially affecting up to 50% of patients starting the immediate-release version.
Nausea: A feeling of sickness or an upset stomach is frequently reported, especially when beginning treatment or increasing the dosage.
Abdominal Cramping and Bloating: Discomfort, pain, and increased gas in the stomach area can occur.
Metallic Taste: Some users report a strange or metallic taste in their mouth.

Why Do GI Side Effects Happen?

The pathophysiology behind metformin's GI effects is complex and not fully understood, but several mechanisms are thought to contribute:

Changes in Bile Acids: Metformin can reduce the absorption of bile salts in the small intestine, leading to osmotic diarrhea.
Altered Gut Microbiota: Metformin influences the composition of the gut microbiota. Changes in bacteria can affect intestinal function and contribute to discomfort.
Serotonin Release: The drug may stimulate the release of serotonin from intestinal cells, which can affect gut motility and cause nausea and diarrhea.
Local High Concentration: High concentrations of metformin in the intestinal lumen, especially with immediate-release formulations, can lead to localized effects and discomfort.

How to Manage Gastrointestinal Distress

Start Low and Go Slow: A healthcare provider will typically begin with a low dose and gradually increase it over several weeks. This allows the body to adjust and can significantly reduce the severity of GI issues.
Take with Food: Taking metformin with or after a meal, particularly the evening meal, is highly recommended. This slows absorption and can minimize stomach upset.
Consider Extended-Release (XR) Formulation: For patients who cannot tolerate the immediate-release (IR) version, switching to an XR formulation may be beneficial. The slower drug release with XR is associated with fewer GI side effects.
Dietary Adjustments: Limiting greasy, sugary, or fried foods, and increasing fiber intake, can help manage symptoms.

The Long-Term Concern: Vitamin B12 Deficiency

Beyond initial GI side effects, long-term metformin use poses a risk for developing a vitamin B12 deficiency. This risk increases with higher doses and longer durations of therapy. The mechanism is thought to involve the disruption of calcium-dependent absorption of the B12 complex in the small intestine. Symptoms of a deficiency may include:

Anemia
Neuropathy, such as numbness and tingling in the hands and feet
Fatigue and weakness
Memory problems

Given these risks, many guidelines and healthcare providers recommend periodic monitoring of vitamin B12 levels, especially for individuals on long-term therapy. Supplementation with oral or intramuscular B12 may be necessary if a deficiency is detected.

Understanding Less Common and Serious Side Effects

While GI issues and B12 deficiency are the most common concerns, other effects should be noted. Metformin can cause modest weight loss, which can be a beneficial side effect for some patients. In contrast, a rare but life-threatening complication is lactic acidosis.

Lactic Acidosis: This occurs when there is an excessive buildup of lactic acid in the bloodstream. It is extremely rare but has a high mortality rate. The risk is significantly increased in individuals with impaired kidney function, liver disease, severe infection, or excessive alcohol use.
Hypoglycemia: Metformin alone does not typically cause low blood sugar (hypoglycemia). However, the risk increases when it is taken in combination with other diabetes medications, such as insulin or sulfonylureas.

Comparison of Metformin Formulations


Feature	Immediate-Release (IR) Metformin	Extended-Release (XR) Metformin
Drug Release	Released into the system immediately after taking.	Released slowly as it passes through the gastrointestinal tract.
Dosing	Often taken two or three times a day with meals.	Typically taken once daily with the evening meal.
Absorption	Can cause high local concentrations in the gut, contributing to GI side effects.	Slower, more gradual absorption, resulting in less concentrated GI exposure.
Gastrointestinal Side Effects	Higher incidence and severity, particularly during the initial titration phase.	Significantly lower incidence and milder severity, making it better tolerated by many.
Cost	Generally more affordable.	Can be more expensive than the immediate-release version.

Conclusion: Navigating Metformin Side Effects for Successful Treatment

Metformin's place as a first-line therapy for type 2 diabetes is well-deserved due to its efficacy and long-term benefits. For many patients, managing the two most common side effects—gastrointestinal distress and long-term vitamin B12 deficiency—is key to a successful treatment plan. By starting with a low dose, taking the medication with food, or considering an extended-release formulation, initial GI symptoms can often be mitigated. Furthermore, proactive monitoring for B12 deficiency is crucial, especially for those on long-term therapy or with increased risk factors. For all metformin users, maintaining open communication with a healthcare provider is essential to address any side effects, understand risks, and ensure the medication's benefits are maximized safely over time. The American Diabetes Association provides standards of care that recommend metformin for initial management.

Frequently Asked Questions

Metformin's GI side effects are primarily caused by its actions within the gastrointestinal tract, including changes to the gut microbiota, increased serotonin release, and alterations in bile acid absorption.

For most people, gastrointestinal side effects like nausea and diarrhea tend to resolve on their own as the body adjusts to the medication, usually within a few weeks of starting treatment.

Yes, taking metformin with food is a standard recommendation to help reduce or eliminate the nausea and stomach upset that are common side effects, especially during the initial phase of treatment.

The risk of vitamin B12 deficiency is associated with long-term and higher-dose metformin use. It is a genuine risk that can lead to anemia and neuropathy if not monitored and addressed.

If you experience persistent or intolerable gastrointestinal side effects with immediate-release metformin, switching to an extended-release (XR) formulation is a common and effective strategy to improve tolerance.

Symptoms of the rare but serious lactic acidosis include unusual muscle pain, trouble breathing, severe weakness, extreme tiredness, stomach pain, dizziness, and feeling cold, especially in the hands and feet. Immediate medical attention is required if these occur.

Metformin is associated with modest and often inconsistent weight loss, which is sometimes considered a side effect. It is not FDA-approved specifically as a weight-loss drug, but the effect is well-documented in many studies.