Metformin and vitamin B12 deficiency are closely linked, with long-term metformin use commonly reducing B12 levels in patients with type 2 diabetes. Metformin, the first-line treatment recommended by NICE for type 2 diabetes, interferes with vitamin B12 absorption in the gut through a calcium-dependent mechanism. This effect is dose-dependent and duration-dependent, meaning higher doses and prolonged use increase deficiency risk. Whilst not all patients develop deficiency, awareness of this association is essential for early detection and prevention of potentially irreversible neurological complications. Understanding the relationship between metformin and vitamin B12 enables healthcare professionals and patients to implement appropriate monitoring and intervention strategies.

How Metformin Affects Vitamin B12 Levels

Metformin is the first-line pharmacological treatment for type 2 diabetes mellitus in the UK, recommended by NICE for its efficacy in improving glycaemic control with potential cardiovascular benefits in some patients. However, long-term metformin use is associated with reduced vitamin B12 levels, listed as a 'common' side effect (affecting up to 1 in 10 patients) in the medication's Summary of Product Characteristics (SmPC).

The primary mechanism by which metformin interferes with vitamin B12 absorption involves calcium-dependent membrane action in the terminal ileum, where vitamin B12 is absorbed. This effect appears to be dose-dependent and duration-dependent, meaning higher doses and longer treatment periods increase the risk of deficiency.

Research indicates that the reduction in serum B12 levels typically becomes clinically significant after several years of continuous metformin therapy. Studies have shown that patients taking metformin for longer periods have lower B12 levels compared to those on other glucose-lowering medications. The MHRA has acknowledged this association in a Drug Safety Update, highlighting the importance of awareness and appropriate monitoring.

It is important to note that not all patients on metformin will develop B12 deficiency, and the clinical significance varies between individuals. Factors such as dietary B12 intake, baseline B12 stores, concurrent medications, and individual absorption capacity all influence whether deficiency develops. Understanding this relationship allows healthcare professionals to implement appropriate monitoring strategies and intervene before symptomatic deficiency occurs.

Symptoms of Vitamin B12 Deficiency in Metformin Users

Vitamin B12 deficiency can present with a wide spectrum of clinical manifestations, ranging from subtle symptoms to severe neurological complications. The insidious onset of symptoms means that deficiency may go unrecognised for extended periods, particularly in patients who attribute fatigue or cognitive changes to their diabetes or ageing.

Haematological symptoms are among the earliest manifestations and include:

• Fatigue and generalised weakness

• Pallor due to anaemia (which may be macrocytic, though this is not universal)

• Shortness of breath on exertion

• Palpitations or tachycardia

Neurological symptoms can be particularly concerning and may include:

• Peripheral neuropathy with tingling, numbness, or burning sensations in the hands and feet (paraesthesia)

• Loss of vibration sense and proprioception

• Ataxia and difficulty with balance or coordination

• Cognitive impairment, including memory problems and difficulty concentrating

• Mood disturbances, including depression and irritability

In patients with diabetes, distinguishing between diabetic neuropathy and B12 deficiency-related neuropathy can be challenging, as both conditions may coexist. B12 deficiency neuropathy can mimic diabetic neuropathy and may involve the upper limbs; biochemical testing is needed to distinguish between these conditions.

Other symptoms may include:

• Glossitis (sore, red tongue)

• Mouth ulcers

• Visual disturbances (rare, due to optic neuropathy, requiring urgent assessment)

• Gastrointestinal symptoms such as diarrhoea or constipation

It is crucial to recognise that neurological damage from B12 deficiency can become irreversible if left untreated for prolonged periods. Subacute combined degeneration of the spinal cord, though rare, represents a serious complication requiring urgent treatment. Early identification and treatment of B12 deficiency in metformin users can prevent these potentially irreversible complications and significantly improve quality of life.

Who Should Have Their B12 Levels Monitored

The MHRA advises checking vitamin B12 levels if deficiency is suspected and considering periodic monitoring in patients at risk. A risk-stratified approach ensures efficient use of healthcare resources whilst protecting vulnerable patients.

High-risk groups who should be considered for monitoring include:

• Patients taking metformin for more than three years

• Those on high-dose metformin (≥2g daily)

• Older adults (aged 65 years and above), who have reduced gastric acid production and lower B12 stores

• Patients with pre-existing risk factors for B12 deficiency, including previous gastric surgery, pernicious anaemia, or inflammatory bowel disease

• Individuals following vegan or vegetarian diets with limited dietary B12 intake

• Those taking acid-suppressing medications (proton pump inhibitors or H2-receptor antagonists)

• Patients with symptoms suggestive of B12 deficiency

• Patients with unexplained anaemia or neuropathy

The frequency of monitoring should be guided by clinical judgement and local pathways, with consideration of individual risk factors. There is no universal recommendation for baseline testing or fixed monitoring intervals unless locally commissioned.

It is worth noting that serum B12 levels may not always accurately reflect tissue B12 status, and laboratory reference ranges vary. Many UK laboratories now measure holotranscobalamin (active B12). In cases where clinical suspicion remains high despite normal B12 levels, additional testing with methylmalonic acid (MMA) or homocysteine levels may be helpful, though availability is limited in the UK and results can be affected by renal function.

Patients with established B12 deficiency who continue metformin therapy require more frequent monitoring to ensure replacement therapy maintains adequate levels. Healthcare professionals should maintain a low threshold for testing in patients presenting with compatible symptoms, regardless of treatment duration. Proactive monitoring allows early detection and intervention, preventing the development of irreversible neurological complications and improving long-term outcomes for patients with type 2 diabetes.

Preventing and Treating B12 Deficiency on Metformin

Prevention and management of vitamin B12 deficiency in metformin users involves a combination of dietary optimisation, appropriate supplementation, and, when necessary, therapeutic replacement.

Dietary measures form the foundation of prevention. Patients should be encouraged to consume B12-rich foods, including:

• Meat, particularly liver and kidney

• Fish and shellfish

• Dairy products (milk, cheese, yoghurt)

• Eggs

• Fortified breakfast cereals and plant-based milk alternatives

For patients following plant-based diets, fortified foods and supplementation become essential, as vitamin B12 is naturally found almost exclusively in animal products.

Oral supplementation is appropriate for patients with dietary deficiency or for prevention in high-risk individuals. For dietary deficiency, oral cyanocobalamin 50-150 micrograms daily is typically recommended in the UK. Oral supplementation is generally well-tolerated with minimal adverse effects, though absorption may remain suboptimal in some metformin users due to the ongoing interference with absorption mechanisms.

Intramuscular replacement therapy is indicated for patients with:

• Significant B12 deficiency (thresholds depend on local laboratory reference ranges)

• Neurological symptoms or signs

• Pernicious anaemia

• Malabsorption syndromes

The standard UK regimen for patients without neurological involvement involves hydroxocobalamin 1mg intramuscularly three times weekly for two weeks, followed by maintenance injections every 2-3 months (often 3-monthly). For patients with neurological involvement, hydroxocobalamin 1mg intramuscularly on alternate days until no further improvement is seen, followed by maintenance injections every 2 months.

It is important to check and replace folate after starting B12 therapy, as coexisting deficiencies are common and correcting B12 alone can precipitate or worsen folate deficiency.

In line with MHRA advice, metformin should generally be continued while B12 deficiency is investigated and treated, given its important role in diabetes management. Regular monitoring ensures treatment efficacy and allows dose adjustments as needed. Suspected adverse reactions to metformin or B12 therapy should be reported via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app).

When to Speak to Your GP About B12 Supplementation

Patients taking metformin should be aware of when to seek medical advice regarding vitamin B12 status and supplementation. Early consultation allows timely investigation and prevents progression to more serious complications.

You should contact your GP if you experience:

• Persistent fatigue or weakness that affects daily activities

• Tingling, numbness, or pins and needles in your hands or feet

• Difficulty with balance or coordination

• Memory problems or difficulty concentrating

• Mood changes, particularly low mood or irritability

• A sore, red tongue or recurrent mouth ulcers

• Unexplained shortness of breath or palpitations

These symptoms warrant investigation, which typically includes blood tests to measure B12 levels (or active B12 depending on the laboratory), full blood count to assess for anaemia, folate levels, and potentially other tests such as anti-intrinsic factor antibodies if pernicious anaemia is suspected.

Routine monitoring discussions should occur if:

• You have been taking metformin for more than three years without recent B12 testing

• You are taking high-dose metformin (2g or more daily)

• You are aged 65 or older

• You follow a vegan or vegetarian diet

• You are taking acid-suppressing medications (such as omeprazole or ranitidine)

• You have other risk factors for B12 deficiency

Patients should not commence B12 supplementation without medical advice, as inappropriate supplementation may mask underlying conditions such as pernicious anaemia or other causes of deficiency that require specific investigation and management.

Urgent medical attention is required if you develop:

• Severe weakness or difficulty walking

• Significant confusion or cognitive decline

• Visual disturbances

• Loss of bladder or bowel control

For these severe neurological symptoms, seek urgent care via NHS 111, your local Emergency Department, or call 999 if severely unwell.

Your GP can arrange appropriate testing, interpret results in the context of your individual circumstances, and recommend the most suitable management strategy. If B12 deficiency is confirmed, your GP will discuss whether oral supplementation or intramuscular injections are most appropriate and arrange follow-up to monitor treatment response. Open communication with your healthcare team ensures optimal management of both your diabetes and vitamin B12 status, supporting long-term health and wellbeing whilst continuing the benefits of metformin therapy.

Frequently Asked Questions