What are the long-term side effects of using metformin (Metformin) and Wellbutrin (Bupropion)?

Long-Term Side Effects of Metformin and Wellbutrin

The most clinically significant long-term side effect of metformin is vitamin B12 deficiency, which requires periodic monitoring, while Wellbutrin (bupropion) carries risks of seizures and neuropsychiatric effects including suicidal ideation that necessitate careful patient selection and monitoring.

Metformin Long-Term Side Effects

Vitamin B12 Deficiency (Most Important)

Long-term metformin use is definitively associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in all metformin-treated patients, especially those with anemia or peripheral neuropathy 1.

• The absolute risk of vitamin B12 deficiency (<150 pmol/L) increases by 7.2 percentage points after 4.3 years of metformin use, with a number needed to harm of 13.8 2
• Each year of metformin use increases the odds of B12 deficiency by 13% (OR 1.13; 95% CI 1.06-1.20) 3
• Vitamin B12 deficiency can worsen peripheral neuropathy symptoms and cause macrocytic anemia 4, 5
• Annual monitoring of vitamin B12 levels is recommended for patients on long-term metformin therapy 4

Gastrointestinal Side Effects

• Chronic gastrointestinal symptoms (diarrhea, nausea, abdominal discomfort, bloating) can persist or emerge even after years of stable therapy 6
• These effects are dose-dependent and may require dose reduction or switching to extended-release formulation 4, 7
• Reduced appetite can be problematic, especially in older adults 4

Lactic Acidosis (Rare but Serious)

• Metformin-associated lactic acidosis (MALA) is rare (2-9 cases per 100,000 patient-years) but carries a 30-50% mortality rate if not promptly treated 4
• Risk factors include: severe kidney problems (eGFR <30 mL/min/1.73 m²), liver impairment, severe heart failure (LVEF <30%), dehydration, or hypoxemic conditions 4, 7
• Metformin must be discontinued when eGFR falls below 30 mL/min/1.73 m² and dose reduction considered when eGFR is 30-45 mL/min/1.73 m² 4, 6

Monitoring Requirements for Metformin

• Check vitamin B12 levels annually in long-term users 4, 3
• Monitor renal function (eGFR) every 3-6 months in patients at risk for kidney function decline 4
• Assess for signs of peripheral neuropathy or anemia 1

Wellbutrin (Bupropion) Long-Term Side Effects

Seizure Risk (Most Serious)

The chance of having seizures increases with higher doses of bupropion, especially in patients with certain medical problems or who take certain medicines 8.

• If a seizure occurs while taking bupropion, stop the medication immediately and do not restart 8
• Risk is dose-dependent and increases with concomitant medications that lower seizure threshold 8

Neuropsychiatric Effects

Bupropion carries a black box warning for suicidal thoughts and behaviors, particularly in young adults, and can cause new or worsening mental health problems 8.

• New or worse depression, anxiety, agitation, hostility, aggression, or suicidal thoughts can occur 8
• These symptoms may appear when starting treatment, after several weeks, or even after stopping the medication 8
• Symptoms occur more frequently in patients with a history of mental health problems 8
• Patients require close monitoring for mood changes, especially during initiation and dose changes 8

Cardiovascular Effects

• High blood pressure (hypertension) can develop and may be severe during long-term bupropion use 8
• Risk increases if nicotine replacement therapy is used concomitantly 8

Manic Episodes

• Bupropion can trigger manic episodes, particularly in patients with bipolar disorder or family history of bipolar illness 8

Critical Monitoring for Wellbutrin

• Monitor for new or sudden changes in mood, behavior, thoughts, or feelings 8
• Watch for signs of suicidal ideation: thoughts about suicide or dying, new or worse depression, severe agitation, panic attacks, insomnia, irritability, aggression, or unusual behavior changes 8
• Assess blood pressure regularly, especially if using nicotine replacement 8
• Never stop bupropion suddenly without medical supervision 8

Combined Use Considerations

When using both medications long-term:

• Maintain separate monitoring schedules for each medication's specific risks
• Be aware that gastrointestinal side effects from metformin may complicate assessment of bupropion tolerability
• Ensure renal function monitoring for metformin is not compromised by other medication effects
• Document baseline mental health status before initiating bupropion in patients already on metformin