Which medication, lisinopril (Angiotensin-Converting Enzyme Inhibitor) or metformin (Biguanide), is associated with a decrease in vitamin B12 levels?

Metformin Decreases Vitamin B12, Not Lisinopril

Metformin is the medication associated with decreased vitamin B12 levels, while lisinopril (an ACE inhibitor) has no established association with vitamin B12 deficiency. 1

Evidence for Metformin-Induced B12 Deficiency

Magnitude of Effect

• Metformin reduces serum vitamin B12 levels by 19-29% in patients with type 2 diabetes 1
• Meta-analysis demonstrates a mean reduction of 57 pmol/L after 6 weeks to 3 months of use 2
• The Hyperinsulinemia study showed a 19% reduction (95% CI: -24%, -14%; p < 0.001) at 52 months 1

Prevalence Data

• Vitamin B12 deficiency (≤148 pmol/L) occurs in 5.8% of metformin users versus 2.4% of non-users (p = 0.0026) 1
• After adjusting for confounders, metformin use carries an adjusted odds ratio of 2.92 (95% CI: 1.26,6.78) for B12 deficiency 1
• Approximately 22.2% of metformin users develop vitamin B12 deficiency defined as <300 pg/mL 3

Dose-Response Relationship

• Daily doses ≥1500 mg are a major risk factor for deficiency 3
• Compared to <1000 mg daily, the adjusted odds ratios are:
  • 1000-1500 mg: OR 1.72 (p = 0.080)
  • 1500-2000 mg: OR 3.34 (p < 0.001)
  • ≥2000 mg: OR 8.67 (p < 0.001) 3

Duration of Therapy

• Risk increases with duration of use, with higher risk after 4-5 years when hepatic B12 stores become depleted 4, 5
• Both dose and duration are independent risk factors for deficiency 1

Mechanism of Metformin-Induced Deficiency

• Metformin causes malabsorption through disruption of calcium-dependent ileal receptors that bind the intrinsic factor-B12 complex 1
• Bacterial overgrowth may also contribute to malabsorption 1
• The FDA label confirms this mechanism, noting interference with B12 absorption from the B12-intrinsic factor complex 6

Clinical Consequences

Neurological Complications

• Vitamin B12 deficiency can cause or worsen peripheral neuropathy, autonomic neuropathy, and cardiac denervation 4, 5
• Progressive demyelination and irreparable neuropathic damage may occur if deficiency remains undiagnosed 1
• Worsening of neuropathy symptoms has been documented in metformin users with B12 deficiency 1

Hematological Effects

• Megaloblastic anemia can develop 1
• The Diabetes Prevention Program showed increased anemia rates (p = 0.02) after 5 years 1

Metabolic Markers

• Elevated homocysteine levels (p < 0.01) 1
• Increased methylmalonic acid (MMA) by 0.006 μmol/L (p < 0.001) 1

Official Guideline Recommendations

FDA Drug Label Requirements

• The FDA label states that approximately 7% of patients develop subnormal B12 levels in 29-week trials 6
• Measure hematologic parameters annually and vitamin B12 at 2-3 year intervals in all patients on metformin 6

American Diabetes Association Guidelines

• The 2025 ADA Standards of Care recommend periodic testing of vitamin B12 levels, particularly in patients with anemia or peripheral neuropathy 1
• The 2021 ADA guidelines specifically recommend periodic B12 testing based on Diabetes Prevention Program Outcomes Study data 1

Annual Review of Nutrition Consensus

• Periodic evaluation of vitamin B12 status is justified based on strong evidence from observational studies, RCTs, and meta-analyses 1
• Monitoring should prioritize high-risk populations: elderly, vegetarians/vegans, and patients on multiple medications 1

Lisinopril and Vitamin B12

• The evidence documents discuss ACE inhibitors in the context of micronutrient effects on potassium, calcium, and magnesium—not vitamin B12 1
• No association exists between lisinopril (or other ACE inhibitors) and vitamin B12 deficiency based on the available guideline literature 1

Monitoring Algorithm for Metformin Users

Initial Assessment

• Measure baseline vitamin B12 levels before starting metformin or early in therapy 4, 6
• Consider baseline homocysteine and MMA if B12 levels are borderline (functional deficiency can occur at normal serum levels) 1, 4

Ongoing Monitoring

• Annual monitoring after 4 years of continuous metformin use 4
• Every 2-3 years for all metformin users per FDA recommendations 6
• More frequent monitoring if:
  • Daily dose ≥1500 mg 3
  • Concurrent proton pump inhibitor use 1, 5
  • History of bariatric surgery 5
  • Elderly patients 1, 5
  • Symptoms of neuropathy develop 1

Diagnostic Approach

• Do not rely solely on serum B12 levels due to sensitivity/specificity issues 1, 4
• Concurrent assessment of multiple biomarkers is preferred:
  • Serum vitamin B12
  • Methylmalonic acid (MMA)
  • Homocysteine 1, 4

Common Pitfalls to Avoid

• Waiting for frank deficiency before treating: Irreparable neuropathic damage can occur; treat borderline levels in symptomatic patients 1, 4
• Ignoring functional B12 deficiency: Normal serum B12 does not exclude tissue-level deficiency; check MMA and homocysteine 1, 4, 3
• Underestimating dose effects: Doses ≥1500 mg carry substantially higher risk (OR 3.34-8.67) 3
• Forgetting accelerating factors: Proton pump inhibitors, bariatric surgery, advanced age, and increased RBC turnover hasten hepatic B12 store depletion 5
• Not considering prophylaxis: Multivitamin supplementation may protect against deficiency (OR 0.23; p < 0.001) 3

Treatment Considerations

• Prophylactic calcium and vitamin B12 supplements can be considered 5
• Intramuscular or oral vitamin B12 therapy for established deficiency 5
• With adequate B12 replacement, neuropathy symptoms may stabilize but objective findings typically do not improve 5
• Deficiency appears rapidly reversible with discontinuation or supplementation 6