Which medications interfere with vitamin B12 absorption?

Medications That Interfere with Vitamin B12 Absorption

The correct answers are (a) biguanides and (c) proton pump inhibitors (PPIs)—both medication classes have strong evidence demonstrating interference with vitamin B12 absorption through distinct mechanisms. 1

Biguanides (Metformin)

Metformin causes vitamin B12 malabsorption through disruption of calcium-dependent ileal receptors and potential bacterial overgrowth. 1

Evidence Strength

• Multiple randomized controlled trials demonstrate 19-29% reductions in serum vitamin B12 levels with chronic metformin use 1
• The landmark Diabetes Prevention Program showed metformin users had significantly higher rates of vitamin B12 deficiency (≤203 pg/mL) at 5 years (p = 0.02), along with increased anemia (p = 0.02) and homocysteine levels (p < 0.01) 1
• Meta-analysis of 6 RCTs found dose-dependent reductions in serum B12 (-53.93 pmol/L; 95% CI: -81.44, -26.42; p = 0.0001) 1
• NHANES data showed metformin users had 2.92 times higher odds of B12 deficiency (95% CI: 1.26,6.78) even after adjusting for confounders 1

Clinical Implications

• The FDA drug label explicitly warns about vitamin B12 deficiency risk, recommending measurement of hematologic parameters annually and vitamin B12 at 2-3 year intervals 2
• Approximately 7% of metformin users develop subnormal B12 levels in trials of 29-week duration 2
• Duration and dose are independent risk factors—deficiency risk increases substantially after 5 years when hepatic B12 stores become depleted 3
• Metformin-induced B12 deficiency can cause or worsen distal symmetrical polyneuropathy, autonomic neuropathy, and cardiac denervation, which increases cardiac arrhythmias and mortality 3

Proton Pump Inhibitors (PPIs)

PPIs reduce gastric acid production, which impairs the release of vitamin B12 from food proteins and reduces intestinal absorption. 1, 4

Evidence Strength

• Large nested case-control study from Kaiser Permanente found that ≥2 years of PPI use at high doses (>1.5 pills/day) had OR of 1.95 (95% CI: 1.77,2.15) for diagnosed B12 deficiency 1
• Duration matters: inverse correlation exists between PPI duration and B12 levels, even in patients taking multivitamins with 100% daily value of B12 1, 4
• The FDA includes precautionary notices regarding vitamin B12 deficiency risk with long-term PPI use 1, 4

Important Caveats

• Some cross-sectional studies in elderly patients found no mean differences in serum B12 between PPI users and non-users 1, 4
• RCTs comparing PPIs to antireflux surgery showed no significant B12 differences after 5 years 1, 4
• However, these RCTs were not designed to detect clinically relevant changes and relied solely on serum B12 levels without assessing functional markers like methylmalonic acid or homocysteine 1

Clinical Implications

• Genetic variations in CYP2C19 may alter individual susceptibility to PPI-induced B12 deficiency 1, 4
• Patients taking B12-containing multivitamins may still develop deficiency with long-term PPI use, as supplementation may not fully prevent PPI-induced malabsorption 4
• The American Gastroenterological Association does not recommend routine screening for all PPI users, but individual risk assessment is warranted 1, 4

Medications NOT Associated with B12 Interference

Digitalis (b), quinolones (d), and macrolides (e) have no established evidence for interfering with vitamin B12 absorption. These medication classes work through entirely different mechanisms unrelated to gastric acid production or intestinal B12 absorption pathways.

Monitoring Recommendations

For patients on metformin:

• Measure hematologic parameters annually 2
• Check vitamin B12 levels every 2-3 years 2
• Increase monitoring frequency in high-risk patients: elderly, those with inadequate dietary B12/calcium intake, concurrent PPI use, or post-bariatric surgery 2, 3
• If borderline B12 levels, measure methylmalonic acid and homocysteine to detect early deficiency 3, 5

For patients on PPIs:

• Consider B12 assessment in high-risk patients on long-term therapy (≥2 years), particularly elderly patients or those with additional malabsorption risk factors 4, 6
• Use multiple analyte testing (≥2 of 4 biomarkers: serum B12, holotranscobalamin, homocysteine, methylmalonic acid) for increased sensitivity and specificity 5

For patients on both metformin AND PPIs:

• This combination creates additive risk for B12 deficiency 7
• Though one study found no deficiency in patients with ≤4 years combined therapy, longer durations warrant closer monitoring 7