Long-term use of acid-suppressive drugs associated with vitamin B₁₂ deficiency

Long-term use of proton-pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) may be associated with vitamin B₁₂ deficiency, according to a new study.

Researchers used data from patients who were part of the Kaiser Permanente Northern California (KPNC) network to perform a nested case-control study evaluating whether use of acid-suppressive therapy was associated with deficiencies in vitamin B₁₂. Pharmacy, laboratory and diagnostic databases were used to determine individuals' exposures and outcomes. Cases were KPNC members who were at least 18 years old, who had been members for at least a year before the index date, and who were initially diagnosed with vitamin B₁₂ deficiency between January 1997 and June 2011. For each case, a maximum of 10 matched-control KPNC members without a vitamin B₁₂ deficiency at the time of the case diagnosis were selected.

Results appeared in the Dec. 11 Journal of the American Medical Association.

A total of 25,956 cases and 184,199 controls were included in the final analyses. Most case-patients were female (57.4%), of non-Hispanic white ethnicity (68.4%) and at least 60 years old (67.2%). Overall, 3,120 case-patients (12%) and 13,210 (7.2%) controls received 2 or more years' worth of PPIs; 1,087 case-patients (4.2%) and 5,897 controls (3.2%) received 2 or more years' worth of H2RAs without PPIs; and 21,749 (83.8%) case-patients and 165,092 controls (89.6%) had not been prescribed either type of drug.

Increased risk for vitamin B₁₂ deficiency was associated with 2 or more years' worth of either PPIs and H2RAs (odds ratios, 1.65 [95% CI, 1.58 to 1.73] and 1.25 [95% CI, 1.17 to 1.34], respectively). Higher doses of PPIs (>1.5 pills/d) had a stronger association with risk for vitamin B₁₂ deficiency than lower doses of PPIs (<0.75 pills/d), with odds ratios of 1.95 (95% CI, 1.77 to 2.15) and 1.63 (95% CI, 1.48 to 1.78) (P=0.007 for interaction). The association between PPI use and vitamin B₁₂ deficiency weakened after the drugs were discontinued. Association of vitamin B₁₂ deficiency with PPI use of at least 2 years was stronger among patients younger than 30 years of age and decreased as age increased; it was also stronger in women than in men.

The authors acknowledged that they did not examine associations with short-term use of acid-suppressive medications and that the calculated daily doses may not have accurately represented patients' use, among other limitations. However, although they could not rule out residual confounding in their study, they concluded that patients who use acid-suppressive medications may be at increased risk for vitamin B₁₂ deficiency.

“These findings do not recommend against acid suppression for persons with clear indications for treatment, but clinicians should exercise appropriate vigilance when prescribing these medications and use the lowest possible effective dose,” the authors wrote.