Taking Acid Inhibitors Long-term May Lead to B12 Deficiency

Larry Hand

December 11, 2013

Use of acid-inhibiting medications for 2 or more years may lead to vitamin B12 deficiency, especially among women and younger individuals who take stronger doses, according to a study published in the December 11 issue of JAMA.

Jameson R. Lam, MPH, from the Division of Research, Kaiser Permanente, Oakland, California, and colleagues conducted a case-control study involving the Kaiser Permanente Northern California adult patient population. They compared the electronic records of 25,956 patients with diagnoses of vitamin B12 deficiency between January 1997 and June 2011 with the records of 184,199 patients without the deficiency but matched for sex, region of home clinic, race/ethnicity, year of birth, and membership duration.

The researchers evaluated whether the long-term use of proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) was associated with vitamin B12 deficiency. Vitamin B12 deficiency may lead to irreversible neurological damage and other complications if left untreated for a long period.

Among the patients with the deficiency diagnosis (case patients), 3120 (12.0%) had been dispensed 2 or more years' supplies of PPIs, and 1087 (4.2%) had been dispensed 2 or more years' supplies of H2RAs with no PPI use. The rest (83.8%) did not take either medicine. These patients were mainly female (57.4%), 60 years old or older (67.2%), and non-Hispanic white (68.4%).

Among the patients without the vitamin deficiency diagnosis (control patients), 13,210 (7.2%) had been dispensed 2 or more years' supplies of PPIs, and 5897 (3.2%) had been dispensed 2 or more years' supplies of H2RAs, with the remaining patients not taking either medication.

Higher Dose, Stronger Association

Using conditional logistic regression analysis, with adjustments including conditions and other medications associated with vitamin B12 deficiency and health service usage, the researchers found that deficiency diagnoses were 65% more common among case patients prescribed PPIs compared with patients not taking PPIs (odds ratio [OR] 1.65; 95% confidence interval [CI], 1.58-1.73). Patients taking H2RAs had a lesser risk (OR, 1.25; 95% CI, 1.17-1.34).

The higher the dose, the stronger the association. Patients taking more than 1.5 pills a day had almost twice the risk for vitamin B12 deficiency (OR, 1.95; 95% CI, 1.77 - 2.15), whereas patients taking 0.75 pills a day had a lower but still significant risk (OR, 1.63; 95% CI, 1.48 - 1.78).

The researchers found that the association between long-term PPI use and vitamin B12 deficiency was strongest among patients younger than 30 years (OR, 8.12; 95% CI, 3.36 - 19.59) but decreased with age, and the association was stronger among women than men.

The researchers also found, however, that the association diminished after PPIs were discontinued.

Causal Association?

The researchers write that a number of findings in their study, including association, plausibility, and consistency, meet "criteria for possible causal association between the use of acid-suppressing medications and vitamin B12 deficiency."

T.S. Dharmarajan, MD, vice chairman, Department of Medicine, and clinical director of the Division of Geriatrics of Montefiore Medical Center (Wakefield), Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, who led a previous study into the association between PPIs and B12 deficiency, agrees with the findings, with one comment: "The strength of the study lies in its large size. I have a little difficulty with the fact that B12 levels are not precisely mentioned, but that's probably the only negative aspect of the study," Dr. Dharmarajan told Medscape Medical News.

"The most important feature of their findings is logic: It's a very logical conclusion. You need acid to separate B12 from food protein, the first step in absorption, which takes place in the stomach. Once you knock off that acid, you have knocked off the essential first step required for B12 absorption.

Better Screening

"The most important thing is that, today, [PPIs] are used like water. They're among the largest class of drugs that are prescribed," he said. Some individuals take over-the-counter PPIs that their physicians may be unaware of, he added.

Dr. Dharmarajan said he thinks what will happen over the next several months is that a greater number of patients taking PPIs will be checked for the vitamin deficiency. "That's a good thing, because they're going to detect a lot of lower levels for which there'll be a ready explanation, and the deficiency can be readily corrected," he explained.

He said he thinks physicians will start to consider discontinuing PPIs in some patients or prescribing for the short-term. "Patients may be reluctant to give up the drug, so it will force the doctor now to engage the patient in a meaningful discussion," he added.

However, for patients taking PPIs long-term, "it's only proper to check B12 levels and treat people who need treatment. I think that is the strongest message that can come out of this paper."

This research was supported by a Kaiser Permanente Community Benefit Grant. One coauthor has reported receiving a grant or grant pending from Wyeth/Pfizer. The other authors and Dr. Dharmarajan have disclosed no relevant financial relationships.

JAMA. 2013;310:2435-2442. Abstract

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