Metformin and proton pump inhibitors have been implicated in decreasing levels of vitamin B12 independently. The purpose of this study was to evaluate the effect of concomitant use of metformin and proton pump inhibitors on the incidence of vitamin B12 deficiency.
A retrospective chart review was done using the computerized patient record system at the Memphis VA Medical Center for 614 patients with type 2 diabetes and previously collected vitamin B12 levels. Patients were excluded if they were over the age of 60 years; on a vegetarian diet; had been diagnosed with pernicious anemia, documented by a positive Schilling test or anti-intrinsic factor antibody, or pancreatic exocrine insufficiency; had undergone a gastrectomy or bowel resection; or had been treated with supplemental calcium, H2 blocker, or B12 within 3 months of data collection. The vitamin B12 levels were assessed using a competitive immunoassay with direct chemiluminescent technology. Deficiency was defined as vitamin B12 levels <300 pg/mL. A χ2 test was used to compare patients taking metformin or proton pump inhibitors alone and those taking both with a control population taking neither medication.
Mean ± SD age was 65.08 ± 9.23 years, with a majority of male patients (96.3%). African Americans comprised 40.07% of the study population and Caucasians 50.33%; 9.6% had “other” listed for race. The incidence of vitamin B12 deficiency was found in 48 (22.2%) of the 216 control subjects. This was not significantly different compared with 32 (21.91%) of the 146 metformin subjects or 33 (25.58%) of the 129 proton pump inhibitor alone subjects (P = 0.9454 and 0.4763). However, there was a significant difference found in 42 (34.15%) of the 123 concomitant metformin and proton pump inhibitor subjects compared with the control group (P = 0.0096).
Metformin is a first-line medication used in the treatment of type 2 diabetes but has also been shown in multiple studies to reduce serum B12 levels in 10–30% of patients (1). Proton pump inhibitors are also commonly used medications for the treatment of gastroesophageal reflux disease and peptic ulcer prevention and treatment and, short-term, have been shown to decrease B12 levels from 3.4 to 0.4% (P < 0.05) in a 2-week period (2). However, studies looking at long-term proton pump inhibitor use and vitamin B12 deficiency have yielded conflicting results (3,4). Ting et al. (5) found no significantly increased risk for concurrent use of histamine H2 receptor antagonist or proton pump inhibitor in the development of metformin-related B12 deficiency. However, they did not separate out the use of H2 blockers from proton pump inhibitors in calculating the risk of developing metformin-related B12 deficiency.
Proton pump inhibitors and metformin alone were not associated with a significant difference in vitamin B12 deficiency, but the combination was associated with a significant increase in vitamin B12 deficiency. More studies are needed to elucidate the exact mechanisms by which proton pump inhibitors and metformin affect vitamin B12 levels and relate these changes to clinical findings.
This project was supported in part by National Institutes of Health Grant 5T35-DK-074005-27 (to S.S.S.). Additionally, this research would not have been possible without the support of the University of Tennessee Health Science Center and the Memphis VA Medical Center.
No potential conflicts of interest relevant to this article were reported.
A.N.L. contributed to the discussion, wrote the manuscript, researched data, and reviewed and edited the manuscript. C.L.A. researched data and contributed to the discussion. W.Y. contributed to the discussion, researched data, and reviewed and edited the manuscript. S.S.S. contributed to the discussion and reviewed and edited the manuscript. S.S.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Parts of this study were presented in abstract form at the Annual Meeting of the Southern Society for Clinical Investigation, New Orleans, Louisiana, 17–19 February 2011.
The authors thank S. Dagogo-Jack, Department of Endocrinology, University of Tennessee Health Science Center, for reviewing the manuscript prepublication.