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Proton Pump Inhibitor Use and Risk of Dementia in the Veteran Population

There was a statistically significant association between use of proton pump inhibitors and dementia diagnosis in a 11-year retrospective study of patients at the Sioux Falls Veteran Affairs Health Care System.
Federal Practitioner. 2019 June;36(4)s:S27-S31
June 1, 2020|Federal Practitioner
Jenna Welu, PharmD;Justin Metzger, PharmD;Scott Bebensee, PharmD, BCPS;April Ahrendt, MS, RDN, CNSC, LN;Micheal Vasek, MBA
Author and Disclosure Information

Jenna Welu is a Pharmacy Resident, Justin Metzger is Chief of Pharmacy, Scott Bebensee is a Home-Based Primary Care Clinical Pharmacy Specialist, April Ahrendt is a Systems Redesigner, and Micheal Vasek is a Program Analyst, all at the Sioux Falls VA Health Care System in South Dakota. April Ahrendt is an Academic Assistant Professor at the University of South Dakota School of Health Sciences in Vermillion.
Correspondence: Jenna Welu (jenna.donnelly@ jacks.sdstate.edu)

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Secondary Endpoints

Users of rabeprazole had the highest rate of dementia (12.8%), followed by lansoprazole (10.9%), omeprazole (9.7%), esomeprazole (7.7%), and pantoprazole (7.0%). The rate of dementia for non-PPI users was 6.3% (P < .001). The median cumulative doses of PPIs were not significant: 597 DDDs (95% CI, 540-630) in the dementia group vs 570 DDDs (95% CI, 540-624) in the nondementia group (P = .79). The median cumulative duration of PPI use in the dementia group was 4.6 years (95% CI, 4.25-4.92) vs 5.3 years (95% CI, 5.08-5.42) in the nondementia group (P < .001).

Exploratory Endpoint

The median B12 level in the PPI group was 521 pg/mL (95% CI, 509-533) compared with 480 pg/mL (95% CI, 465-496) in the non-PPI group (P < .001). However, both groups fell within the normal range for vitamin B12 (200-900 pg/mL).16

Discussion

The aim of this study was to determine whether an association existed between PPI use and dementia. This study showed a statistically significant association between PPI use and dementia within the veteran population. This study also showed a significant association between specific PPI agents and dementia. When analyzing the individual PPI agents, the rabeprazole group yielded the strongest relationship. However, this study was not powered to evaluate and compare risks of dementia between individual PPI agents. More data are needed to determine statistical and clinical significance of associations between individual PPI agents and risk of dementia.

The veterans with dementia had a higher median cumulative PPI dose than did the veterans without dementia; however, the results were not statistically significant. Therefore, the data cannot correlate higher doses of PPI use to increased risk of dementia.

The cumulative duration of PPI use was statistically significant but opposite of the expected outcome. The dementia group had a lower median lifetime duration of PPI use compared with that of the nondementia group. It is difficult to determine the reason for this outcome, but it seems that for this study population, a longer duration of PPI use was not associated with an increased risk of dementia.

Finally, the exploratory endpoint analyzed vitamin B12 levels, since it has been shown that PPI use can lead to vitamin B12 deficiency and that B12 deficiency can lead to dementia.6-8 This study found that the dementia group had significantly higher vitamin B12 levels than the nondementia group. These data suggest that PPI use may not be associated with vitamin B12 deficiency. However, it is important to note that this study was unable to collect data on the use of vitamin B12 supplementation due to the unreliability of over-the-counter (OTC) and non-VA medication use records. Therefore, it is possible that the PPI group had higher rates of B12 deficiency but were effectively treated with B12 supplementation. More research is needed to determine the exact relationship between PPI use, vitamin B12 deficiency, and dementia risk.

Strengths/Limitations

Strengths of this study that support its findings include the large population size. Additionally, the use of the VA EHR allowed for a complete drug dispensing history to be collected, which improves reliability of the data.

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