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

To analyze the primary endpoint of association between PPI use and dementia, the study compared the rate of dementia in a cohort of veterans who had received an outpatient prescription for a PPI within the study time frame vs the rate of dementia in a random, equal number of veterans who had never been prescribed PPIs within the study time frame. In this study, veterans were classified as having dementia if they had a diagnosis of dementia based on ICD-9 or ICD-10 codes (Table 1), or if they had been prescribed medications used to treat dementia (donepezil, ergoloid mesylates, galantamine, memantine, and rivastigmine).

Secondary endpoints included analysis of the effects of PPI agent, PPI dose, and PPI duration on the risk of dementia. For the PPI dose analysis, cumulative doses were converted into defined daily doses (DDDs) using the World Health Organization calculation to equalize the different potencies of PPI agents (Table 2).¹⁴ In addition, the effect of PPI use on vitamin B₁₂ levels was analyzed as an exploratory endpoint to investigate the hypothesis that PPI may be associated with vitamin B₁₂ deficiency, which in turn may be associated with dementia.^6,7

Baseline characteristics were collected to determine the variability between the treatment and control group. Data collected included age, gender, past medical history of diseases that may increase risk of dementia, and anticholinergic drug use. Anticholinergic drugs were included if they were classified as having “definite anticholinergic effects” based on the Aging Brain Care Anticholinergic Burden Scale (Appendix).¹⁵

Statistical Analysis

The primary endpoint was analyzed using a χ² for association test. For the secondary endpoints, a χ² for association test was used for endpoints with nominal data, and the Mood median test was used for endpoints with continuous data. The exploratory endpoint analyzing vitamin B₁₂ levels was analyzed with the Mood median test. A P value of < .05 was defined as being statistically significant. Power analysis was not performed since all veterans who met the criteria were included in the study.

Results

Records of 23,656 veterans were included in the study with 11,828 veterans in both the PPI cohort and the non-PPI cohort (Table 3).

Primary Endpoint

Within the PPI group, 1,119 (9.5%) veterans had dementia compared with only 740 (6.3%) veterans in the non-PPI group. There was a statistically significant association between PPI use and dementia (P < .001). These results yielded an odds ratio of 1.55 for dementia risk in PPI users vs nonusers and a relative risk increase of 51.4% for dementia risk with PPI use compared with no PPI use.