DISCUSSION

The current study investigated the association between six PPI agents and the risk of dementia, compared different time interval of PPIs treatment and dementia events. The results indicated no association between dementia events and PPI agents, including dexlansoprazole, lansoprazole, pantoprazole, omeprazole, esomeprazole and rabeprazole. To the best of our knowledge, this was the first study concerned the association between PPIs use and dementia risk based on FAERS database.
With the widespread use of PPI agents, PPIs-associated adverse events had caught health professionals’ attention, as well as the public and the media. In FAERS database, nearly three quarter of the PPIs AE cases were reported by non-health professionals. To reduce the influence of non-health professionals, we only included cases reported by health professionals. However, the number of dementia cases treated by PPIs were increasing by years in FAERS, the risk of stimulated reporting could not be complete ruled out.
Based on the β-amyloid enhancement [8], vitamin B12 deficiency phenomena [9] and the widespread PPIs use, the risk of dementia and PPIs use had become a hot topic. Professor Akter first revealed five different PPI agents had varying degrees of influence on different cognitive domains associated with dementia based on the Cambridge Neuropsychological Test Automated Battery (CANTAB) software test [10]. Professor Haenisch conducted the first epidemiological investigation, indicated PPIs might have an impact on dementia risk based on the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe) [11]. Then, professor Gomm conducted the first prospective cohort study, revealed regular PPIs treatment had a significantly increased risk of dementia using data derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK) [12], which had been hotly commented.
However, conflicting results had been gradually published. Professor Lochhead conducted a nationwide prospective cohort study and divided PPI users into four groups based on duration of PPIs treatment, revealed a modest association between duration of PPIs use and cognitive function, however, Lochhead stated that the results could not support PPIs use increases dementia risk [33]. Professor Taipale finished a nationwide nested case–control study which set a lag window of different duration, found PPIs use was not associated with risk of Alzheimer’s disease with a 3-year lag window [34]. Professor Gray reported a prospective cohort study and found no association between PPIs exposure and dementia risk after a mean follow-up of 7.5 years [20]. Professor Cooksey conducted a large population-based study based on electronic health-data from the Secure Anonymised Information Linkage (SAIL) Databank from 1999 to 2015, could not confirm an association between PPIs use and an increased risk of dementia [17]. The current study based the FAERS big data, indicated no significant signal between PPIs use and the risk of dementia. Even compared in different time duration, no significant difference of dementia events was found between short- and long- time interval groups.
Our study revealed no association between dementia risk and PPIs treatment based on the FAERS real world big data, however, certain limitations existed. FAERS is a spontaneous reporting system, voluntary and opened to health professional as well as the public, so under-reporting, over-reporting or missing data was inevitable [35]. The time event comparison only included limited cases with time data reported. Although non-health professionals’ reports excluded, the risk of stimulated reporting could not be eliminated.
In summary, the current study revealed no association between six PPI agents and the risk of dementia based on the FAERS data. Our findings suggested that dementia events might not be considered as a factor in discontinuing PPIs treatment.

Conflicts of Interest

The authors have no conflicts.

Funding information

National Key Research and Development Program of China (Number: 2020YFC2008302).
Sichuan Science and Technology Program (Number: 2020JDR0143).

Data availability statement

All original data could be downloaded freely in FAERS website.
https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html

Authors Contributions

Bin Wu and Ting Xu designed the research.
Bin Wu, Fang-yuan Tian, Qiao-zhi Hu, Feng-bo Wu, Yu-wen Li and Ting Xu wrote the article. Bin Wu and Fang-yuan Tian collected the data. Bin Wu and Qiao-zhi Hu performed data analysis.
Bin Wu, Feng-bo Wu, Yu-wen Li and Ting Xu contributed to data interpretation and intellectual content.