Associations between the use of histamine‐2 receptor antagonists vs. proton pump inhibitors and cognitive decline: A stratified longitudinal study in people with and without cognitive impairment

Abstract

AbstractBackgroundStudies suggest associations between proton pump inhibitors (PPI) and higher dementia risk compared with no use; however, several studies did not consider histamine‐2 receptor antagonists (H2RAs), the other common acid suppressant for similar indications. Comparisons between them are clinically relevant, both in older people with and without cognitive impairment due to Alzheimer’s disease (AD).MethodParticipants using a PPI or H2RA were selected from the National Alzheimer's Coordinating Center database from September 2005 to February 2021. Cox regressions were used to compare 5‐year conversion from normal cognition to mild cognitive impairment (MCI) or dementia, and 5‐year conversion from MCI to dementia, between PPI and H2RA users. In a propensity score matched sample of clinically diagnosed mild‐moderate AD, a linear mixed‐effects regression was used to assess PPI vs. H2RA use in rates of decline in global cognition (Clinical Dementia Rating [CDR®] Sum of Boxes; CDR‐SOB) up to 5 years. Delayed memory recall (Wechsler Memory Scale–Logical Memory test) was explored using a mixed‐effects negative binomial regression. Demographics, smoking, alcohol abuse, baseline CDR‐SOB, comorbidities, concurrent medications used, and apolipoprotein E genotype were included as covariates in Cox regressions or in propensity score.ResultCognitively normal H2RA (n=547, events=62) vs. PPI users (n=2237, events=312) did not differ in their risk for MCI or AD (Hazard Ratio; HR [95% Confidence Interval; CI] = 1.067 [0.807‐1.410]). In MCI, H2RA use (n=288, events=75) was associated with faster 5‐year dementia conversion (HR [95% CI] = 1.402 [1.085‐1.811]), compared with PPI use (n=1413, events=355). In AD, H2RA (n=212) vs. PPI (n=636) use was not associated with differential rates of decline in global cognition (B [95% CI] = ‐0.023 [‐0.324, 0.277] CDR‐SOB per year). However, H2RA use was associated with faster memory decline (Rate Ratio [95% CI] = 0.783 [0.671‐0.915]) in AD, but no associations with memory decline were found in MCI or normal cognition.ConclusionDifferential associations with cognitive decline were not observed in cognitively normal older people. Among people with MCI or AD, H2RA use was associated with faster rates of conversion to dementia, or memory decline, respectively. Anti‐cholinergic burden might explain the associations.