Time-Varying Use of Proton Pump Inhibitors and Cognitive Impairment and Dementia: A Real-World Analysis from Germany

Background Cumulative evidence of dementia risk in patients taking proton pump inhibitors (PPIs) is still inconclusive, probably due to a variety of study designs. Objective This study aimed to compare how the association between dementia risk and use of PPIs differs by different outcome and exposure definitions. Methods We conceptualized a target trial using claims data with 7,696,127 individuals aged 40 years or older without previous dementia or mild cognitive impairment (MCI) from the Association of Statutory Health Insurance Physicians in Bavaria. Dementia was defined as either including or excluding MCI to compare how the results alter by different outcome definitions. We used weighted Cox models to estimate the PPI initiation effect on dementia risk and weighted pooled logistic regression to assess the effect of time-varying use versus non-use during 9 years of study period, including 1 year of wash-out period (2009–2018). The median follow-up time of PPI initiators and non-initiators was 5.4 and 5.8 years, respectively. We also evaluated the association between each PPI agent (omeprazole, pantoprazole, lansoprazole, esomeprazole, and combined use) and dementia risk. Results A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk. A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03–1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80–1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03–1.05) and 1.82 (1.77–1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk. Conclusion Our large study supports existing evidence that PPI use is related to an increased risk of dementia.