Sustained proton-pump inhibitor exposure and incident age-related macular degeneration: a new-user, population-based cohort study.

OBJECTIVE: Proton-pump inhibitors (PPIs) may disrupt lysosomal acidification, a pathway implicated in age-related macular degeneration (AMD) pathogenesis. We evaluated whether sustained PPI exposure increased the risk of incident AMD in older adults aged ≥60 years. METHODS AND ANALYSIS: This retrospective observational cohort study included adults aged ≥60 years with sustained PPI exposure, matched 1:1 to unexposed controls on demographics, overall health, healthcare utilisation, cardiometabolic factors. Participants were identified from electronic health records. Sustained PPI exposure was defined as ≥2 years of cumulative use within 3 years of the first prescription. Fine-Gray models treating death as a competing event estimated subdistribution hazard ratios (sHRs) for AMD within 10 years; cause-specific Cox models provided complementary HRs. Analyses included histamine H2-receptor antagonists (H2-antagonists) as a negative exposure control and active comparator. RESULTS: Incident AMD occurred in 814/49 796 PPI exposed participants (1.64%) and 668/49 796 controls (1.34%) (overall sHR=1.24, 95% CI 1.12 to 1.38; p<0.001; HR=1.25, 95% CI 1.13 to 1.38, p<0.001). Proportional sHRs were non-constant; sHRs were 1.09 (95% CI 0.91 to 1.29) before 2.5 years and 1.33 (95% CI 1.17 to 1.51) thereafter. For non-exudative AMD, 640 PPI exposed (1.29%) and 510 unexposed (1.02%) participants developed disease (overall sHR=1.28, 95% CI 1.14 to 1.44; p<0.001, HR=1.29, 95% CI 1.14 to 1.44, p<0.001). Among those with non-exudative AMD, 190/2503 PPI-exposed participants (7.59%) and 179/2503 controls (7.15%) progressed to exudative AMD (sHR and HR=1.03, 95% CI 0.84 to 1.26; p=0.802 and p=0.801, respectively). No association was observed between H2-antagonists and AMD (sHR=1.02, 95% CI 0.88 to 1.19; p=0.784; HR=1.03, 95% CI 0.88 to 1.20, p=0.729). Results were consistent in the active-comparator analysis (reciprocal overall sHR=1.24, 95% CI 1.04 to 1.48; p=0.016; HR=1.25, 95% CI 1.05 to 1.49, p=0.012). CONCLUSION: Sustained PPI exposure was associated with a modestly higher AMD risk, whereas no association was observed with H2-antagonists. The consistency of the active-comparator findings supports the potential specificity of this association and warrants further investigation to determine its clinical implications.