Supplementary Material for: Phosphodiesterase-5 Inhibitors and Dementia Risk: A Real-World Study

Biological and scarce epidemiological evidence suggested that phosphodiesterase-5 inhibitors (PDE5i) might reduce dementia risk. We aimed to examine the association between PDE5i and dementia using real-world data. Two retrospective cohorts within the database of Clalit, the largest healthcare provider in Israel (2005-2023), were studied. The first cohort included new daily users, older than 50 years of age, of low dose tadalafil, prescribed for benign prostatic hypertrophy (BPH), propensity-score matched to new-users of alpha-1 blockers, and analyzed using 2-year lag time. The second cohort included patients with erectile dysfunction, with/without any PDE5i treatment, using time-dependent analysis. Individuals in the cohorts were followed through May 2023 for the occurrence of dementia. The first cohort included 5,204 tadalafil initiators propensity-score matched to 18,565 alpha-1 blockers initiators. There was no association between tadalafil use and dementia risk HR=0.99 95%CI (0.88, 1.12), p=0.927. Similar results were obtained in a competing risk analysis, and in a sensitivity analysis in which we restricted the cohort to patients older than 60 years at cohort entry. The second cohort of 133,336 patients with erectile dysfunction included new-users and non-users of any PDE5i.In a mean follow-up of 7.9 years, 8,631 patients were newly diagnosed with dementia. In a time-dependent multivariable analysis PDE5i use was not associated with reduced dementia risk HR=0.95 (95%CI, 0.86-1.04). Results were not changed in sensitivity analyses (patients older than 60 years, or stratification by PDE5i type). This study suggests that use of PDE5 inhibitors is not associated with decreased risk of dementia.