Key result
Initiation of phosphodiesterase-5 inhibitors was not associated with a reduced risk of incident Alzheimer's disease and related dementia compared to endothelin receptor antagonists (HR 0.99).
Why the study?
To evaluate the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer's disease and related dementia.
Does initiation of phosphodiesterase-5 inhibitors reduce the incidence of Alzheimer's disease and related dementia in patients with pulmonary hypertension?
Cohort (n=13,021)
Does initiation of phosphodiesterase-5 inhibitors reduce the incidence of Alzheimer's disease and related dementia in patients with pulmonary hypertension?
Hazard Ratio: 0.99 (95% CI 0.69–1.43)
Absolute Event Rate: 17.9% vs 18.8%
Initiation of phosphodiesterase-5 inhibitors in patients with pulmonary hypertension is not associated with a reduced risk of incident Alzheimer's disease and related dementia, challenging their potential as repurposing candidates.
No reduced dementia risk with PDE5 inhibitors in pulmonary hypertension; leaves open repurposing potential in other populations.
We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer's disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer's disease and related dementia after phosphodiesterase-5 inhibitor initiation versus endothelin receptor antagonist initiation among patients with pulmonary hypertension after controlling for 76 confounding variables through propensity score matching. Across four separate analytic approaches designed to address specific types of biases including informative censoring, reverse causality, and outcome misclassification, we observed no evidence for a reduced risk of Alzheimer's disease and related dementia with phosphodiesterase-5 inhibitors;hazard ratio (95% confidence interval): 0.99 (0.69-1.43), 1.00 (0.71-1.42), 0.67 (0.43-1.06), and 1.15 (0.57-2.34). We also did not observe evidence that sildenafil ameliorated molecular abnormalities relevant to Alzheimer's disease in most cell culture-based phenotypic assays. These results do not provide support to the hypothesis that phosphodiesterase-5 inhibitors are promising repurposing candidates for Alzheimer's disease and related dementia.
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Desai et al. (2022) conducted a cohort in Pulmonary arterial hypertension (n=13,021). Phosphodiesterase-5 inhibitors vs. Endothelin receptor antagonists was evaluated on Incident Alzheimer's disease and related dementia (HR 0.99, 95% CI 0.69-1.43). Initiation of phosphodiesterase-5 inhibitors was not associated with a reduced risk of incident Alzheimer's disease and related dementia compared to endothelin receptor antagonists (HR 0.99).
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