Treatment with PDE5 inhibitors not associated with reduced risk for AD, dementia

Treatment with sildenafil or tadalafil was not associated with a reduced risk for incident Alzheimer’s disease and related dementia in patients with pulmonary hypertension, according to a study published in Brain Communications.

“In recent years, there has been significant interest in using computational biology-based approaches to identify novel drug repurposing candidates for [Alzheimer’s disease and related dementia],” Rishi J. Desai, MS, PhD, assistant professor of medicine at Harvard Medical School and associate epidemiologist at Brigham and Women’s Hospital, and colleagues wrote.

Desai and fellow researchers sought to evaluate whether treatment with phosphodiesterase-5 (PDE5) inhibitors sildenafil and tadalafil was associated with reduced incidence of AD and related dementia, compared with use of endothelin receptor antagonists (ERA), in patients with pulmonary hypertension.

Using Medicare fee-for-service claims data from the Drug Repurposing for Effective Alzheimer’s Medicines study from 2007 to 2018, researchers identified 9,968 initiators of PDE5 inhibitors and 3,053 ERA initiators. Researchers then determined incidence of AD and related dementia in patients after PDE5 initiation compared with ERA initiation after controlling for 76 confounding variables via propensity-score matching. Adjusting for confounders, researchers matched 2,888 PDE5 inhibitor initiators with the same number of ERA initiators (average age, 74 years; 69% women).

Researchers evaluated the treatments using four alternative analyses, which were designed to address various biases including exposed person-time misclassification, informative censoring, reverse causality and outcome onset misclassification. Across the four analyses, there was no evidence for reduced risk for incident AD and related dementia after treatment with PDE5 inhibitors compared with ERA (HR = 0.99 [95% CI, 0.69-1.43], 1.00 [0.71-1.42], 0.67 [0.43-1.06] and 1.15 [0.57-2.34], respectively).

In addition, researchers did not find that sildenafil had a protective effect relevant to AD in most cell culture-based phenotypic assays.

“While wider use of routinely collected health care data to evaluate biological hypotheses for drug repurposing is a welcome development, caution is warranted to avoid common pitfalls and consequent overinterpretation of estimates generated from these data,” Desai and colleagues wrote.