Real world clinical perspective on PDE5i utility in dementia
Abstract
Abstract Background There is clearly a large unmet need for more drug treatments in dementia due to Alzheimer pathology (AD) and in VCID. Mechanistic studies in rodents and in vitro support a benefit of PDE5 inhibitors in AD. Method A Big data approach recently confirmed this potential benefit with an independent study incorporating multiple levels of biology with in silico network drug discovery for amyloid and tau endophenotypes, data mining from insurance records, as well as in vitro modeling using derived induced pluripotent stem cell (iPSC) neuronal models of AD. Results Collectively, this body of work is cause of optimism. However, a real‐world randomized clinical trial (RCT) of the PDE5i tadalafil in older people, incorporating biomarkers, detected no significant effect with respect to cerebral blood flow. Conclusion These results raise multiple questions for the dementia clinician‐scientist. Do in vitro and in vivo preclinical paradigms provide non‐translatable findings because these systems are not capturing a key component of AD, such as human aging? Is it still worth pursuing PDE5i as a therapeutic route? What could be some factors that contributed to the negative RCT results and what should be emphasized in the design of a definitive RCT for this class of therapeutics? Finally, what role do biomarkers play in filling critical gaps in knowledge to bridge the path between bench and bedside.
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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