PDE5A variation is associated with tadalafil response in men with diabetes mellitus and erectile dysfunction: a prospective proof-of-concept pharmacogenetic study

Erectile dysfunction (ED) is a common complication of diabetes mellitus (DM), occurring earlier and with greater severity than in the general population. Epidemiological data indicate that more than half of men with DM experience some degree of ED, highlighting the need for effective treatment strategies.1 The pathophysiology of diabetic ED is multifactorial and involves endothelial dysfunction, neuropathy, impaired nitric oxide bioavailability and structural alterations of the penile vasculature. Penile erection is mediated by the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) signaling pathway, which promotes cavernosal smooth muscle relaxation and penile blood flow.2 Phosphodiesterase type-5 inhibitors (PDE5Is) are the first-line pharmacological therapy for ED. These agents act by inhibiting phosphodiesterase type-5 (PDE5), the enzyme responsible for cGMP degradation. Among PDE5Is, tadalafil is widely used, because of its prolonged half-life and favorable pharmacokinetic profile.3 However, treatment response varies considerably, particularly among men with DM. Interindividual variability may partly reflect genetic differences, including polymorphisms in PDE5A, the gene encoding the pharmacological target of PDE5Is.4 This study aimed to evaluate the association between selected PDE5A polymorphisms and tadalafil response in men with DM and ED.