Seeking evidence-based strategies for pharmacologic management of erectile dysfunction in medically complex patients, beyond first-line PDE5 inhibitors. Specific questions for discussion:
Sequencing and combination therapy: In men with cardiometabolic comorbidity (hypertension, diabetes, dyslipidemia), what protocols do you use to decide between on-demand versus daily tadalafil, and when do you layer therapies (e.g., adding an alpha-1 blocker for LUTS/BPH)? Any comparative data on hypotension risk and timing separation among tamsulosin, silodosin, and alfuzosin when co-administered with a PDE5 inhibitor?
Defining and managing “nonresponse”: What is your operational definition of PDE5 inhibitor nonresponse after proper trials (attempt count, timing relative to meals, dose adequacy)? Which reversible factors most often convert nonresponders (e.g., medication interactions via CYP3A4, untreated hypogonadism, uncontrolled diabetes, SSRI-induced dysfunction), and what sequence of corrective steps has the strongest evidence?
Disease modification versus symptomatic relief: Beyond erection hardness and IIEF domain scores, is there convincing evidence that chronic low-dose PDE5 inhibitors improve endothelial function (e.g., flow-mediated dilation, arterial stiffness) in a way that sustains erectile improvements after discontinuation, particularly in diabetes or post-prostatectomy rehabilitation?
Pharmacogenomics and precision dosing: Are there clinically actionable variants (e.g., in CYP3A, ABCB1, PDE11A, NOS3) that predict efficacy or adverse effects with specific PDE5 inhibitors? Has anyone incorporated pharmacogenetic panels into ED treatment selection in routine practice?
Interactions and safety with contemporary drugs: Practical guidance on managing PDE5 inhibitors with potent CYP3A inhibitors such as ritonavir (e.g., during Paxlovid therapy) and with alpha-1 blockers to minimize orthostatic symptoms. Any real-world protocols for washout and re-initiation that balance safety with continuity of sexual function?
Second-line pharmacotherapies: Comparative effectiveness and adherence data for intraurethral alprostadil versus intracavernosal alprostadil or combination injections (e.g., phentolamine/papaverine/alprostadil). Best practices for titration, minimizing fibrosis risk, and patient training that reduce drop-out rates.
Emerging mechanisms: Status of soluble guanylate cyclase stimulators/activators, Rho-kinase inhibitors, and other nitric-oxide-independent pathways in ED-any robust human data, and where might they fit for PDE5 nonresponders, especially with severe vasculogenic disease? Safety concerns when combined with PDE5 inhibitors?
Cardiometabolic co-therapies and ED: Observed effects of GLP-1 receptor agonists or dual incretin therapies and SGLT2 inhibitors on erectile function independent of weight loss or glycemic control; any interaction signals with PDE5 inhibitors. Antihypertensive selection to minimize sexual side effects (e.g., nebivolol versus non-NO-mediated beta-blockers; ACE/ARB versus thiazides).
Tolerance and long-term outcomes: Is tachyphylaxis to PDE5 inhibitors a true clinical phenomenon or primarily behavioral/expectation-driven? Longitudinal data on dose escalation, persistence, and outcomes over years.
Objective monitoring and escalation triggers: Which metrics (IIEF-EF changes, Erection Hardness Score, penile duplex Doppler parameters) best guide when to escalate from oral agents to injection therapy or consider penile prosthesis?
Interested in protocols, references to high-quality trials or guidelines, and practical pearls from multidisciplinary care (urology, cardiology, endocrinology).