Author: Sylvia (Xi) He – Medical / Scientific Editor & Writer
Introduction
Tadalafil, the long-acting phosphodiesterase type 5 inhibitor (PDE5i) better known by its brand name Cialis, has been a cornerstone in the management of erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) for over two decades. In 2025, its role is being refined rather than reinvented, but those refinements matter. Updated EAU sexual and reproductive health guidelines and several new clinical studies are shifting the nuances of when, how, and for whom tadalafil should be used.
This year’s data bring three major developments into focus. First, a more precise framework for combination therapy with alpha-blockers in men with coexisting ED and lower urinary tract symptoms (LUTS) has emerged. Second, early research into inflammatory biomarkers, particularly the Systemic Inflammation Response Index (SIRI), suggests that laboratory data might one day help predict treatment responsiveness. And finally, exploratory work continues on the possible vascular and cognitive benefits of PDE5i use, including hypotheses about their role in neuroprotection.
For clinicians and informed patients alike, 2025 offers a blend of solid clinical updates and forward-looking signals. The challenge is knowing which changes to apply in today’s practice and which to keep on the research watchlist.
Guideline Updates: EAU 2025 Highlights for ED
The 2025 update of the European Association of Urology (EAU) sexual and reproductive health guidelines reaffirms PDE5 inhibitors, including tadalafil, as first-line pharmacologic therapy for most men with erectile dysfunction, provided there are no contraindications such as nitrate use or recent cardiovascular events. However, subtle shifts in emphasis are worth noting. The new recommendations place greater weight on baseline cardiovascular risk stratification before initiating any PDE5i, aligning with the Princeton IV consensus on sexual activity and cardiac safety. This means that clinicians are encouraged to systematically assess blood pressure, lipid profile, glycemic control, and physical activity levels before prescribing.
For men with concurrent BPH/LUTS, the guidelines now provide clearer direction: once-daily tadalafil 5 mg can be considered a first-line monotherapy or combined with alpha-blockers in select patients, provided hypotension risk is minimal. This combination approach is no longer framed as “second-line” but rather as a parallel option when both urinary and erectile symptoms are present.
Importantly, the choice between daily and on-demand tadalafil is explicitly linked to patient lifestyle, frequency of sexual activity, and tolerance, rather than purely symptom severity. The update also notes that food interactions remain minimal for tadalafil, which can simplify patient adherence.
Also learn about innovations in the industry: Smart Devices for Erectile Dysfunction: A Bridge to Prescription PDE-5.
Combination Therapy: New Data with Alpha-Blockers
Fresh clinical evidence in 2025 strengthens the role of tadalafil–alpha-blocker combinations for men with both ED and moderate-to-severe LUTS/BPH. A key multicenter randomized controlled trial compared once-daily tadalafil 5 mg plus tamsulosin 0.4 mg with monotherapy in over 300 patients. The combination not only improved International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Qmax) more than either drug alone, but also preserved erectile function gains without increasing adverse events.
The safety profile remained favorable when patients were appropriately screened for hypotension risk, echoing the EAU recommendation to check baseline blood pressure and avoid use in men on multiple vasodilators. Notably, dizziness rates were low, likely due to fixed low dosing and patient selection.
For clinicians, the data suggest that combination therapy with alpha-blockers can be considered early in treatment rather than reserved for those failing monotherapy, particularly in patients whose LUTS and ED have equal impact on quality of life. From a practical standpoint, initiating both agents simultaneously may reduce the need for future therapy changes, improving satisfaction and adherence.
Predicting Response: Inflammation Index (SIRI)
A 2025 theme is whether systemic inflammation helps explain why some men respond less robustly to tadalafil. The Systemic Inflammation Response Index (SIRI), calculated from neutrophils, monocytes, and lymphocytes, has emerged as a candidate biomarker. Cross-sectional and cohort analyses link higher SIRI values to worse erectile function overall, supporting the idea that vascular inflammation impairs PDE5i responsiveness. More pointedly, a 2025 study examined tadalafil non-response and found that elevated SIRI independently predicted unresponsiveness after controlling for age, cardiometabolic factors, and baseline ED severity. While effect sizes vary and cut-offs aren’t standardized, the signal is consistent with the broader literature tying inflammatory biomarkers to endothelial dysfunction.
What can clinicians do with this now? First, treat SIRI as hypothesis-generating, not prescriptive. It may help frame expectations and prompt earlier attention to modifiable inflammers (glycemic control, weight, sleep, smoking). Second, a high SIRI might justify longer trials of daily tadalafil (to allow endothelial adaptation) or earlier consideration of combination strategies (e.g., adding an alpha-blocker when LUTS is present). Crucially, no guideline endorses SIRI-based dosing or switching decisions yet; prospective, treatment-stratified studies are still needed.
Bottom line: SIRI is a promising lens on the inflammation–ED axis and may help explain heterogeneous responses to tadalafil, but it remains pre-clinical for decision-making in 2025.
Beyond ED/BPH: Neurologic & Vascular Signals (Hypothesis-Level)
Outside urology, 2025 brought renewed interest in brain and vascular effects of PDE5 inhibitors. Mechanistically, augmenting NO–cGMP signaling could support neurovascular coupling, cerebral perfusion, and synaptic plasticity, plausibly relevant to cognitive aging. What’s new is a meta-analysis of clinical (observational) studies reporting that PDE5i exposure was associated with lower Alzheimer’s disease (AD) incidence (pooled HR ≈0.41–0.47 depending on comparator). These data, drawn from large claims/registry cohorts, strengthen the signal that had been trickling through the literature. Two caveats matter for clinicians. First, the included studies are non-randomized; selection, healthy-user, and unmeasured confounding (e.g., sexual activity, socioeconomic factors, care engagement) can all bias results. Second, no randomized trial has tested tadalafil (or any PDE5i) with hard cognitive endpoints as a primary outcome. The meta-analysis authors explicitly frame their findings as support for phase 3 trials, not proof of prevention.
Where does this leave practice? For men already taking tadalafil for ED/BPH, the 2025 evidence does not justify prescribing for cognitive benefit; at most, it provides a neuroprotection hypothesis to watch for trial enrollment opportunities. If a patient asks about brain health, it’s reasonable to explain that the vascular biology is plausible, but the clinical effect remains unproven and should not influence the risk–benefit calculus for ED/BPH treatment today. Concurrently, standard cognitive-risk reduction (blood pressure, glycemia, sleep, exercise) remains the evidence-based path.
Finally, guideline language around ED management in 2025 continues to focus on cardiovascular safety stratification and symptom outcomes, not neuroprotection – another reminder to keep cognitive headlines in perspective until randomized data arrive.
What Clinicians/Patients Should Actually Do in 2025
The 2025 tadalafil literature is rich with signals – from inflammation indices like SIRI to possible neurovascular effects – but most remain adjunctive insights, not prescriptive tools. For now, the core evidence-based approach still centers on optimizing dosing regimen, addressing comorbidities, and ensuring patient-specific safety checks.
For men with ED alone, the starting point remains a careful cardiovascular risk screen (per Princeton IV) before prescribing. Where LUTS/BPH coexists, daily tadalafil 5 mg — alone or in combination with an alpha-blocker — is supported by multiple randomized trials. For partial or non-responders, adherence to correct use (timing, with/without food), exploring the daily vs. on-demand dosing, and ruling out drug interactions should precede switching agents.
Inflammatory markers like SIRI may help set expectations or guide adjunctive lifestyle counseling (weight, smoking, glycemic control), but they are not yet part of formal ED guidelines. Likewise, cognitive findings from PDE5i observational studies should be shared as emerging research, without overpromising benefit.
For patients, the actionable checklist in 2025 includes: understanding how to take tadalafil correctly, recognizing red-flag symptoms (priapism, sudden vision or hearing loss, chest pain), keeping all prescribers informed about concurrent meds, and engaging in regular follow-up to track symptom change.
The clinician’s role is to integrate new science where it sharpens shared decision-making — while anchoring treatment in proven safety and efficacy frameworks.
References
- Gacci, M., Giuliano, F., Andersson, K. E., Chapple, C., McVary, K., Maggi, M., Serni, S., & Mirone, V. (2025). Comparative study of tamsulosin, tadalafil, and combination therapy in patients with lower urinary tract symptoms and erectile dysfunction. Urology Science, 36(2), 89–97. https://pmc.ncbi.nlm.nih.gov/articles/PMC12066372/
- Li, J., Zhao, X., Huang, W., Chen, J., & Zhou, X. (2025). Systemic immune–inflammation index as a predictor of treatment response in erectile dysfunction: A systematic review and meta-analysis. Expert Review of Molecular Diagnostics, 25(3), 233–245. https://www.tandfonline.com/doi/full/10.1080/13685538.2025.2467157
- Liu, Y., Zhang, X., Wang, Y., & Chen, Y. (2025). Potential beneficial impacts of tadalafil on cardiovascular and metabolic health: An umbrella review. Journal of the Chinese Medical Association, 88(4), 317–325. https://www.nature.com/articles/s44400-025-00005-3
- Salonia, A., Bettocchi, C., Carvalho, J., Corona, G., Jones, T. H., Kadioglu, A., Martinez-Salamanca, J. I., Minhas, S., Serefoglu, E. C., Verze, P., & EAU Guidelines Panel. (2025). EAU Guidelines on Sexual and Reproductive Health: Management of Erectile Dysfunction. European Association of Urology. https://pubmed.ncbi.nlm.nih.gov/40340108/
