Tadalafil Reduces Mortality and MACE, Renoprotective and Neuroprotective Effects

by Jeffrey Dach MD

Beyond the Bedroom: The Surprising Systemic Benefits of PDE5 Inhibitors

Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are best known for treating erectile dysfunction (ED) and benign prostatic hypertrophy (BPH). Narrative and overview reviews of the literature, including those by Daniszewski et al. (2025) and Nemr et al. (2025), synthesize evidence that these drugs also influence cardiovascular, renal, neurological, and other systems through the nitric oxide–cGMP pathway. They promote smooth-muscle relaxation, improve endothelial function, and may exert anti-inflammatory and anti-remodeling effects. While most data come from observational studies, small trials, and meta-analyses rather than large randomized controlled trials for non-urological indications, the findings suggest potential adjunctive roles. Further rigorous trials are needed before guideline changes.

Cardiovascular Protection and Lower Mortality

In 2023 Dr. Robert A. Kloner and colleagues examined a large U.S. claims database of men with erectile dysfunction and cardiovascular risk factors. Exposure to PDE5 inhibitors was associated with a 13% lower risk of major adverse cardiovascular events (MACE) and a 25% lower risk of overall mortality compared with non-exposure; higher exposure correlated with greater risk reduction. (1)

A 2024 systematic review and meta-analysis by Dr. Stergios Soulaidopoulos and colleagues, pooling cohort data from more than one million subjects, likewise found PDE5-inhibitor use linked to roughly 22% lower MACE and 30% lower all-cause mortality, primarily in middle-aged men. These associations are consistent with improved vascular function and possible anti-remodeling effects observed in smaller studies, though causality is not established by observational designs. (1, 2)

Header Image: German packet of Cialis (tadalafil). 14 tablets of 5 mg.July 2012. Author Mr.Brightside47 CC 3.0 Link to original image on wikimedia commons with attribution.

Below Image: 3D of sildenafil in cGMP-specific phosphodiesterase type 5 (PDE5).Date 4 November 2013 Source Own work. Author ExtraChem CC 3.0 Link to image on wikimedia

Renal Benefits in Diabetes

In 2024 Dr. Sahar Kamal Hegazy and colleagues conducted a randomized trial in patients with type 2 diabetes and diabetic kidney disease. Adjunctive tadalafil (every other day) significantly reduced the urinary albumin-to-creatinine ratio (by nearly 50%) alongside improvements in glycemic markers, comparable to the effects seen with pentoxifylline.

Preclinical and smaller clinical data have long suggested that PDE5 inhibition can reduce albuminuria and oxidative stress in diabetic nephropathy models by elevating cGMP and modulating mesangial function. While GFR changes are modest or neutral in most human data and larger confirmatory trials are lacking, the albuminuria reduction is clinically relevant because proteinuria strongly predicts progression and cardiovascular risk. (3, 4)

Practical Clinical Measurement of Renal Function and Its Decline in CKD

In 2024 the Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group updated its clinical practice guideline, recommending that estimated glomerular filtration rate (eGFR) be calculated from serum creatinine using validated equations (preferably the race-free 2021 CKD-EPI creatinine equation or the combined creatinine-cystatin C equation) for routine assessment of kidney function.

Serial measurements of eGFR over months to years allow clinicians to quantify the rate of decline (typically expressed as mL/min/1.73 m² per year); a sustained drop or slope steeper than about –3 to –5 mL/min/1.73 m²/year signals progressive CKD and guides the intensity of monitoring and therapy. (9)

In 2021 Dr. Lesley A. Inker and colleagues developed and validated the race-free CKD-EPI creatinine and creatinine-cystatin C equations, demonstrating greater accuracy and smaller differences across populations compared with prior race-inclusive formulas; the combined equation is especially useful when creatinine may be confounded by muscle mass, diet, or extremes of body composition. These laboratory-based estimates, repeated at guideline-recommended intervals (annually in low-risk patients, more frequently in advanced stages), remain the most practical and widely available tools for tracking GFR decline in everyday clinical practice. (10)

Measuring and Tracking Albuminuria – The urine albumin-to-creatinine ratio (UACR) from a spot urine sample

In 2024 the KDIGO CKD Work Group emphasized that the urine albumin-to-creatinine ratio (UACR) from a spot urine sample is the preferred, practical method for detecting and quantifying albuminuria, with categories of <30 mg/g (normal to mildly increased), 30–300 mg/g (moderately increased), and >300 mg/g (severely increased). A single elevated UACR should be confirmed on a repeat sample because day-to-day variation is common; persistent elevation for ≥3 months, together with reduced eGFR or other markers of damage, establishes CKD and stratifies progression and cardiovascular risk. Tracking serial UACR values (ideally on first-morning voids when feasible) allows clinicians to assess response to therapy—reductions of ≥30% are associated with better kidney and cardiovascular outcomes—and to adjust treatment intensity. Spot UACR is far more convenient and reproducible for longitudinal monitoring than 24-hour urine collections, which are reserved for selected cases when total protein excretion or timed quantification is specifically needed. (9, 10)

Effective Drugs and Natural Treatments for Albuminuria

Several classes of prescription drugs that have been shown in large randomized controlled trials and meta-analyses to reduce albuminuria (urine albumin-to-creatinine ratio, UACR) and slow CKD progression.

Guideline-directed therapies such as ACE inhibitors/ARBs, SGLT2 inhibitors, and the non-steroidal mineralocorticoid receptor antagonist finerenone are established and widely recommended.

High-quality evidence for most herbal supplements, “detox” products, or unregulated natural agents is limited to small trials, observational data, or animal studies; results are inconsistent, and some products can be harmful in CKD.

Lifestyle measures (optimized blood pressure, glycemic control, smoking cessation, and individualized diet) support medical therapy but are not substitutes for proven drugs. Always consult a clinician before adding any treatment.

SGLT2 Inhibitors (Dapagliflozin brand name Farxiga) Reduce Albuminuria and CKD Progression 

In 2020 Dr. Hiddo J. L. Heerspink and colleagues reported the DAPA-CKD trial, in which 4,304 patients with CKD (with or without type 2 diabetes) and elevated albuminuria were randomized to dapagliflozin 10 mg daily or placebo. Over a median of 2.4 years, dapagliflozin reduced the primary composite of sustained ≥50% eGFR decline, end-stage kidney disease, or renal/cardiovascular death by 39% (HR 0.61) and produced substantial reductions in albuminuria; benefits were independent of diabetes status. Subsequent large trials (EMPA-KIDNEY) and meta-analyses have confirmed consistent albuminuria-lowering and kidney-protective effects across the spectrum of eGFR and UACR. (11, 12)

Finerenone Lowers Albuminuria and Kidney Outcomes in Diabetic CKD

Finerenone (marketed as Kerendia) is a non-steroidal mineralocorticoid receptor antagonist (MRA) that protects the heart and kidneys in people with chronic kidney disease (CKD) and type 2 diabetes. The drugs mechanism is it blocks the overactivation of aldosterone receptors to reduce inflammation, organ fibrosis, and decline in kidney function.

In 2020 Dr. George L. Bakris and colleagues published the FIDELIO-DKD trial of the selective non-steroidal mineralocorticoid receptor antagonist finerenone in 5,734 patients with type 2 diabetes and CKD already on maximized ACE inhibitor or ARB therapy. Finerenone reduced the primary kidney composite (kidney failure, sustained ≥40% eGFR decline, or renal death) by 18% and also lowered cardiovascular events; early and sustained reductions in UACR mediated a large portion of the benefit. Hyperkalemia was more common but rarely led to discontinuation. Complementary trials (FIGARO-DKD) and combination studies with SGLT2 inhibitors have reinforced additive albuminuria reduction. (13, 14)

Dapagliflozin and SGLT2 Inhibitors: Mechanism and Role in A
lbuminuria and CKD

Dapagliflozin (brand name Farxiga) is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. These oral medications block the SGLT2 protein in the proximal tubules of the kidneys. This protein normally reabsorbs most of the filtered glucose (and accompanying sodium) back into the bloodstream. By inhibiting it, SGLT2 inhibitors increase urinary excretion of glucose and sodium. The result is modest lowering of blood glucose, reduced intraglomerular pressure, natriuresis, and downstream effects that protect the heart and kidneys. The action is independent of insulin, so the risk of hypoglycemia is low when used alone or with agents that do not stimulate insulin release.

Core Evidence for Albuminuria Reduction and Kidney Protection

In 2020 Dr. Hiddo J. L. Heerspink and colleagues reported the DAPA-CKD trial. In this large randomized controlled study of 4,304 patients with chronic kidney disease (with or without type 2 diabetes) and elevated albuminuria, dapagliflozin 10 mg daily reduced the primary composite outcome of sustained ≥50% eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% (hazard ratio 0.61) compared with placebo over a median of 2.4 years.

Albuminuria fell substantially, and benefits occurred across the spectrum of baseline kidney function and diabetes status. Complementary large trials such as EMPA-KIDNEY (empagliflozin) and subsequent meta-analyses have confirmed consistent reductions in albuminuria and hard kidney outcomes with the SGLT2 inhibitor class. (11,12,12a)

These agents are now guideline-recommended foundational therapy for patients with CKD and albuminuria (typically UACR ≥200 mg/g), whether or not they have type 2 diabetes, on top of maximized ACE inhibitor or ARB therapy when tolerated. They also carry indications for heart failure and type 2 diabetes with cardiovascular risk. Blood pressure tends to fall modestly, weight declines slightly from caloric loss in the urine, and the main class-specific side effects include genital mycotic infections and volume depletion; euglycemic diabetic ketoacidosis is rare but requires awareness in at-risk patients.

How the Kidney Benefits Arise

The initial drop in albuminuria is driven in large part by hemodynamic changes: reduced proximal sodium and glucose reabsorption lowers glomerular hyperfiltration via tubuloglomerular feedback. Over longer periods, anti-inflammatory, antifibrotic, and metabolic effects (including improved mitochondrial function and reduced oxidative stress) contribute to sustained slowing of disease progression. These mechanisms help explain why the albuminuria-lowering and outcome benefits persist even in patients without diabetes.

ACE Inhibitors and ARBs Remain Foundational for Albuminuria Reduction

In 2001 Dr. Barry M. Brenner and colleagues reported the RENAAL trial, in which 1,513 patients with type 2 diabetes and nephropathy were randomized to the ARB losartan or placebo (added to conventional antihypertensives). Losartan reduced the primary composite of doubling of serum creatinine, end-stage renal disease, or death by 16%, cut end-stage renal disease by 28%, and lowered proteinuria by 35% beyond blood-pressure effects. Parallel trials of other ARBs and ACE inhibitors, plus network meta-analyses, established RAAS blockade as first-line therapy for proteinuric CKD, with additive benefits when combined with SGLT2 inhibitors or finerenone under appropriate monitoring. (15, 16)

Natural, Dietary, and Non-Pharmaceutical Approaches to Albuminuria

Curcumin and Turmeric Supplementation

In 2019 Dr. Azam Vanaie and colleagues conducted a randomized double-blind trial in 46 patients with type 2 diabetes and overt albuminuria. Curcumin 500 mg three times daily for 16 weeks produced a significant reduction in 24-hour albuminuria (from approximately 900 mg to 540 mg), which was greater than the change seen with placebo. Systematic reviews and meta-analyses of multiple smaller trials have reported an overall favorable effect of turmeric/curcumin on proteinuria in CKD populations, supporting its use as a potential adjunctive option. (17, 18)

Plant-Based and Lower-Animal-Protein Dietary Patterns

In 2024 the KDIGO CKD Work Group recommended favoring plant-based foods over animal-based ones and limiting ultra-processed foods, noting associations with improved blood pressure, acid-base balance, and slower progression. Meta-analyses of observational cohorts involving tens of thousands of participants have linked higher adherence to plant-based diets with lower incidence of CKD and slower progression; substituting plant protein for animal protein has been associated with reduced hyperfiltration and albuminuria in diabetic kidney disease settings. Practical approaches include partial swaps (e.g., two of three meals) rather than strict veganism, while monitoring potassium and phosphorus as needed. (19, 20)

Omega-3 Fatty Acid Supplementation

In 2017 Dr. Jing Hu and colleagues published a meta-analysis of nine randomized trials (444 patients with CKD). Omega-3 supplementation was associated with a significant reduction in proteinuria (standardized mean difference –0.31) and a lower risk of end-stage kidney disease. A 2020 meta-analysis focused on diabetic nephropathy similarly found reduced proteinuria with longer-duration (≥24 weeks) omega-3 use in type 2 diabetes, without adverse effects on glycemic or lipid markers in the included studies. (21, 22)

Astragalus (Huang Qi) Preparations

In 2024 a multicenter randomized trial of add-on oral astragalus granules in 118 patients with type 2 diabetes, stage 2–3 CKD, and macroalbuminuria showed a significantly slower rate of eGFR decline (estimated 4.6 mL/min/1.73 m² per year difference) compared with standard care alone. Earlier meta-analyses of dozens of trials, predominantly of injectable or oral preparations, reported reductions in albuminuria and proteinuria when astragalus was added to conventional therapy. (23, 24)

Sodium Restriction, Weight Management, and Lifestyle Measures

Dietary sodium restriction (typically targeting <2 g sodium per day) consistently lowers blood pressure and reduces albuminuria in proteinuric CKD, acting synergistically with pharmacologic RAAS blockade.

Weight loss in overweight or obese individuals with CKD improves albuminuria, blood pressure, and metabolic parameters. Regular physical activity and smoking cessation further support these benefits through improved endothelial function and reduced inflammation. These measures are recommended across major guidelines as foundational non-pharmacologic therapy. (19, 25)

Additional Botanicals and Supplements with Supporting Signals

Other agents reported in smaller trials or reviews to show possible albuminuria-lowering effects include propolis, certain polyphenol-rich extracts, and carefully dosed vitamin D repletion in deficient patients. Low-protein diets (approximately 0.8 g/kg/day, or lower with ketoanalogue supplementation in selected metabolically stable patients) can reduce hyperfiltration and proteinuria when implemented under dietitian supervision. These options are typically considered adjunctive rather than primary.

**Reservations and Caveats**

Evidence for most supplements and botanicals is limited to small or heterogeneous trials, short follow-up, and surrogate endpoints; larger, high-quality randomized trials with hard kidney outcomes are generally lacking. Results for curcumin, for example, have been mixed in larger or longer studies. Product quality, bioavailability, potential drug interactions (especially with anticoagulants, immunosuppressants, or potassium-sparing agents), and contamination risks are concerns. Dietary changes must be individualized to avoid malnutrition, electrolyte imbalances, or inadequate protein intake. These approaches should not replace proven pharmacologic therapy and require medical supervision, laboratory monitoring, and coordination with a renal dietitian. No natural treatment has been shown to match the magnitude or certainty of benefit seen with guideline-directed drugs in large outcome trials.

**Animal Model Evidence for Natural and Non-Pharmaceutical Interventions in Albuminuria**

**Curcumin and Related Polyphenols**

In 2016 Dr. researchers studying Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a model of type 2 diabetic nephropathy, showed that curcumin (100 mg/kg/day) significantly lowered 24-hour urinary albumin and albumin-to-creatinine ratio, reduced glomerular pathologic changes, decreased urinary malondialdehyde, and improved superoxide dismutase activity via Nrf2 and AMPK pathways. Multiple additional studies in streptozotocin-induced diabetic rats and db/db mice have demonstrated that curcumin reduces albuminuria, mesangial expansion, podocyte injury, oxidative stress, and fibrosis markers. A 2014 meta-analysis of 14 animal experiments confirmed consistent reductions in urinary protein, blood urea nitrogen, and serum creatinine with curcumin treatment. (26, 27)

**Astragalus membranaceus (Huang Qi) and Astragaloside IV**

In 2023 a study using 5/6 nephrectomized rats found that oral astragalus root (400–800 mg/kg equivalents) improved creatinine clearance, lowered urinary albumin and NGAL, reduced blood pressure, and decreased oxidative stress markers (8-OHdG) and renin-angiotensin system gene expression. A 2024 systematic review and meta-analysis of 40 animal studies in diabetic kidney disease models reported significant reductions in urinary albumin excretion rate, serum creatinine, blood urea nitrogen, and histologic injury, with improvements in oxidative stress, inflammation, and fibrosis markers (TGF-β1, collagen IV). Earlier systematic reviews of Astragalus root in diabetic rat models similarly showed lowered urinary albumin excretion and improved glomerular filtration rate. (28, 29)

**Omega-3 Fatty Acids and Fish Oil**

In 2009 a study in streptozotocin-induced diabetic rats demonstrated that a high n-3 PUFA diet (canola oil) completely prevented the rise in urine albumin excretion, glomerulosclerosis, and tubulointerstitial fibrosis seen in diabetic controls, while also lowering inflammatory markers (IL-6, MCP-1, TGF-β). Other work has shown that fish oil reduces proteinuria and mesangial proliferation in antithymocyte serum glomerulonephritis models and that DHA/EPA supplementation attenuates distal tubular damage in diabetic nephropathy. Dietary fish oil prevented progression to end-stage renal disease features in severe atherosclerotic diabetic mouse models. (30, 31)

**Plant Proteins, Soy, and Dietary Modifications**

In 2008 a study in obese fa/fa Zucker rats showed that replacing animal protein (egg white) with soy protein reduced kidney weight and glomerular size while lowering cyclooxygenase-related prostanoid production linked to hyperfiltration. Experiments in db/db diabetic mice found that soy protein diets prevented the rise in urinary albumin excretion that occurred with casein-based diets at equivalent protein levels. Additional animal data indicate that plant-based or soy-enriched diets reduce hyperfiltration, metabolic acidosis, and proteinuria compared with animal-protein diets in models of reduced kidney mass or diabetic nephropathy. (32, 33)

**Other Botanicals and Interventions with Supporting Animal Data**

Additional preclinical studies have reported albuminuria or proteinuria reductions with agents such as propolis, green tea polyphenols, resveratrol, and certain traditional herbal combinations in streptozotocin or other diabetic and remnant-kidney models, often through antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. Low-protein diets and ketoanalogue supplementation have long been shown in rodent models to lessen hyperfiltration and albuminuria. These findings collectively support a range of dietary and botanical approaches that reduce albuminuria in experimental settings.

**Reservations and Caveats**

Animal models (typically rodents with induced diabetes or surgical reduction of kidney mass) do not fully replicate human CKD pathophysiology, genetics, comorbidities, or long-term progression. Effective doses in animals are often high and may not translate directly to safe human intakes; bioavailability, metabolism, and species differences limit extrapolation. Many studies are short-term and focus on surrogate markers rather than hard outcomes such as kidney failure. Heterogeneity in models, dosing, and endpoints, plus potential publication bias favoring positive results, further qualify the findings. These data are hypothesis-generating and supportive of further clinical investigation but do not establish efficacy or safety in humans.

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Continue on with Tadalafil

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Tadalafil Neuroprotective Signals for Cognition and Stroke

In 2021 Dr. Feixiong Cheng and colleagues used network-medicine approaches plus insurance-claims analysis of more than 7 million individuals and reported that sildenafil use was associated with a 69% lower incidence of Alzheimer’s disease. Mechanistic work in patient-derived neurons showed reduced tau phosphorylation and enhanced neurite outgrowth. Subsequent observational and meta-analytic work has generally supported an inverse association between PDE5-inhibitor exposure and Alzheimer’s risk, although Mendelian-randomization studies have not confirmed causality and results for other PDE5 inhibitors are less consistent. Preclinical evidence also points to possible benefits in ischemic stroke via improved cerebral perfusion and anti-apoptotic effects; human data remain limited and hypothesis-generating. (5, 6)

Urological Symptom Relief Beyond Erectile Dysfunction

In 2007 Dr. Kevin T. McVary and colleagues published one of the first randomized trials showing that daily tadalafil improved International Prostate Symptom Score (IPSS) totals and quality-of-life measures in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). Subsequent larger trials and meta-analyses of 5 mg daily tadalafil confirmed statistically and clinically meaningful IPSS reductions versus placebo, with additional benefits for storage and voiding subscores and quality of life; the drug is now approved for this indication. The mechanism appears to involve relaxation of prostatic and bladder smooth muscle via the NO–cGMP pathway rather than changes in prostate size or peak flow alone. (7, 8)

Other Vascular and Emerging Indications

Reviews also note symptomatic improvement in Raynaud’s phenomenon (reduced attack frequency and better ulcer healing with sildenafil or vardenafil), established use in pulmonary arterial hypertension, and exploratory signals in conditions such as high-altitude illness, intrauterine growth restriction models, and certain inflammatory or proliferative states. Antiproliferative and anti-inflammatory (COX-related) activities have been observed in laboratory settings. These findings reinforce the pharmacological versatility of the class but remain largely outside routine clinical guidelines pending more definitive trials.

Overall, the literature portrays PDE5 inhibitors as agents with effects that extend well beyond erectile function. Cardiovascular and urological benefits are the best supported by human data; renal and cognitive signals are promising but require confirmation in randomized trials. Patients should continue to use these drugs only under medical supervision, particularly if they have cardiovascular disease or take nitrates.

Adverse Side Effects of Long-Term Daily Tadalafil: Focus on Ocular Effects and Interactions

Long-term daily tadalafil (typically 2.5–5 mg for erectile dysfunction or benign prostatic hyperplasia/lower urinary tract symptoms, or higher doses for pulmonary arterial hypertension) is generally well tolerated.

Classic visual side effects linked to phosphodiesterase type 6 (PDE6) inhibition in the retina, such as blue-tinged vision or color discrimination changes, are uncommon with tadalafil because of its high selectivity for PDE5 over PDE6. Nonetheless, observational data, pharmacovigilance reports, and case series describe ocular events that warrant attention, particularly with chronic daily use.

These include rare associations with non-arteritic anterior ischemic optic neuropathy (NAION), central serous chorioretinopathy (CSCR), and a modest signal for glaucoma or ocular hypertension. Drug interactions that raise tadalafil exposure can increase the likelihood of adverse effects overall.

Overview of Ocular Safety with Daily Dosing

In 2009 Dr. William H. Cordell and colleagues randomized adults to daily tadalafil 5 mg, sildenafil 50 mg, or placebo for 6 months and assessed electroretinography, color discrimination, visual acuity, visual fields, and intraocular pressure. No significant differences emerged between groups on the primary or secondary retinal function measures, and no treatment-related findings suggested drug toxicity. The medications were well tolerated. This trial provides the longest controlled retinal safety data for daily low-dose tadalafil. (34)

Glaucoma and Ocular Hypertension Signal with Chronic Use

In 2026 a multinational retrospective cohort study using the TriNetX database followed 36,927 men prescribed tadalafil for lower urinary tract symptoms and an equal number of matched non-users for up to 5 years. Tadalafil use was associated with a 22% higher risk of glaucoma (hazard ratio 1.22), higher risks of ocular hypertension and primary open-angle glaucoma, and greater initiation of glaucoma treatment. Five-year cumulative incidence of glaucoma was 3.93% versus 3.16% in non-users. Associations held across subgroups and after lag-time analyses. The authors recommended baseline ophthalmic assessment and follow-up for patients on long-term therapy, especially those with glaucoma risk factors, while noting that the findings do not contraindicate use. (35-36)

Non-Arteritic Anterior Ischemic Optic Neuropathy and Other Vascular Events

In 2022 Dr. Mahyar Etminan and colleagues analyzed a large U.S. cohort and found that regular PDE5 inhibitor users (including tadalafil) had elevated rates of serous retinal detachment, retinal vascular occlusion, and ischemic optic neuropathy compared with non-users, with evidence of a dose-response for higher prescription counts.

Pharmacovigilance analyses of FDA Adverse Event Reporting System data through 2023 confirmed elevated reporting odds for ocular events across PDE5 inhibitors; tadalafil showed signals for ischemic optic neuropathy and related findings. NAION remains a rare but labeled concern; sudden vision loss requires immediate medical attention and drug discontinuation. Case reports also describe CSCR or serous detachments temporally linked to tadalafil that often resolved after cessation. (37-38)

Choroidal and Retinal Vascular Changes

Smaller prospective studies of men taking tadalafil 20 mg on alternate days for months after prostatectomy have documented reductions in deep capillary plexus and choriocapillaris vessel density on optical coherence tomography angiography, along with increases in subfoveal choroidal thickness. These structural and perfusion changes suggest possible chronic effects on ocular blood flow, although clinical significance and long-term progression require further study. (39)

Drug Interactions That Can Amplify Side Effects

In prescribing information and pharmacokinetic studies, strong CYP3A4 inhibitors such as ketoconazole, ritonavir, and certain other antifungals or protease inhibitors substantially increase tadalafil exposure (AUC increases of 100% or more depending on the agent and dose). Higher systemic levels can elevate the risk of adverse effects, including those involving the eye. Grapefruit juice may produce milder increases.

Nitrates and guanylate cyclase stimulators are absolutely contraindicated because of profound hypotension. Alpha-blockers require caution due to additive blood-pressure lowering. CYP3A4 inducers (e.g., rifampin) reduce tadalafil levels and efficacy. Patients on interacting agents may need dose adjustment or avoidance; clinicians should review all medications. (40-41)

Mechanism of Ocular Adverse Effects with PDE5 Inhibitors

PDE5 inhibitors raise intracellular cyclic guanosine monophosphate (cGMP) by blocking its breakdown. In ocular tissues this amplifies nitric-oxide signaling, promotes smooth-muscle relaxation, and can alter local blood flow, vessel permeability, and aqueous humor dynamics. The precise sites of PDE5 expression help explain the pattern of reported ocular events.

In 2008 Dr. Carlo Foresta and colleagues used Western blot and immunohistochemistry on human retinal tissue and donor eyes to map PDE5. They demonstrated PDE5 protein in the smooth-muscle and endothelial cells of retinal and choroidal vessels, as well as in retinal ganglion cells (third neuron) and bipolar cells (second neuron). By contrast, PDE6 was localized exclusively to the rod and cone photoreceptors, accounting for the more frequent color-vision changes seen with less-selective agents such as sildenafil. The same group also showed that single doses of tadalafil and sildenafil alter ophthalmic-artery blood-flow velocity in a time-dependent manner in healthy volunteers, consistent with a direct vascular effect of PDE5 inhibition. (1d)

Because PDE5 is present in choroidal and retinal vasculature, inhibition produces vasodilation, increased choroidal blood flow, and measurable thickening of the choroid. Elevated hydrostatic pressure within the choroid can promote leakage across the retinal pigment epithelium, providing a plausible pathway for the subretinal fluid seen in case reports of central serous chorioretinopathy. Transient changes in deep capillary plexus and choriocapillaris density on optical coherence tomography angiography after repeated tadalafil dosing are consistent with these vascular effects. (2d, 3d)

PDE5 is also expressed in the trabecular meshwork, where cGMP participates in regulation of aqueous outflow. Functional studies in human trabecular meshwork cells have confirmed PDE5 activity that modulates cGMP levels. Chronic elevation of cGMP could theoretically alter outflow facility or interact with choroidal volume changes to influence intraocular pressure, offering a potential mechanism for the modest observational signals of glaucoma and ocular hypertension with long-term tadalafil use. Short-term controlled studies have generally found little or no clinically significant rise in intraocular pressure, suggesting that any effect is subtle or requires prolonged exposure and additional risk factors. (4d)

At the optic nerve head, the short posterior ciliary arteries supply a watershed region that is vulnerable to hypoperfusion. Systemic vasodilation and possible nocturnal blood-pressure dips associated with PDE5 inhibition may impair autoregulation in eyes with a small cup-to-disc ratio (“disc at risk”), contributing to the rare but labeled association with non-arteritic anterior ischemic optic neuropathy. Direct local effects on optic-nerve vasculature remain incompletely proven. (5d,e,f)

Tadalafil’s high selectivity for PDE5 over PDE6 largely spares the photoreceptors, which is why classic blue-tinged vision and color-discrimination changes are uncommon at therapeutic doses. Residual effects on ganglion and bipolar cells, where PDE5 has been localized, are theoretically possible but have not been linked to clinically detectable visual dysfunction in controlled trials.

Overall, the distribution of PDE5 in ocular vessels, the trabecular meshwork, and inner retinal neurons supplies a coherent anatomic basis for the vascular, choroidal, and aqueous-related adverse events that have been observed, while the rarity of serious outcomes reflects both the modest magnitude of these effects at usual doses and the contribution of patient-specific risk factors.

**References**

1d. Foresta, Carlo, et al. “Expression of the PDE5 Enzyme on Human Retinal Tissue: New Aspects of PDE5 Inhibitors Ocular Side Effects.” *Eye*, vol. 22, no. 1, 2008, pp. 144–149. https://doi.org/10.1038/sj.eye.6702908 or https://pubmed.ncbi.nlm.nih.gov/17585311/

2d. da Cruz, Natasha F. S., et al. “Effects of Phosphodiesterase Type 5 Inhibitors on Choroid and Ocular Vasculature: A Literature Review.” *International Journal of Retina and Vitreous*, vol. 6, 2020, article 38. https://doi.org/10.1186/s40942-020-00241-0

3d. Kerr, N. M., and H. V. Danesh-Meyer. “Phosphodiesterase Inhibitors and the Eye.” *Clinical & Experimental Ophthalmology*, vol. 37, no. 5, 2009, pp. 514–523. https://doi.org/10.1111/j.1442-9071.2009.02070.x

4d. Zhou, L., et al. “Functional Identification of Phosphodiesterase Activity in Human Trabecular Meshwork Cells.” *Experimental Eye Research*, vol. 70, no. 5, 2000, pp. 593–599. (PDE5 activity confirmed in HTM cells; full bibliographic details available via PubMed search for authors and title.)

5d. Liu, Bing, et al. “The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis.” Sexual Medicine, vol. 6, no. 3, 2018, pp. 185–192. https://doi.org/10.1016/j.esxm.2018.03.001 or https://pubmed.ncbi.nlm.nih.gov/29884471/

5e. Penedones, Ana, et al. “Risk of Nonarteritic Ischaemic Optic Neuropathy with Phosphodiesterase Type 5 Inhibitors: A Systematic Review and Meta-Analysis.” Acta Ophthalmologica, vol. 98, no. 1, 2020, pp. 22–31. https://doi.org/10.1111/aos.14253 or https://pubmed.ncbi.nlm.nih.gov/31559705/

5f. Campbell, Ulka B., et al. “Association Between Phosphodiesterase-5 Inhibitors and Nonarteritic Anterior Ischemic Optic Neuropathy.” Journal of Neuro-Ophthalmology, vol. 35, no. 1, 2015, pp. 12–15. https://doi.org/10.1097/WNO.0000000000000186

Practical Considerations and Monitoring

Patients starting or continuing long-term daily tadalafil should report any sudden vision changes, color shifts, or field defects immediately. Those with pre-existing ocular conditions (crowded optic disc, retinitis pigmentosa, glaucoma risk factors, or prior NAION) warrant specialist discussion before initiation.

Baseline and periodic eye examinations are reasonable for long-term users, particularly when glaucoma risk factors are present. Overall, serious ocular events remain uncommon, and the 6-month controlled data support short-to-intermediate daily safety for retinal function, yet real-world signals for glaucoma and rare vascular events support informed shared decision-making.

5 days on 2 days off

In my practice, to avoid ocular side effects, we recommend using tadalafil 5 mg 5 out of 7 days. This give 2 days off per week. This particular protocol has not been studied. However, we have found no reports of ocular side effects, so far, using the 5 days on 2 days off protocol.

Conclusion: Tadalafil (PDE5 inhibitor) routine use is for erectile dysfunction and BPH. However, other health benefits have been discovered for reducing all cause mortality and cardiac events, for renal protection, and neurological protection. However, ocular adverse side effects have been reported.

Articles with Related Interest:

Mortality Reduction in Diabetics with PDE5 inhibitor Cialis

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my web site: https://drjeffreydachmd.com/
my personal blog: www.jeffreydachmd.com 

References Final

1) Kloner, Robert A., et al. “Effect of Phosphodiesterase Type 5 Inhibitors on Major Adverse Cardiovascular Events and Overall Mortality in a Large Nationwide Cohort of Men with Erectile Dysfunction and Cardiovascular Risk Factors: A Retrospective, Observational Study Based on Healthcare Claims and National Death Index Data.” *Journal of Sexual Medicine*, vol. 20, no. 1, 2023, pp. 38–48. https://pubmed.ncbi.nlm.nih.gov/36897243/ or https://doi.org/10.1093/jsxmed/qdac005

2) Soulaidopoulos, Stergios, et al. “Long-Term Effects of Phosphodiesterase-5 Inhibitors on Cardiovascular Outcomes and Death: A Systematic Review and Meta-Analysis.” *European Heart Journal – Cardiovascular Pharmacotherapy*, vol. 10, no. 5, 2024, pp. 403–412. https://doi.org/10.1093/ehjcvp/pvae029

3) Hegazy, Sahar Kamal, et al. “Tadalafil versus Pentoxifylline in the Management of Diabetic Kidney Disease: A Randomized Clinical Trial.” *Diabetology & Metabolic Syndrome*, vol. 16, 2024, article 138. https://doi.org/10.1186/s13098-024-01363-3

4) Scheele, Wim, et al. “Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy.” Journal of the American Society of Nephrology, vol. 27, no. 11, 2016, pp. 3459–3468. https://doi.org/10.1681/ASN.2015050473 or https://pubmed.ncbi.nlm.nih.gov/27151925/

4a) Afsar, Baris, et al. “Phosphodiesterase Type 5 Inhibitors and Kidney Disease.” International Urology and Nephrology, vol. 47, no. 9, 2015, pp. 1521–1528. https://doi.org/10.1007/s11255-015-1071-4 or https://pubmed.ncbi.nlm.nih.gov/26242375/

et al. “Endophenotype-Based in Silico Network Medicine Discovery Combined with Insurance Record Data Mining Identifies Sildenafil as a Candidate Drug for Alzheimer’s Disease.” *Nature Aging*, vol. 1, 2021, pp. 1175–1188. https://www.nature.com/articles/s43587-021-00138-z

6) Fang, J., et al. / subsequent validations (e.g., 2024 cohort and meta-analyses confirming reduced AD incidence with PDE5-inhibitor use; see also Abouelmagd et al. 2024 systematic review). https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.051847 (related Cheng abstract) and peer-reviewed follow-ups.

7) McVary, Kevin T., et al. “Tadalafil Relieves Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.” *Journal of Urology*, vol. 177, no. 4, 2007, pp. 1401–1407. https://pubmed.ncbi.nlm.nih.gov/17382741/

8) Cui, Jianwei, et al. “Efficacy and Safety of 12-week Monotherapy With Once Daily 5 mg Tadalafil for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: Evidence-based Analysis.” Frontiers in Medicine, vol. 8, 2021, article 744012. https://doi.org/10.3389/fmed.2021.744012 or https://pubmed.ncbi.nlm.nih.gov/34712682/ or https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.744012/full

9) Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. “KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.” *Kidney International*, vol. 105, no. 4S, 2024, pp. S117–S314. https://doi.org/10.1016/j.kint.2023.10.018 or https://pubmed.ncbi.nlm.nih.gov/38490803/

10) Inker, Lesley A., et al. “New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.” *New England Journal of Medicine*, vol. 385, no. 19, 2021, pp. 1737–1749. https://doi.org/10.1056/NEJMoa2102953 or https://pubmed.ncbi.nlm.nih.gov/34554658/

11) Heerspink, Hiddo J. L., et al. “Dapagliflozin in Patients with Chronic Kidney Disease.” *New England Journal of Medicine*, vol. 383, no. 15, 2020, pp. 1436–1446. https://doi.org/10.1056/NEJMoa2024816 or https://pubmed.ncbi.nlm.nih.gov/32970396/

12) The EMPA-KIDNEY Collaborative Group. “Empagliflozin in Patients with Chronic Kidney Disease.” New England Journal of Medicine, vol. 388, no. 2, 2023, pp. 117–127. https://doi.org/10.1056/NEJMoa2204233 or https://www.nejm.org/doi/10.1056/NEJMoa2204233 or https://pubmed.ncbi.nlm.nih.gov/36331190/

12a) Neuen, Brendon L., et al. “SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis.” JAMA, 2025 (or corresponding volume/issue). https://doi.org/10.1001/jama.2025.XXXX or https://pubmed.ncbi.nlm.nih.gov/41203232/

13) Bakris, George L., et al. “Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.” *New England Journal of Medicine*, vol. 383, no. 23, 2020, pp. 2219–2229. https://doi.org/10.1056/NEJMoa2025845 or https://pubmed.ncbi.nlm.nih.gov/33264825/ or https://www.nejm.org/doi/full/10.1056/NEJMoa2025845

14) Pitt, Bertram, et al. “Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.” *New England Journal of Medicine*, vol. 385, no. 24, 2021, pp. 2252–2263. https://doi.org/10.1056/NEJMoa2110956 or https://pubmed.ncbi.nlm.nih.gov/34449181/ or https://www.nejm.org/doi/full/10.1056/NEJMoa2110956

15) Brenner, Barry M., et al. “Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy.” New England Journal of Medicine, vol. 345, no. 12, 2001, pp. 861–869. https://doi.org/10.1056/NEJMoa011161 or https://pubmed.ncbi.nlm.nih.gov/11565518/ or https://www.nejm.org/doi/full/10.1056/NEJMoa011161

16) Xie, Xinfang, et al. “Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients with CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials.” American Journal of Kidney Diseases, vol. 67, no. 5, 2016, pp. 728–741. https://doi.org/10.1053/j.ajkd.2015.10.011 or https://pubmed.ncbi.nlm.nih.gov/26597926/

17) Vanaie, Azam, et al. “Curcumin as a Major Active Component of Turmeric Attenuates Proteinuria in Patients with Overt Diabetic Nephropathy.” *Journal of Research in Medical Sciences*, vol. 24, 2019, p. 77. https://doi.org/10.4103/jrms.JRMS_1055_18 or https://pubmed.ncbi.nlm.nih.gov/31523263/

18) Malekmakan, Leila, et al. “Efficacy and Safety of Turmeric Dietary Supplementation on Proteinuria in CKD: A Systematic Review and Meta-analysis of RCT.” *Iranian Journal of Kidney Diseases*, vol. 16, no. 3, 2022, pp. 153–161. https://pubmed.ncbi.nlm.nih.gov/35714209/

19) Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. “KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.” *Kidney International*, vol. 105, no. 4S, 2024, pp. S117–S314. https://doi.org/10.1016/j.kint.2023.10.018

20) Dang, Zihan, et al. “Plant-Based Diet and Chronic Kidney Disease: A Systematic Review and Meta-Analysis.” Journal of Renal Nutrition, vol. 35, no. 4, 2025, pp. 517–530. https://doi.org/10.1053/j.jrn.2025.03.002 or https://pubmed.ncbi.nlm.nih.gov/40081608/ or https://www.sciencedirect.com/science/article/abs/pii/S1051227625000275

21) Hu, Jing, et al. “Omega-3 Fatty Acid Supplementation as an Adjunctive Therapy in the Treatment of Chronic Kidney Disease: A Meta-analysis.” *Clinics*, vol. 72, no. 1, 2017, pp. 58–64. https://doi.org/10.6061/clinics/2017(01)10 or https://pmc.ncbi.nlm.nih.gov/articles/PMC5251198/

22) Chewcharat, Api, et al. “The Effects of Omega-3 Fatty Acids on Diabetic Nephropathy: A Meta-analysis of Randomized Controlled Trials.” *PLOS ONE*, vol. 15, no. 2, 2020, e0228315. https://doi.org/10.1371/journal.pone.0228315

23. Chan, Kam Wa, et al. “Add-on Astragalus in Type 2 Diabetes and Chronic Kidney Disease: A Multi-Center, Assessor-Blind, Randomized Controlled Trial.” Phytomedicine, vol. 130, 2024, article 155457. https://doi.org/10.1016/j.phymed.2024.155457 or https://pubmed.ncbi.nlm.nih.gov/38810556/

24. Zhang, Lihong, et al. “Astragalus membranaceus (Huang Qi) as Adjunctive Therapy for Diabetic Kidney Disease: An Updated Systematic Review and Meta-analysis.” *Journal of Ethnopharmacology*, vol. 239, 2019, article 111921. https://doi.org/10.1016/j.jep.2019.111921 or https://pubmed.ncbi.nlm.nih.gov/31034954/

25. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. “KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.” *Kidney International*, vol. 105, no. 4S, 2024, pp. S117–S314. https://doi.org/10.1016/j.kint.2023.10.018 (Supporting evidence on sodium restriction and weight management is drawn from this guideline and related cohort/intervention literature.)

26. Kim, Bo Hwan, et al. “Protective Effects of Curcumin on Renal Oxidative Stress and Lipid Metabolism in a Rat Model of Type 2 Diabetic Nephropathy.” *Yonsei Medical Journal*, vol. 57, no. 3, 2016, pp. 664–673. https://doi.org/10.3349/ymj.2016.57.3.664 or https://pmc.ncbi.nlm.nih.gov/articles/PMC4800357/

27. Wu, Wei, et al. “Effect of Curcumin on Rats/Mice with Diabetic Nephropathy: A Systematic Review and Meta-analysis of Randomized Controlled Trials.” *Journal of Traditional Chinese Medicine*, vol. 34, no. 4, 2014, pp. 419–429. https://doi.org/10.1016/S0254-6272(15)30041-8 or https://pubmed.ncbi.nlm.nih.gov/25185359/

28. Goto, Shunsuke, et al. “Renal Protective Effects of Astragalus Root in Rat Models of Chronic Kidney Disease.” *Clinical and Experimental Nephrology*, vol. 27, no. 7, 2023, pp. 593–602. https://doi.org/10.1007/s10157-023-02356-8 or https://pubmed.ncbi.nlm.nih.gov/37140734/

29. Liu, Meifang, et al. “Renal Protective Effects and Mechanisms of Astragalus membranaceus for Diabetic Kidney Disease in Animal Models: An Updated Systematic Review and Meta-analysis.” *Phytomedicine*, 2024. https://doi.org/10.1016/j.phymed.2024.155XXX (or corresponding volume/article) or https://pubmed.ncbi.nlm.nih.gov/38733903/

30. Garman, Joseph H., et al. “Omega-3 Fatty Acid Rich Diet Prevents Diabetic Renal Disease.” *American Journal of Physiology-Renal Physiology*, vol. 296, no. 2, 2009, pp. F306–F316. https://doi.org/10.1152/ajprenal.90326.2008 or https://pubmed.ncbi.nlm.nih.gov/19052104/

31) Grande, Joseph P., et al. “Suppressive Effects of Fish Oil on Mesangial Cell Proliferation in Vitro and in Vivo.” Kidney International, vol. 57, no. 3, 2000, pp. 1027–1040. https://doi.org/10.1046/j.1523-1755.2000.00930.x or https://pubmed.ncbi.nlm.nih.gov/10720955/ or https://www.kidney-international.org/article/S0085-2538(15)46834-6/fulltext

32) Hwang, Sun-Young, et al. “Dietary Soy Protein Reduces Early Renal Disease Progression and Alters Prostanoid Production in Obese fa/fa Zucker Rats.” Journal of Nutritional Biochemistry, vol. 19, no. 4, 2008, pp. 255–262. https://doi.org/10.1016/j.jnutbio.2007.03.001 or https://pubmed.ncbi.nlm.nih.gov/17656081/

33) Teixeira, Sandra R., et al. “Altering Dietary Protein Type and Quantity Reduces Urinary Albumin Excretion without Affecting Plasma Glucose Concentrations in BKS.cg-m +Leprdb/+Leprdb (db/db) Mice.” Journal of Nutrition, vol. 133, no. 3, 2003, pp. 673–678. https://doi.org/10.1093/jn/133.3.673 or https://pubmed.ncbi.nlm.nih.gov/12612136/

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34) Cordell, William H., et al. “Retinal Effects of 6 Months of Daily Use of Tadalafil or Sildenafil.” Archives of Ophthalmology, vol. 127, no. 4, 2009, pp. 367–373. https://doi.org/10.1001/archophthalmol.2009.36 or https://jamanetwork.com/journals/jamaophthalmology/fullarticle/422745

35). Hsia, Yun, et al. “Risk of Glaucoma among Patients Using Tadalafil for Lower Urinary Tract Symptoms: A Multinational Cohort Study.” *British Journal of Ophthalmology*, 2026, bjo-2026-329957. https://doi.org/10.1136/bjo-2026-329957 or https://bjo.bmj.com/content/early/2026/07/28/bjo-2026-329957

36) Supporting summary of the TriNetX multinational cohort (approximately 36,927 tadalafil users vs. matched non-users): higher risk of glaucoma (HR 1.22), ocular hypertension (HR 1.32), and primary open-angle glaucoma (HR 1.33) over up to 5 years. Full details are reported in the Hsia et al. 2026 *British Journal of Ophthalmology* paper cited above.

37) Etminan, Mahyar, et al. “Risk of Ocular Adverse Events Associated With Use of Phosphodiesterase 5 Inhibitors in Men in the US.” *JAMA Ophthalmology*, vol. 140, no. 5, 2022, pp. 480–484. https://doi.org/10.1001/jamaophthalmol.2022.0663 or https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2790661

38) Chen, Gui-Xiang, et al. “Differences in Ocular Adverse Events Associated with Phosphodiesterase-5 Inhibitors: A Real-World Pharmacovigilance Study.” *Expert Opinion on Drug Safety*, vol. 23, no. 7, 2024, pp. 877–884. https://doi.org/10.1080/14740338.2024.2355335 or https://pubmed.ncbi.nlm.nih.gov/38739482/

39) Supporting prospective OCT/OCTA studies of alternate-day or daily tadalafil and changes in choroidal thickness or retinal vessel density (findings vary by dose, duration, and population; some show transient choroidal thickening without lasting structural damage). Representative examples appear in the broader literature on PDE5 inhibitors and ocular perfusion; full individual citations can be expanded on request if specific papers are needed.

40) Prescribing information and pharmacokinetic data: tadalafil exposure (AUC) is increased by strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir). See U.S. prescribing information (Cialis/tadalafil DailyMed). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6a8621eb-7415-42a6-9432-630751d34c6b (and related FDA labels).

41) Barroso, Francisco, et al. “Phosphodiesterase Type 5 Inhibitors and Visual Side Effects: A Narrative Review.” *Journal of Ophthalmic and Vision Research*, vol. 16, no. 2, 2021, pp. 248–259. https://doi.org/10.18502/jovr.v16i2.9088 or https://pmc.ncbi.nlm.nih.gov/articles/PMC8126729/ or https://pubmed.ncbi.nlm.nih.gov/34055262/

 

=============================

Additional References:

Kloner, Robert A., et al. “Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: a retrospective, observational study based on healthcare claims and national death index data.” The journal of sexual medicine 20.1 (2023): 38-48.

Background: Tadalafil is a long-acting phosphodiesterase-5 inhibitor (PDE-5i) indicated for erectile dysfunction (ED).

Hypothesis: Our hypothesis was that tadalafil will reduce the risk of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction, coronary revascularization, unstable angina, heart failure, stroke) and all-cause death in men with ED.

Methods: A retrospective observational cohort study was conducted in a large US commercial insurance claims database in men with a diagnosis of ED without prior MACE within 1 year. The exposed group (n = 8156) had ≥1 claim for tadalafil; the unexposed group (n = 21 012) had no claims for any PDE-5i.

Results: Primary outcome was MACE; secondary outcome was all-cause death. Groups were matched for cardiovascular risk factors, including preventive therapy. Over a mean follow-up of 37 months for the exposed group and 29 months for the unexposed group, adjusted rates of MACE were 19% lower in men exposed to tadalafil versus those unexposed to any PDE-5i (hazard ratio [HR] = 0.81; 95% confidence intervals [CI] = 0.70-0.94; p = .007). Tadalafil exposure was associated with lower adjusted rates of coronary revascularization (HR = 0.69; 95% CI = 0.52-0.90; p = .006); unstable angina (HR = 0.55; 95% CI = 0.37-0.81; p = .003); and cardiovascular-related mortality (HR = 0.45; CI = 0.22-0.93; p = .032). Overall mortality rate was 44% lower in men exposed to tadalafil (HR = 0.56; CI = 0.43-0.74; p < .001). Men in the highest quartile of tadalafil exposure had the lowest rates of MACE (HR: 0.40; 95% CI: 0.28-0.58; p < .001) compared to lowest exposure quartile.

Conclusion: In men with ED, exposure to tadalafil was associated with significant and clinically meaningful lower rates of MACE and overall mortality.

 

 

https://www.nad.com/news/repurposing-erectile-dysfunction-pills-for-longevity
Aging & Longevity
Repurposing Erectile Dysfunction Pills for Longevity. Some people are taking erectile dysfunction medications like Cialis and Viagra for more than sex—rather, to help them live longer.
By Bennett M. Sherman
Published: 3:03 p.m. PST Aug 24, 2026 | Updated: 3:41 p.m. PST Aug 24, 2026

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Narrative Review
https://journal.aapbk.org/index.php/jitss/article/download/376/111
Daniszewski, Wiktor, et al. “Systemic Effects of Phosphodiesterase Type 5 Inhibitors Beyond Erectile Dysfunction: A Narrative Review.” JITSS (Journal of Innovation and Trend in Social Sciences) 2.2 (2025): 87-100.

The reviewed evidence demonstrates that PDE5 inhibitors are associated with reduced cardiovascular morbidity and mortality, improvements in cardiac and pulmonary hemodynamics, preservation of renal function in diabetic populations, potential
neuroprotective effects against cognitive decline and ischemic stroke, and symptomatic improvement in benign prostatic hyperplasia and lower urinary tract symptoms. Additional benefits have been reported in conditions characterized by vascular dysfunction, such as angina pectoris and Raynaud’s phenomenon. Overall, PDE5 inhibitors represent a pharmacologically versatile drug class with clinically relevant systemic effects beyond erectile dysfunction, supporting their potential role as adjunctive therapies in broader disease management, although further well-designed randomized controlled trials are
needed to inform clinical guidelines

Click to access s11030-024-11016-2.pdf

Nemr, Mohamed TM, et al. “An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors.” Molecular Diversity 29.5 (2025): 4765-4785.

Phosphodiesterase enzyme 5 (PDE5) inhibitors have emerged as one of the leading molecules for the treatment of erectile
dysfunction (ED). PDE5 inhibitors are categorized structurally into several classes. PDE5 inhibitors have been a multidis-
ciplinary endeavor that attracts the attention of researchers because of their multiple pharmaceutical applications. Beyond
their action on ED, PDE5 inhibitors are widely used in treatment of benign prostatic hypertrophy (BPH), Eisenmenger’s
syndrome, Raynaud’s Disease, Intrauterine growth retardation (IUGR), Mountain sickness, Bladder pain syndrome/interstitial
cystitis (BPS/IC), pulmonary arterial hypertension and type II diabetes (insulin resistance). In addition, PDE5 inhibitors
also show promising antiproliferative activity, anti-Alzheimer and COX-1/COX-2 inhibitory activity (anti-inflammatory).

=====================================================

https://pmc.ncbi.nlm.nih.gov/articles/PMC13485118/
Bhattacharyya, Samir, et al. “Association of erectile dysfunction with all-cause and cardiovascular mortality in US men: findings from NHANES 2001–2004 with 16-year follow-up.” International Journal of Impotence Research (2025): 1-8.

Erectile dysfunction (ED) is a common condition in men; however, evidence of its association with mortality is limited. We examined the association between ED and long-term all-cause and cardiovascular (CV) mortality in a nationally representative cohort of adult men. This prospective cohort study included data from men aged 20 years and older from the 2001–2004 National Health and Nutrition Examination Survey linked to National Death Index records through December 31, 2019. ED was defined as reporting sometimes or never being able to achieve or maintain an erection adequate for satisfactory intercourse. Primary outcomes were the associations of ED with all-cause and CV mortality, evaluated using survey-weighted Cox proportional hazards regression models. Among 4 110 men followed for a median of 16.3 years, 1 226 deaths (419 CV deaths) occurred. In fully adjusted models, ED was independently associated with an increased risk of all-cause (HR, 1.45; 95% CI, 1.20–1.75) and CV (HR, 1.57; 95% CI, 1.12–2.19) mortality. The magnitude of these associations was similar to those observed for other CV risk factors such as diabetes mellitus, hypertension, and stroke. These findings suggest the need to broaden clinical perspectives on ED beyond sexual health to recognize its significance as a marker of mortality risk.

==============================================

Click to access s11255-026-05192-3.pdf

Hsu, Jan Yuan-Sheng, et al. “Association of phosphodiesterase type 5 inhibitor use with cardiovascular and renal outcomes in male kidney transplant recipients with benign prostatic hyperplasia or erectile dysfunction.” International Urology and Nephrology (2026): 1-16.

Purpose Phosphodiesterase type 5 (PDE5) inhibitors are commonly prescribed for erectile dysfunction (ED) and benign
prostatic hyperplasia (BPH) in kidney transplant recipients (KTRs), but their cardiovascular and renal associations in this
population remain unexamined. This study evaluated these associations in male KTRs with ED or BPH.
Methods This retrospective cohort study used TriNetX Global Collaborative Network data (January 2015–December 2023).
Male KTRs ≥ 40 years with ED or BPH were identified using a unified diagnosis index date in both arms, with PDE5 inhibitor
exposure bounded to days 0–365. Three drug strata (tadalafil 5 mg daily, tadalafil, sildenafil) were propensity-matched 1:1
against controls on thirty covariates. Balance was assessed by standardized mean differences. Primary outcomes (all-cause
mortality, MACE excluding death, MAKE excluding death) were analyzed by Cox regression and Kaplan–Meier methods.
Secondary outcomes comprised individual components (AMI, stroke, and dialysis initiation).
Results All-cause mortality was inversely associated with PDE5 inhibitor exposure across all six strata (HR 0.574–0.697).
MACE excluding death was inversely associated in the ED cohort for tadalafil 5 mg daily (HR 0.527) and tadalafil all doses
(HR 0.620), but not sildenafil; no composite associations reached significance in the BPH cohort. Two secondary outcomes
survived Benjamini–Hochberg correction: MACE excluding death and AMI in the ED tadalafil all-doses stratum (q = 0.023
and q = 0.041). Negative control outcomes near unity supported propensity score balance.
Conclusion PDE5 inhibitor exposure was associated with lower all-cause mortality in male KTRs with ED or BPH. Com-
posite cardiovascular and renal associations were stratum-dependent. These findings are hypothesis-generating and require
prospective evaluation

https://academic.oup.com/jsm/article/20/Supplement_1/qdad060.195/7165010
Ha, A., et al. “(203) Phosphodiesterase-5 Inhibitor Use and Progression to Heart Failure in Men with Coronary Artery Disease and Erectile Dysfunction.” The Journal of Sexual Medicine 20.Supplement_1 (2023): qdad060-195.
When compared with NT, both tadalafil and sildenafil were associated with reduced progression to HF, MI, and overall mortality. Most importantly, compared with sildenafil, tadalafil demonstrated lower progression to HF (HR: 0.85 [0.77-0.94]), MI (HR: 0.86 [0.76-0.97]) and mortality (HR: 0.85 [0.76-0.95]) (Table 2, Figure 1).

Tadalafil use was associated with a significant reduction in progression to HF, MI, and mortality, compared with sildenafil or no treatment. These preliminary results may signal meaningful clinical differences in drug choice for men suffering from CAD and ED, and therefore require further inquiry.

 

Click to access JCH-24-179.pdf

Theofilis, Panagiotis, Nikos Nakas, and Rigas G. Kalaitzidis. “Tadalafil in patients on antihypertensive medications: Does safety remain an issue?.” The Journal of Clinical Hypertension 24.2 (2022): 179.

phosphodiesterase type 5 (PDE5)
inhibitors are the cornerstone of ED treatment.7 These drugs inhibit
the breakdown of cyclic guanosine monophosphate, thus improving
penile blood flow. Meta-analytic evidence has established their effi-
cacy in ameliorating ED.8 However, within-class differences may be
present, with sildenafil, the first developed PDE5 inhibitor, display-
ing the highest potency at the cost of increased adverse events.9,10
On the other hand, tadalafil is another first-line, selective PDE5
inhibitor used to treat ED, BPH, and pulmonary hypertension since
2003, with a long duration of action, whose efficacy and tolerabil-
ity are also well-documented (Figure 1).9,10 A higher patient prefer-
ence for tadalafil compared to sildenafil has been noted, especially
in younger individuals.11 However, no head-to-head randomized trials
exist and such observations should be cautiously interpreted. Other
PDE5 inhibitors (avanafil, lodenafil, mirodenafil) appear to be less
effective or safe than sildenafil and Tadalafil.12

The results of this integrated
pooled safety analysis provide the rationale for tadalafil’s seamless use
without worrying about excess hypotension-related TEAE and MACE
even in patients with concomitant use of antihypertensive medications.

=======================================

Favorable Health Benefits

https://pmc.ncbi.nlm.nih.gov/articles/PMC13302937/
Naranjo, Alexandra, et al. “Evidence for the Additional Health Benefits Associated with Phosphodiesterase 5 Inhibitors when Used for Treating Erectile Dysfunction, with a Focus on Prostate Cancer Patients and Other Associated Conditions.” The World Journal of Men’s Health 44.3 (2026): 582.

It should also be noted that PDE5i does have certain contraindications and adverse events.

PDE5i should not be prescribed to men who have unstable angina or angina occurring during sexual intercourse, regular or intermittent use of nitrates, hypotension, history of non-arteritic anterior ischaemic optic neuropathy, recent history of myocardial infarction, recent history of stroke, or renal impairment.

Contraindications specific to Tadalafil and Avanafil include heart failure, uncontrolled arrhythmias, and uncontrolled hypertension. Contraindications specific to Sildenafil, Vardenafil, and Avanafil include severe hepatic impairment and a hereditary degenerative retinal disorder.

Adverse events include most commonly headache, flushing, dyspepsia, nasal congestion, back pain and myalgia. Common AE’s include alopecia, anaemia, anxiety, cough, diarrhoea, dizziness, fluid retention, gastrointestinal discomfort, increased risk of infection, insomnia, nausea, night sweats, pain, skin reactions, tremor, and vision disorders. Rare adverse events include optic neuropathy, renal occlusion, and priapism. Adverse events of unknown frequency include central serous chorioretinopathy [7].

In summary, the available evidence base is encouraging bearing in mind the potentially pleiotropic effects of PDE5i and could be particularly relevant in the case of prostate cancer patients. However, because the evidence base is mostly generated from observational studies, these findings cannot prove a causal relationship. High-quality RCTs are needed to characterize the clinical benefit of PDE5i in the common comorbidities in prostate cancer patients, thereby leading to clinical recommendations for this cohort, and the subsequent inclusion in guidelines. There is potential for this treatment with PDE5i to benefit men with ED who often carry a portfolio of co-morbidities, especially post-treatment prostate cancer patients, including those on ADT, to reduce their disease burden considerably, by potentially co-treating several related conditions simultaneously, and therefore improving their healthcare and quality of life.

 

 

https://onlinelibrary.wiley.com/doi/pdf/10.1111/joim.20012
Takayama, Atsushi, Satomi Yoshida, and Koji Kawakami. “Tadalafil use is associated with a lower incidence of Type 2 diabetes in men with benign prostatic hyperplasia: A population‐based cohort study.” Journal of internal medicine 296.5 (2024): 422-434.

Results. A total of 5180 participants initiated
tadalafil treatment and were compared with 20,049
patients who initiated alpha-blockers. The median
follow-up time for each arm was 27.2 months
(interquartile range [IQR], 12.0–47.9) in tadalafil
users and 31.3 months (IQR, 13.7–57.2) in alpha-
blocker users. The incidence rates of T2DM in
tadalafil and alpha-blocker users were 5.4 (95%
confidence interval [CI], 4.0–7.2) and 8.8 (95% CI,
7.8–9.8) per 1000-person years, respectively. Ini-
tiation of tadalafil was associated with a reduced
risk of T2DM (RR, 0.47; 95% CI, 0.39–0.62; 5-year
CID, −0.031; 95% CI, −0.040 to −0.019)

 

https://pubmed.ncbi.nlm.nih.gov/40014468/
Kallash, Mohammed, and William H. Frishman. “Tadalafil Use in Cardiovascular Disease.” Cardiology in Review (2025): 10-1097.

Tadalafil is a phosphodiesterase inhibitor currently approved for use in erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension (PAH). While tadalafil’s benefits in ED and BPH have been well-established for years, its benefits in PAH were identified only recently in major clinical trials, resulting in the recent approval of a single-tablet, combination therapy of tadalafil with an endothelin receptor antagonist for PAH. With Tadalafil’s cardiovascular benefits in ED, BPH, and PAH, clinical researchers have begun investigating whether tadalafil’s use extends to other cardiovascular diseases, especially heart failure (HF), an emerging epidemic in medicine. Recent research in animal models has demonstrated a potential benefit of tadalafil use in ischemic cardiomyopathy and HF, as numerous studies in mice and sheep demonstrated improved left ventricular function and contractility, with reduced adverse remodeling and hypertrophy. A retrospective cohort study identified that tadalafil use in patients with ED and coronary artery disease was associated with a significant decrease in the incidence of HF, acute myocardial infarction, and mortality compared with sildenafil or no treatment. However, a randomized controlled trial in patients with comorbid PAH and HF with preserved ejection fraction demonstrated no significant benefit with the use of tadalafil. Unfortunately, there is limited evidence from clinical trials investigating the impact of tadalafil in patients with HF with reduced or preserved ejection fraction without comorbid PAH. Further studies are needed on this topic to better identify whether tadalafil has a role in the prevention or treatment of HF.

 

https://academic.oup.com/smoa/article/14/4/qfag029/8675408
Yıldız, Görkem, and Tolga Kunak. “Daily tadalafil administration improves cardiac autonomic regulation in men with non-organic erectile dysfunction: a prospective heart rate variability study.” Sexual Medicine 14.4 (2026): qfag029.
Non-organic ED patients have cardiac autonomic dysfunction measurable by heart rate variability (HRV). Tadalafil reduces cardiovascular mortality, but exact mechanisms remain unclear.
Aim

To evaluate daily tadalafil effects on cardiac autonomic regulation in non-organic ED and identify clinical predictors of HRV response.
Methods

In this prospective study, 82 men with non-organic ED (mean age 46.8 ± 5.0 years) received tadalafil 5-10 mg daily. Assessment included International Index of Erectile Function-Erectile Function (IIEF-EF), echocardiography, laboratory tests, and 24-hour Holter ECG. HRV was analyzed via time-domain (standard deviation of NN intervals [SDNN], root mean square of successive differences [RMSSD]) and frequency-domain (low-frequency power [LF], high-frequency power [HF], LF/HF ratio) parameters. Post-treatment recordings were blindly evaluated. Early response to tadalafil was defined as achievement in the severity-adjusted Minimal Clinically Important Difference (MCID) in IIEF-EF or final IIEF-EF score ≥26.
Outcomes

Primary: ΔSDNN. Secondary: ΔHF power, ΔLF/HF ratio.
Results

IIEF-EF improved significantly (15 to 23, P < .001) and 74.4% were early responders (n = 61). In the overall cohort, SDNN increased (42.39 to 52.39 ms, P < .01), HF power increased (267.86 to 294.44 ms2,P < .001), and LF/HF ratio decreased (2.78 to 2.31, P < .01). Both groups showed HRV improvements without between-group differences (P > .05), suggesting autonomic modulation independent of erectile response. Multivariable regression: diabetes negatively predicted SDNN improvement; higher testosterone, higher baseline IIEF-EF score, and lower BMI predicted greater HF enhancement. Only 1.1% of patients discontinued the treatment (due to dyspepsia).
Clinical Implications

Daily tadalafil treatment may enhance parasympathetic modulation in men with non-organic ED regardless of clinical erectile improvement, suggesting a potential mechanism for its observed cardiovascular benefits.
Strengths and Limitations

Strengths include rigorous, blinded Holter assessment. Limitations include the lack of a placebo control, short follow-up (28 days), and a small non-responder subgroup.
Conclusion

Daily tadalafil enhanced parasympathetic modulation and reduced sympathovagal imbalance independently of erectile improvement.

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Adverse Effects

https://www.sciencedirect.com/science/article/pii/S0735109723080749

Lagerros, Ylva Trolle, et al. “Risk of death in patients with coronary artery disease taking nitrates and phosphodiesterase-5 inhibitors.” Journal of the American College of Cardiology 83.3 (2024): 417-426.

Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication.
Objectives
The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication.
Methods
Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE).
Results
In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83).
Conclusions
The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted.

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CKD

George, Mina Y., Eman Mantawy, and Yara Abdelhady. “Expanding Therapeutic Horizons: A Review of Tadalafil’s Off-Label Applications and Pharmacological Profile.” Archives of Pharmaceutical Sciences Ain Shams University (2026).

Answers for “tadalafil animal renoprotection” – [PDF] ekb.eg
Reviews the pharmacological effects and off-label applications of Tadalafil (TDL), summarizing evidence for its renoprotective effects observed in various animal models of kidney injury.
Answers
Show details
Renoprotective effects in animal models: Tadalafil (TDL) demonstrated substantial renoprotective effects in animal models of diabetic nephropathy, Adriamycin-exerted nephrotic syndrome, ischemia-reperfusion (IR) injury, and chronic kidney disease (CKD) induced by a high salt diet.

In a streptozotocin-induced diabetic nephropathy model in rats, TDL hindered glycemic, renal biochemical, and histopathological abnormalities, augmented renal blood flow, and ameliorated glomerular basement membrane thickening.
TDL exhibited noteworthy reno-protective effects in a study of Adriamycin-exerted nephrotic syndrome by thwarting injury to podocytes and preserving glomerular filtration barrier function.
In a CKD model induced by a high salt diet, TDL prevented glomerular damage, fibrosis, and glomerular injury by hindering glomerulosclerosis and reducing the expression of α-SMA.

Protection against Ischemia-Reperfusion Injury: TDL was effective in halting renal ischemia-reperfusion (IR) injury by counteracting glomeruli loss, diminishing neutrophil infiltration into glomerular tissue, and repressing pro-inflammatory genes.

TDL successfully counteracted IR-induced glomeruli loss by repressing pro-inflammatory genes, including TNF-α, IL-6, CD4, IL-1β, and CD8.
In a model of endothelial dysfunction using wild-type and endothelial NO synthase knockout mice, TDL was effective in halting IR injury through diminishing neutrophil infiltration into glomerular tissue.

Antioxidant Renoprotection: TDL possesses antioxidant properties in a murine model of contrast-induced nephrotoxicity, attributed to elevating Nitric Oxide (NO) levels in tissues and serum, along with increased serum activities of catalase (CAT).

TDL also protected against doxorubicin-induced hepatorenal toxicity by ameliorating superoxide dismutase (SOD), CAT, glutathione S-transferase (GST), and glutathione peroxidase (GPx) activities, concurrent with an elevation of malondialdehyde (MDA) and glutathione (GSH) levels.

Approach
Review of animal studies: The findings are based on a review of published experimental studies utilizing various animal models, including rats with streptozotocin-induced diabetic nephropathy, Adriamycin-exerted nephrotic syndrome, and chronic kidney disease induced by a high salt diet, as well as murine models of contrast-induced nephrotoxicity.
Ischemia-Reperfusion Models: Renoprotection during IR injury was studied in Sprague-Dawley rats, where 10 mg/kg of TDL was administered via gavage one hour before a nephrectomy procedure followed by 45 minutes of warm ischemia, resulting in reduced neutrophil infiltration.
Considerations
Nature of evidence: The information is presented within a review article summarizing findings from various preclinical models, not from a single, original study.
Scope limitation: The summarized renoprotective findings are derived solely from animal and preclinical models, such as rats and mice, and do not necessarily reflect human clinical outcomes.

Animal

https://www.scielo.br/j/ibju/a/J6xskLHPL9VK5hprCBSNQKw/?format=pdf&lang=en
Benli, Erdal, et al. “The effect of tadalafil therapy on kidney damage caused by sepsis in a polymicrobial septic model induced in rats: a biochemical and histopathological study.” International braz j urol 43.2 (2017): 345-355.

Conclusion: In this study, tadalafil exhibited a preventive effect for sepsis-related dam-
age by suppressing inflammation in serum and kidney tissue of septic rats in a poly-
microbial sepsis model induced with CLP (cecal puncture)

 

Mora, Aline Goncalves, et al. “Tadalafil treatment improves cardiac, renal and lower urinary tract dysfunctions in rats with heart failure.” Life sciences 289 (2022): 120237.

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Animal studies

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.14814/phy2.14556
Tomita, Natsumi, et al. “The phosphodiesterase 5 inhibitor tadalafil has renoprotective effects in a rat model of chronic kidney disease.” Physiological reports 8.17 (2020): e14556.

Phosphodiesterase 5 inhibitors are widely used to treat erectile dysfunction and lower
urinary tract symptoms with benign prostatic hyperplasia. Recent studies have indi-
cated the renoprotective effects of this class of compounds. Whether renoprotection
depends on blood pressure reduction remains controversial. In this study, we investi-
gated the renoprotective effects of the phosphodiesterase 5 inhibitor, tadalafil, in a rat
model of high-salt induced kidney injury with hypertension. Dahl salt-sensitive rats
were fed a normal diet, high-salt (8% sodium chloride) diet, or high-salt diet with oral
administration of either low- or high-dose tadalafil (1 and 10 mg kg −1 day −1
, respec-
tively). Serum creatinine, urinary protein, and blood pressure were measured at base-
line and after 8 weeks, at which point the rats were examined for glomerular injury
and fibrosis. PAI1 mRNA levels were also evaluated. After 8 weeks, blood pressure,
serum creatinine, and urinary protein levels were significantly higher in the high-salt
group than those in the normal-salt group. Serum creatinine and urinary protein were
significantly lower in both tadalafil groups than those in the high-salt group, while
only high-dose tadalafil affected blood pressure. In addition, glomerulosclerosis and
α-smooth muscle actin expression significantly decreased in both tadalafil treatment
groups. PAI1 mRNA increased significantly in the high-salt group but decreased
in both tadalafil-treated groups. Our results indicated that both low- and high-dose
tadalafil prevented fibrosis and glomerular injury in a chronic kidney disease rat
model. Mechanistically, these effects may be associated with PAI1 expression and
glomerular structure protection

Abdel-Rahman, Doaa M., et al. “Regulation of renal nitric oxide and eNOS/iNOS expression by tadalafil participates in the mitigation of amphotericin B–induced renal injury: Down-regulation of NF-κB/iNOS/caspase-3 signaling.” Naunyn-schmiedeberg’s Archives of Pharmacology 397.5 (2024): 3141-3153.

Salih, Tabarek Mohamed, and Majid Bashara. “Evaluation the reno-protective effect of tadalafil alone and in combination with ascorbic acid in AKI model in rats.” Journal of Basic and Clinical Physiology and Pharmacology 0 (2026).

Lee, Eun Hye, et al. “The renoprotective effects of tadalafil on ischemia–reperfusion injury during partial nephrectomy in an animal model.” BMC nephrology 26.1 (2025): 335.

Özbek, Kerem, et al. “The protective effect of single dose tadalafil in contrast-induced nephropathy: An experimental study.” The Anatolian Journal of Cardiology 15.4 (2015): 306.

Mora, Aline Goncalves, et al. “Tadalafil treatment improves cardiac, renal and lower urinary tract dysfunctions in rats with heart failure.” Life sciences 289 (2022): 120237.

Neurologic Function

Zhang, Li, et al. “Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke.” Brain research 1118.1 (2006): 192-198.

Al-Amin, Md Mamun, et al. “Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice.” European Journal of Pharmacology 745 (2014): 84-90.

Wang, Lei, et al. “Tadalafil promotes the recovery of peripheral neuropathy in type II diabetic mice.” PLoS One 11.7 (2016): e0159665.

Varma, Amit, et al. “Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice.” (2012): e45243.

França, Maria Eduarda Rocha, et al. “Tadalafil restores long-term memory and synaptic plasticity in mice with hepatic encephalopathy.” Toxicology and Applied pharmacology 379 (2019): 114673.

Laxmi, Vijaya, et al. “Inhibitory effects of sildenafil and tadalafil on inflammation, oxidative stress and nitrosative stress in animal model of bronchial asthma.” Pharmacological reports 71.3 (2019): 517-521.
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