PDE5 Inhibitors & Endothelial Function — References

Mirrored Reference Dossier

Parent Topic: PDE5 Inhibitors & Endothelial Function | References Hub: 02 - Compounds & Molecules References MOC

---

Landmark Peer-Reviewed Studies

1. Rosano et al. (2005) — European Urology

• Citation: Rosano, G. M., Aversa, A., Vitale, C., Fabbri, A., Fini, M., & Spera, G. (2005). Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. European Urology, 47(2), 214–222.
• Identifiers: PMID: 15661417 (PubMed · Europe PMC) | DOI: 10.1016/j.eururo.2004.10.021 (DOI · SciDB · Scholar)
• Study Design & Sample Size: 4-week randomized, double-blind, placebo-controlled trial with a 2-week post-treatment follow-up in men with increased cardiovascular risk ($N=32$).
• Key Quantitative Outcomes: Chronic Tadalafil administration ($20\text{ mg}$ on alternate days) more than doubled Brachial Artery Flow-Mediated Dilation (FMD) from $4.2\%\pm 1.2\%$ at baseline to $9.3\%\pm 1.7\%$ at week 4 ($+121\%$ relative improvement vs. no change in placebo, $p<0.01$), increased plasma nitrite/nitrate levels by $+48\%$ ($p<0.05$), and decreased vasoconstrictive Endothelin-1 (ET-1) from $11.5$ to $7.6\text{ pg/mL}$ ($-33.9\%,p<0.01$). Crucially, FMD remained elevated at $8.6\%$ two weeks after discontinuing Tadalafil, demonstrating structural endothelial remodeling.

2. Kloner et al. (2023) — The Journal of Sexual Medicine

• Citation: Kloner, R. A., Stanek, E., Crowe, C. L., Singhal, M., Pepe, R. S., Bradsher, J., & Rosen, R. C. (2023). 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. The Journal of Sexual Medicine, 20(1), 38–48.
• Identifiers: PMID: 36897249 (PubMed · Europe PMC) | DOI: 10.1093/jsxmed/qdac005 (DOI · SciDB · Scholar)
• Study Design & Sample Size: 14-year nationwide retrospective propensity-score-matched cohort analysis ($N=72,498$: $n=23,816$ PDE5i exposed vs. $n=48,682$ unexposed controls).
• Key Quantitative Outcomes: PDE5 inhibitor exposure was associated with a $-13\%$ lower incidence of Major Adverse Cardiovascular Events (MACE) ($\text{HR }0.87,95\%\text{ CI }0.79\text{–}0.95,p=0.001$), including $-15\%$ lower coronary revascularization, $-17\%$ lower heart failure, $-22\%$ lower unstable angina, and a $-25\%$ reduction in overall all-cause mortality ($\text{HR }0.75,95\%\text{ CI }0.65\text{–}0.87,p<0.001$). Men in the highest quartile of PDE5i exposure demonstrated a $-55\%$ reduction in MACE ($\text{HR }0.45$) and $-49\%$ lower overall mortality ($\text{HR }0.51$).

3. Andersson et al. (2017) — Heart (BMJ)

• Citation: Andersson, D. P., Trolle Lagerros, Y., Grotta, A., Bellocco, R., Leinsköld, T., & Holzmann, M. J. (2017). Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction. Heart, 103(16), 1264–1270.
• Identifiers: PMID: 28279964 (PubMed · Europe PMC) | DOI: 10.1136/heartjnl-2016-310746 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Nationwide Swedish cohort study ($N=43,145$ men aged $<80\text{ years}$ following a first myocardial infarction, mean follow-up $3.3\text{ years}$).
• Key Quantitative Outcomes: Post-MI patients treated with PDE5 inhibitors had a $-33\%$ lower adjusted hazard of all-cause death ($\text{HR }0.67,95\%\text{ CI }0.55\text{–}0.81$) and a $-40\%$ lower risk of hospitalization for heart failure ($\text{HR }0.60,95\%\text{ CI }0.44\text{–}0.82$), with a dose-dependent mortality reduction across $>1,>2\text{–}5,\text{and }>5$ dispensed prescriptions ($p_{\text{trend}}<0.001$).

4. Adesuyan et al. (2024) — Neurology

• Citation: Adesuyan, M., Jani, Y. H., Alsugeir, D., Howard, R., Ju, C., Wei, L., & Brauer, R. (2024). Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study. Neurology, 102(4), e209131.
• Identifiers: PMID: 38324745 (PubMed · Europe PMC) | PMCID: PMC11033962 (PMC Full Text) | DOI: 10.1212/WNL.0000000000209131 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Population-based cohort study using IQVIA Medical Research Data UK ($N=269,725$ men aged $\ge 40\text{ years}$, median follow-up $5.1\text{ years}$ totaling $>1.3\text{ million}$ person-years).
• Key Quantitative Outcomes: PDE5 inhibitor initiation was associated with an $-18\%$ lower risk of developing Alzheimer’s disease ($\text{adjusted HR }0.82,95\%\text{ CI }0.72\text{–}0.93$). A strong cumulative dose-response relationship was observed: individuals with $21\text{–}50$ issued prescriptions had a $-35\%$ lower risk ($\text{HR }0.65$), and those with $>50$ prescriptions had a $-44\%$ lower risk of Alzheimer’s disease ($\text{HR }0.56,95\%\text{ CI }0.43\text{–}0.73$).