Long-Term Pentoxifylline Therapy Is Associated with a Reduced Risk of Atherosclerotic Cardiovascular Disease by Inhibiting Oxidative Stress and Cell Apoptosis in Diabetic Kidney Disease Patients

There is limited understanding of the optimal duration and dosage of pentoxifylline (PTX) therapy required to achieve significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk, particularly in patients with diabetic kidney disease (DKD). This study aimed to evaluate the impact of long-term PTX therapy on the risk of ASCVD in patients with DKD who do not have pre-existing cardiovascular disease, while also exploring potential vascular protective mechanisms. This retrospective cohort study included data from Taiwan's Ministry of Health and Welfare's Health and Welfare Data Science Center. In 2008-2019, we identified and analyzed a specific sample of 129,764 patients with DKD without established cardiovascular disease. Participants were categorized according to their PTX treatment regimen. Short-term PTX users (<763 days) had a greater risk of developing ASCVD than non-PTX users. However, those who used PTX for >763 days (long-term PTX treatment) had a significantly lower risk of ASCVD, with a 47% lower cumulative incidence. A dose-dependent reduction in apoptosis was observed via Klotho treatment in cultured human aortic endothelial cells following PTX treatment. Long-term PTX treatment (24 h) caused a higher reduction in H₂O₂-induced reactive oxygen species production and cell apoptosis than short-term PTX treatment (2 h). In the DKD mice model experiments, PTX reduced the ASCVD risk by increasing the Klotho levels to inhibit endothelial cell damage. These findings suggest that the cardiovascular and renoprotective benefits of PTX may be extended to primary prevention strategies for people with DKD.