Pentoxifylline Ameliorates Subclinical Atherosclerosis Progression in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Randomized Pilot Trial

Abstract

Background: Diabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD). Methods: In this open-label, randomized controlled, single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA. Results: Patients treated with PTF presented a better evolution of CIMT, increased Klotho levels and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in peripheral blood cells (PBCs). Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R²= 0.25, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.105 (P = 0.001) and 0.001 (P = 0.005), respectively]. Conclusions: PTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs. Trial registration: The study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009–016595– 77). The validation date was 2010-03-09.