Abstract 3923: The Effect of Selective PKC-Inhibitor Ruboxistaurin on Endothelial Function and Oxidant Stress in Patients with Type 2 Diabetes Mellitus
Background: Patients with diabetes mellitus (DM) continue to be the highest risk group for macrovascular cardiovascular disease (CVD), yet the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves generation of reactive oxygen species (ROS) and endothelial dysfunction via activation of protein kinase C-beta (PKCβ). Prior studies using PKC-β inhibition showed beneficial effects on microvascular disease, but no study to date has examined the effect on macrovascular function or surrogate measures of atherosclerosis.
Methods and Results: The goal of this double-masked, placebo-controlled, parallel trial of patients with type 2 DM (n=52) was to investigate the effect of a PKCβ-specific inhibitor ruboxistaurin (RBX; at 32 mg for 6 weeks) on surrogate measures of macrovascular atherosclerotic disease: ultrasound-based measure of brachial artery flow mediated dilatation (FMD), a surrogate of endothelial function, and urinary isoprostanes, a measure of vascular oxidant stress. Compared to placebo, RBX treatment resulted in significant improvement in FMD (difference in FMD change, mean±SD cm) at 1 (0.013±0.026 cm, p=0.02) & 5 minutes (0.012±0.021 cm, p=0.02; figure⇓) after cuff deflation. RBX had no effect on nitroglycerin-mediated dilatation or on urinary isoprostanes.
Conclusions: In this clinical trial of type 2 DM, RBX was well tolerated and improved brachial artery FMD. This is the first trial showing specific inhibition of PKCβ may represent a novel therapy for macrovascular complications in DM. However, larger trials of clinical endpoints are required to determine the potential efficacy in diabetic CVD.