Reversing Vascular Dysfunction in Rheumatoid Arthritis Improved Augmentation Index but Not Endothelial Function With Peroxisome Proliferator-Activated Receptor γ Agonist Therapy

Objective. To examine the hypothesis that improving insulin sensitivity improves vascular function in rheumatoid arthritis (RA). Methods. We performed a 20-week, single center, randomized, double-blind, placebo-controlled crossover study. Patients with RA (n = 34) with moderate disease activity who were receiving stable disease-modifying antirheumatic drug therapy were randomized to drug sequence, receiving either pioglitazone 45 mg/day or matching placebo for 8 weeks, followed by a 4-week washout period and the alternative treatment for 8 weeks. We measured changes in vascular stiffness (augmentation index and aortic pulse wave velocity [PWV]), endothelial function (reactive hyperemia index), and blood pressure. High-sensitivity C-reactive protein levels and the homeostatic model assessment of insulin resistance were also measured. The treatment effect of pioglitazone on outcomes was analyzed using linear mixed-effects models. Results. Pioglitazone treatment resulted in a change in augmentation index of -4.7% units (95% confidence interval [95% CI] -7.9, -1.5) (P = 0.004) and in diastolic blood pressure of -3.0 mm Hg (95% CI -5.7, -0.2) (P = 0.03), but did not significantly change aortic PWV (P = 0.33) or reactive hyperemia index (P = 0.46). The improvements in augmentation index and diastolic blood pressure were not mediated by the effect of pioglitazone on insulin resistance or inflammation. Conclusion. Our findings indicate that pioglitazone improves some indices of vascular function, including augmentation index and diastolic blood pressure, in patients with RA. This is not mediated by improved insulin sensitivity.